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In reply: Cardiorenal syndrome
In Reply: We thank Dr. Freda for his remarks and observations. Certainly, the clinical importance of this entity and the challenge it poses to clinicians cannot be overemphasized. We concur with the overall message and reply to his specific comments:
We completely agree that clinical data-gathering is of paramount importance. This includes careful history-taking, physical examination, electronic medical record review, laboratory data review, and imaging. As discussed in our article, renal electrolytes will reveal a prerenal state in acute cardiorenal syndrome, and other causes of prerenal acute kidney injury (AKI) should be ruled out. The role of point-of-care ultrasonography (eg, to measure the size and respirophasic variation of the inferior vena cava) as a vital diagnostic tool has been well described, and we endorse it.1 Moreover, apart from snapshot values, trends are also very important. This is especially pertinent when the patient care is being transferred to a new service (eg, from hospitalist service to the critical care service). In this case, careful review of diuretic dosage, renal function trend, intake and output, and weight trend would help in the diagnosis.
Inadequate diuretic therapy is perhaps one of the most common errors made in the management of patients with acute cardiorenal syndrome. As mentioned in our article, diuretics should be correctly dosed based on the patient’s renal function. It is a common misconception that diuretics are nephrotoxic: in reality, there is no direct renal toxicity from the drug itself. Certainly, overdiuresis may lead to AKI, but this is not a valid concern in patients with acute cardiorenal syndrome, who are fluid-overloaded by definition.
Another challenging clinical scenario is when a patient is diagnosed with acute cardiorenal syndrome but renal function worsens with diuretic therapy. In our experience, this is a paradoxical situation and often stems from misinterpretation of clinical data. The most common example is diuretic underdosage leading to inadequate diuretic response. Renal function will continue to decline in these patients, as renal congestion has not yet been relieved. This reiterates the importance of paying close attention to urine output and intake-output data. When the diuretic regimen is strengthened and a robust diuretic response is achieved, renal function should improve as systemic congestion diminishes.
Acute cardiorenal syndrome stems from hemodynamic derangements, and a multidisciplinary approach may certainly lead to better outcomes. Although we described the general theme of hemodynamic disturbances, patients with acute cardiorenal syndrome may have certain unique and complex hemodynamic “phenotypes” that we did not discuss due to the limited scope of the paper. One such phenotype worth mentioning is decompensated right heart failure, as seen in patients with severe pulmonary hypertension. Acute cardiorenal syndrome due to renal congestion is often seen in these patients, but they also have certain other unique characteristics such as ventricular interdependence.2 Giving intravenous fluids to these patients not only will worsen renal function but can also cause catastrophic reduction in cardiac output and blood pressure due to worsening interventricular septal bowing. Certain treatments (eg, pulmonary vasodilators) are unique to this patient population, and these patients should hence be managed by experienced clinicians.
- Blehar DJ, Dickman E, Gaspari R. Identification of congestive heart failure via respiratory variation of inferior vena cava diameter. Am J Emerg Med 2009; 27(1):71–75. doi:10.1016/j.ajem.2008.01.002
- Piazza G, Goldhaber SZ. The acutely decompensated right ventricle: pathways for diagnosis and management. Chest 2005128(3):1836–1852. doi:10.1378/chest.128.3.1836
In Reply: We thank Dr. Freda for his remarks and observations. Certainly, the clinical importance of this entity and the challenge it poses to clinicians cannot be overemphasized. We concur with the overall message and reply to his specific comments:
We completely agree that clinical data-gathering is of paramount importance. This includes careful history-taking, physical examination, electronic medical record review, laboratory data review, and imaging. As discussed in our article, renal electrolytes will reveal a prerenal state in acute cardiorenal syndrome, and other causes of prerenal acute kidney injury (AKI) should be ruled out. The role of point-of-care ultrasonography (eg, to measure the size and respirophasic variation of the inferior vena cava) as a vital diagnostic tool has been well described, and we endorse it.1 Moreover, apart from snapshot values, trends are also very important. This is especially pertinent when the patient care is being transferred to a new service (eg, from hospitalist service to the critical care service). In this case, careful review of diuretic dosage, renal function trend, intake and output, and weight trend would help in the diagnosis.
Inadequate diuretic therapy is perhaps one of the most common errors made in the management of patients with acute cardiorenal syndrome. As mentioned in our article, diuretics should be correctly dosed based on the patient’s renal function. It is a common misconception that diuretics are nephrotoxic: in reality, there is no direct renal toxicity from the drug itself. Certainly, overdiuresis may lead to AKI, but this is not a valid concern in patients with acute cardiorenal syndrome, who are fluid-overloaded by definition.
Another challenging clinical scenario is when a patient is diagnosed with acute cardiorenal syndrome but renal function worsens with diuretic therapy. In our experience, this is a paradoxical situation and often stems from misinterpretation of clinical data. The most common example is diuretic underdosage leading to inadequate diuretic response. Renal function will continue to decline in these patients, as renal congestion has not yet been relieved. This reiterates the importance of paying close attention to urine output and intake-output data. When the diuretic regimen is strengthened and a robust diuretic response is achieved, renal function should improve as systemic congestion diminishes.
Acute cardiorenal syndrome stems from hemodynamic derangements, and a multidisciplinary approach may certainly lead to better outcomes. Although we described the general theme of hemodynamic disturbances, patients with acute cardiorenal syndrome may have certain unique and complex hemodynamic “phenotypes” that we did not discuss due to the limited scope of the paper. One such phenotype worth mentioning is decompensated right heart failure, as seen in patients with severe pulmonary hypertension. Acute cardiorenal syndrome due to renal congestion is often seen in these patients, but they also have certain other unique characteristics such as ventricular interdependence.2 Giving intravenous fluids to these patients not only will worsen renal function but can also cause catastrophic reduction in cardiac output and blood pressure due to worsening interventricular septal bowing. Certain treatments (eg, pulmonary vasodilators) are unique to this patient population, and these patients should hence be managed by experienced clinicians.
In Reply: We thank Dr. Freda for his remarks and observations. Certainly, the clinical importance of this entity and the challenge it poses to clinicians cannot be overemphasized. We concur with the overall message and reply to his specific comments:
We completely agree that clinical data-gathering is of paramount importance. This includes careful history-taking, physical examination, electronic medical record review, laboratory data review, and imaging. As discussed in our article, renal electrolytes will reveal a prerenal state in acute cardiorenal syndrome, and other causes of prerenal acute kidney injury (AKI) should be ruled out. The role of point-of-care ultrasonography (eg, to measure the size and respirophasic variation of the inferior vena cava) as a vital diagnostic tool has been well described, and we endorse it.1 Moreover, apart from snapshot values, trends are also very important. This is especially pertinent when the patient care is being transferred to a new service (eg, from hospitalist service to the critical care service). In this case, careful review of diuretic dosage, renal function trend, intake and output, and weight trend would help in the diagnosis.
Inadequate diuretic therapy is perhaps one of the most common errors made in the management of patients with acute cardiorenal syndrome. As mentioned in our article, diuretics should be correctly dosed based on the patient’s renal function. It is a common misconception that diuretics are nephrotoxic: in reality, there is no direct renal toxicity from the drug itself. Certainly, overdiuresis may lead to AKI, but this is not a valid concern in patients with acute cardiorenal syndrome, who are fluid-overloaded by definition.
Another challenging clinical scenario is when a patient is diagnosed with acute cardiorenal syndrome but renal function worsens with diuretic therapy. In our experience, this is a paradoxical situation and often stems from misinterpretation of clinical data. The most common example is diuretic underdosage leading to inadequate diuretic response. Renal function will continue to decline in these patients, as renal congestion has not yet been relieved. This reiterates the importance of paying close attention to urine output and intake-output data. When the diuretic regimen is strengthened and a robust diuretic response is achieved, renal function should improve as systemic congestion diminishes.
Acute cardiorenal syndrome stems from hemodynamic derangements, and a multidisciplinary approach may certainly lead to better outcomes. Although we described the general theme of hemodynamic disturbances, patients with acute cardiorenal syndrome may have certain unique and complex hemodynamic “phenotypes” that we did not discuss due to the limited scope of the paper. One such phenotype worth mentioning is decompensated right heart failure, as seen in patients with severe pulmonary hypertension. Acute cardiorenal syndrome due to renal congestion is often seen in these patients, but they also have certain other unique characteristics such as ventricular interdependence.2 Giving intravenous fluids to these patients not only will worsen renal function but can also cause catastrophic reduction in cardiac output and blood pressure due to worsening interventricular septal bowing. Certain treatments (eg, pulmonary vasodilators) are unique to this patient population, and these patients should hence be managed by experienced clinicians.
- Blehar DJ, Dickman E, Gaspari R. Identification of congestive heart failure via respiratory variation of inferior vena cava diameter. Am J Emerg Med 2009; 27(1):71–75. doi:10.1016/j.ajem.2008.01.002
- Piazza G, Goldhaber SZ. The acutely decompensated right ventricle: pathways for diagnosis and management. Chest 2005128(3):1836–1852. doi:10.1378/chest.128.3.1836
- Blehar DJ, Dickman E, Gaspari R. Identification of congestive heart failure via respiratory variation of inferior vena cava diameter. Am J Emerg Med 2009; 27(1):71–75. doi:10.1016/j.ajem.2008.01.002
- Piazza G, Goldhaber SZ. The acutely decompensated right ventricle: pathways for diagnosis and management. Chest 2005128(3):1836–1852. doi:10.1378/chest.128.3.1836
Avoiding in-hospital acute kidney injury is a new imperative
NEW ORLEANS– Preventing acute kidney injury and its progression in hospitalized patients deserves to be a high priority – and now there is finally proof that it’s doable, Harold M. Szerlip, MD, declared at the annual meeting of the American College of Physicians.
The PrevAKI study, a recent randomized controlled clinical trial conducted by German investigators, has demonstrated that the use of renal biomarkers to identify patients at high risk for acute kidney injury (AKI) after major cardiac surgery and providing them with a range of internationally recommended supportive measures known as the KDIGO (Kidney Disease: Improving Global Outcomes) care bundle reduced the occurrence of moderate-to-severe AKI by 34% (Intensive Care Med. 2017 Nov;43[11]:1551-61).
The enthusiasm that greeted the PrevAKI trial findings is reflected in an editorial entitled, “AKI: the Myth of Inevitability is Finally Shattered,” by John A. Kellum, MD, professor of critical care medicine and director of the Center for Critical Care Nephrology at the University of Pittsburgh. Dr. Kellum noted that the renal biomarker-based approach to implementation of the KDIGO care bundle resulted in an attractively low number needed to treat (NNT) of only 6, whereas without biomarker-based enrichment of the target population, the NNT would have been more than 33.
“,” Dr. Kellum declared in the editorial (Nat Rev Nephrol. 2017 Mar;13[3]:140-1).
Indeed, another way to do it was recently demonstrated in the SALT-ED trial, in which 13,347 noncritically ill hospitalized patients requiring intravenous fluid administration were randomized to conventional saline or balanced crystalloids. The incidence of AKI and other major adverse kidney events was 4.7% in the balanced crystalloids group, for a significant 18% risk reduction relative to the 5.6% rate with saline (N Engl J Med. 2018 Mar 1;378[9]:819-28).
While that absolute 0.9% risk reduction might initially not sound like much, with 35 million people per year getting IV saline while in the hospital, it translates into 315,000 fewer major adverse kidney events as a result of a simple switch to balanced crystalloids, Dr. Szerlip observed.
The PrevAKI findings validate the concept of AKI ‘golden hours’ during which time potentially reversible early kidney injury detectable via renal biomarkers is occurring prior to the abrupt decline in kidney function measured by change in serum creatinine. “The problem with using change in creatinine to define AKI is the delay in diagnosis, which makes AKI more difficult to treat,” he explained.
The renal biomarkers utilized in PrevAKI were insulin-like growth factor binding protein-7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2), as incorporated in the commercially available urinary NephroCheck test, which was administered to study participants 4 hours after cardiopulmonary bypass. A test result of 0.3 or more identified a group at high risk for AKI for randomization to the KDIGO bundle or usual care. The KDIGO bundle consists of discontinuation of nephrotoxic agents when feasible, early optimization of fluid status, and maintenance of perfusion pressure.
Patients known to be at increased risk for in-hospital AKI include the elderly, those with diabetes, patients with heart failure or other conditions prone to volume contraction or overload, those undergoing major surgery, individuals with chronic kidney disease, and patients with sepsis.
Dr. Szerlip singled out as particularly nephrotoxic several drugs widely used in hospitalized patients, including the combination of vancomycin plus piperacillin-tazobactam, which in a recent metaanalysis was found to have a number needed to harm of 11 in terms of AKI in comparison to vancomycin monotherapy or vancomycin in combination with cefepime or carbapenem (Crit Care Med. 2018 Jan;46[1]:12-20). He was also critical of the American Society of Anesthesiologists practice parameter recommending that in-hospital pain management plans for surgical patients include continuous regimens of NSAIDs or COX-2 inhibitors as a means of combating the ongoing opioid epidemic.
“These are highly toxic drugs to the kidney and we shouldn’t be using them,” Dr. Szerlip said.
He reported receiving research grants from LaJolla, Bayer, Akebia, and BioPorto, serving on a speakers’ bureau for Astute Medical, and acting as a consultant to Zs Pharma, Amarin, and LaJolla.
NEW ORLEANS– Preventing acute kidney injury and its progression in hospitalized patients deserves to be a high priority – and now there is finally proof that it’s doable, Harold M. Szerlip, MD, declared at the annual meeting of the American College of Physicians.
The PrevAKI study, a recent randomized controlled clinical trial conducted by German investigators, has demonstrated that the use of renal biomarkers to identify patients at high risk for acute kidney injury (AKI) after major cardiac surgery and providing them with a range of internationally recommended supportive measures known as the KDIGO (Kidney Disease: Improving Global Outcomes) care bundle reduced the occurrence of moderate-to-severe AKI by 34% (Intensive Care Med. 2017 Nov;43[11]:1551-61).
The enthusiasm that greeted the PrevAKI trial findings is reflected in an editorial entitled, “AKI: the Myth of Inevitability is Finally Shattered,” by John A. Kellum, MD, professor of critical care medicine and director of the Center for Critical Care Nephrology at the University of Pittsburgh. Dr. Kellum noted that the renal biomarker-based approach to implementation of the KDIGO care bundle resulted in an attractively low number needed to treat (NNT) of only 6, whereas without biomarker-based enrichment of the target population, the NNT would have been more than 33.
“,” Dr. Kellum declared in the editorial (Nat Rev Nephrol. 2017 Mar;13[3]:140-1).
Indeed, another way to do it was recently demonstrated in the SALT-ED trial, in which 13,347 noncritically ill hospitalized patients requiring intravenous fluid administration were randomized to conventional saline or balanced crystalloids. The incidence of AKI and other major adverse kidney events was 4.7% in the balanced crystalloids group, for a significant 18% risk reduction relative to the 5.6% rate with saline (N Engl J Med. 2018 Mar 1;378[9]:819-28).
While that absolute 0.9% risk reduction might initially not sound like much, with 35 million people per year getting IV saline while in the hospital, it translates into 315,000 fewer major adverse kidney events as a result of a simple switch to balanced crystalloids, Dr. Szerlip observed.
The PrevAKI findings validate the concept of AKI ‘golden hours’ during which time potentially reversible early kidney injury detectable via renal biomarkers is occurring prior to the abrupt decline in kidney function measured by change in serum creatinine. “The problem with using change in creatinine to define AKI is the delay in diagnosis, which makes AKI more difficult to treat,” he explained.
The renal biomarkers utilized in PrevAKI were insulin-like growth factor binding protein-7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2), as incorporated in the commercially available urinary NephroCheck test, which was administered to study participants 4 hours after cardiopulmonary bypass. A test result of 0.3 or more identified a group at high risk for AKI for randomization to the KDIGO bundle or usual care. The KDIGO bundle consists of discontinuation of nephrotoxic agents when feasible, early optimization of fluid status, and maintenance of perfusion pressure.
Patients known to be at increased risk for in-hospital AKI include the elderly, those with diabetes, patients with heart failure or other conditions prone to volume contraction or overload, those undergoing major surgery, individuals with chronic kidney disease, and patients with sepsis.
Dr. Szerlip singled out as particularly nephrotoxic several drugs widely used in hospitalized patients, including the combination of vancomycin plus piperacillin-tazobactam, which in a recent metaanalysis was found to have a number needed to harm of 11 in terms of AKI in comparison to vancomycin monotherapy or vancomycin in combination with cefepime or carbapenem (Crit Care Med. 2018 Jan;46[1]:12-20). He was also critical of the American Society of Anesthesiologists practice parameter recommending that in-hospital pain management plans for surgical patients include continuous regimens of NSAIDs or COX-2 inhibitors as a means of combating the ongoing opioid epidemic.
“These are highly toxic drugs to the kidney and we shouldn’t be using them,” Dr. Szerlip said.
He reported receiving research grants from LaJolla, Bayer, Akebia, and BioPorto, serving on a speakers’ bureau for Astute Medical, and acting as a consultant to Zs Pharma, Amarin, and LaJolla.
NEW ORLEANS– Preventing acute kidney injury and its progression in hospitalized patients deserves to be a high priority – and now there is finally proof that it’s doable, Harold M. Szerlip, MD, declared at the annual meeting of the American College of Physicians.
The PrevAKI study, a recent randomized controlled clinical trial conducted by German investigators, has demonstrated that the use of renal biomarkers to identify patients at high risk for acute kidney injury (AKI) after major cardiac surgery and providing them with a range of internationally recommended supportive measures known as the KDIGO (Kidney Disease: Improving Global Outcomes) care bundle reduced the occurrence of moderate-to-severe AKI by 34% (Intensive Care Med. 2017 Nov;43[11]:1551-61).
The enthusiasm that greeted the PrevAKI trial findings is reflected in an editorial entitled, “AKI: the Myth of Inevitability is Finally Shattered,” by John A. Kellum, MD, professor of critical care medicine and director of the Center for Critical Care Nephrology at the University of Pittsburgh. Dr. Kellum noted that the renal biomarker-based approach to implementation of the KDIGO care bundle resulted in an attractively low number needed to treat (NNT) of only 6, whereas without biomarker-based enrichment of the target population, the NNT would have been more than 33.
“,” Dr. Kellum declared in the editorial (Nat Rev Nephrol. 2017 Mar;13[3]:140-1).
Indeed, another way to do it was recently demonstrated in the SALT-ED trial, in which 13,347 noncritically ill hospitalized patients requiring intravenous fluid administration were randomized to conventional saline or balanced crystalloids. The incidence of AKI and other major adverse kidney events was 4.7% in the balanced crystalloids group, for a significant 18% risk reduction relative to the 5.6% rate with saline (N Engl J Med. 2018 Mar 1;378[9]:819-28).
While that absolute 0.9% risk reduction might initially not sound like much, with 35 million people per year getting IV saline while in the hospital, it translates into 315,000 fewer major adverse kidney events as a result of a simple switch to balanced crystalloids, Dr. Szerlip observed.
The PrevAKI findings validate the concept of AKI ‘golden hours’ during which time potentially reversible early kidney injury detectable via renal biomarkers is occurring prior to the abrupt decline in kidney function measured by change in serum creatinine. “The problem with using change in creatinine to define AKI is the delay in diagnosis, which makes AKI more difficult to treat,” he explained.
The renal biomarkers utilized in PrevAKI were insulin-like growth factor binding protein-7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2), as incorporated in the commercially available urinary NephroCheck test, which was administered to study participants 4 hours after cardiopulmonary bypass. A test result of 0.3 or more identified a group at high risk for AKI for randomization to the KDIGO bundle or usual care. The KDIGO bundle consists of discontinuation of nephrotoxic agents when feasible, early optimization of fluid status, and maintenance of perfusion pressure.
Patients known to be at increased risk for in-hospital AKI include the elderly, those with diabetes, patients with heart failure or other conditions prone to volume contraction or overload, those undergoing major surgery, individuals with chronic kidney disease, and patients with sepsis.
Dr. Szerlip singled out as particularly nephrotoxic several drugs widely used in hospitalized patients, including the combination of vancomycin plus piperacillin-tazobactam, which in a recent metaanalysis was found to have a number needed to harm of 11 in terms of AKI in comparison to vancomycin monotherapy or vancomycin in combination with cefepime or carbapenem (Crit Care Med. 2018 Jan;46[1]:12-20). He was also critical of the American Society of Anesthesiologists practice parameter recommending that in-hospital pain management plans for surgical patients include continuous regimens of NSAIDs or COX-2 inhibitors as a means of combating the ongoing opioid epidemic.
“These are highly toxic drugs to the kidney and we shouldn’t be using them,” Dr. Szerlip said.
He reported receiving research grants from LaJolla, Bayer, Akebia, and BioPorto, serving on a speakers’ bureau for Astute Medical, and acting as a consultant to Zs Pharma, Amarin, and LaJolla.
EXPERT ANALYSIS FROM ACP INTERNAL MECICINE
MDedge Daily News: Which nonopioids are ripe for abuse?
There’s new clarity on multiple sclerosis therapy. How infections boost Sjogren’s syndrome risk. And bum kidneys shouldn’t stop dabigatran reversal.
Listen to the MDedge Daily News podcast for all the details on today’s top news.
There’s new clarity on multiple sclerosis therapy. How infections boost Sjogren’s syndrome risk. And bum kidneys shouldn’t stop dabigatran reversal.
Listen to the MDedge Daily News podcast for all the details on today’s top news.
There’s new clarity on multiple sclerosis therapy. How infections boost Sjogren’s syndrome risk. And bum kidneys shouldn’t stop dabigatran reversal.
Listen to the MDedge Daily News podcast for all the details on today’s top news.
Impaired kidney function no problem for dabigatran reversal
ORLANDO – Idarucizumab, the reversal agent for the anticoagulant dabigatran, appeared as effective in quickly reversing dabigatran’s effects in patients with severe renal dysfunction as in patients with normally working kidneys, in a post hoc analysis of data collected in the drug’s pivotal trial.
A standard dose of idarucizumab “works just as well in patients with bad kidney function as it does in patients with preserved kidney function,” John W. Eikelboom, MD, said at the annual meeting of the American College of Cardiology. “The time to cessation of bleeding and the degree of normal hemostasis achieved was consistent” across the entire range of renal function examined, from severe renal dysfunction, with a creatinine clearance rate of less than 30 mL/min, to normal function, with an estimated rate of 80 mL/min or greater.
The ability of idarucizumab (Praxbind), conditionally approved by the Food and Drug Administration in 2015 and then fully approved in April 2018, to work in patients with impaired renal function has been an open question and concern because dabigatran (Pradaxa) is excreted renally, so it builds to unusually high levels in patients with poor kidney function. “Plasma dabigatran levels might be sky high, so a standard dose of idarucizumab might not work. That’s been a fear of clinicians,” explained Dr. Eikelboom, a hematologist at McMaster University in Hamilton, Ont.
To examine whether idarucizumab’s activity varied by renal function he used data from the patients enrolled in the RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran) study, the pivotal dataset that led to idarucizumab’s U.S. approval. The new, post hoc analysis divided patients into four subgroups based on their kidney function, and focused on the 489 patients for whom renal data were available out of the 503 patients in the study (N Engl J Med. 2017 Aug 3;377[5]:431-41). The subgroups included 91 patients with severe dysfunction with a creatinine clearance rate of less than 30 mL/min; 127 with moderate dysfunction and a clearance rate of 30-49 mL/min; 163 with mild dysfunction and a clearance rate of 50-79 mL/min; and 108 with normal function and a creatinine clearance of at least 80 mL/min.
Patients in the subgroup with severe renal dysfunction had the worst clinical profile overall, and as predicted, had a markedly elevated average plasma level of dabigatran, 231 ng/mL, nearly five times higher than the 47-ng/mL average level in patients with normal renal function.
The ability of a single, standard dose of idarucizumab to reverse the anticoagulant effects of dabigatran were essentially identical across the four strata of renal activity, with 98% of patients in both the severely impaired subgroup and the normal subgroup having 100% reversal within 4 hours of treatment, Dr. Eikelboom reported. Every patient included in the analysis had more than 50% reversal.
The study followed patients to 12-24 hours after they received idarucizumab, and 55% of patients with severe renal dysfunction showed a plasma dabigatran level that crept back toward a clinically meaningful level and so might need a second idarucizumab dose. In contrast, this happened in 8% of patients with normal renal function.
In patients with severe renal dysfunction given idarucizumab, “be alert for a recurrent bleed,” which could require a second dose of idarucizumab, Dr. Eikelboom suggested.
SOURCE: Eikelboom JW et al. ACC 18, Abstract 1231M-11.
ORLANDO – Idarucizumab, the reversal agent for the anticoagulant dabigatran, appeared as effective in quickly reversing dabigatran’s effects in patients with severe renal dysfunction as in patients with normally working kidneys, in a post hoc analysis of data collected in the drug’s pivotal trial.
A standard dose of idarucizumab “works just as well in patients with bad kidney function as it does in patients with preserved kidney function,” John W. Eikelboom, MD, said at the annual meeting of the American College of Cardiology. “The time to cessation of bleeding and the degree of normal hemostasis achieved was consistent” across the entire range of renal function examined, from severe renal dysfunction, with a creatinine clearance rate of less than 30 mL/min, to normal function, with an estimated rate of 80 mL/min or greater.
The ability of idarucizumab (Praxbind), conditionally approved by the Food and Drug Administration in 2015 and then fully approved in April 2018, to work in patients with impaired renal function has been an open question and concern because dabigatran (Pradaxa) is excreted renally, so it builds to unusually high levels in patients with poor kidney function. “Plasma dabigatran levels might be sky high, so a standard dose of idarucizumab might not work. That’s been a fear of clinicians,” explained Dr. Eikelboom, a hematologist at McMaster University in Hamilton, Ont.
To examine whether idarucizumab’s activity varied by renal function he used data from the patients enrolled in the RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran) study, the pivotal dataset that led to idarucizumab’s U.S. approval. The new, post hoc analysis divided patients into four subgroups based on their kidney function, and focused on the 489 patients for whom renal data were available out of the 503 patients in the study (N Engl J Med. 2017 Aug 3;377[5]:431-41). The subgroups included 91 patients with severe dysfunction with a creatinine clearance rate of less than 30 mL/min; 127 with moderate dysfunction and a clearance rate of 30-49 mL/min; 163 with mild dysfunction and a clearance rate of 50-79 mL/min; and 108 with normal function and a creatinine clearance of at least 80 mL/min.
Patients in the subgroup with severe renal dysfunction had the worst clinical profile overall, and as predicted, had a markedly elevated average plasma level of dabigatran, 231 ng/mL, nearly five times higher than the 47-ng/mL average level in patients with normal renal function.
The ability of a single, standard dose of idarucizumab to reverse the anticoagulant effects of dabigatran were essentially identical across the four strata of renal activity, with 98% of patients in both the severely impaired subgroup and the normal subgroup having 100% reversal within 4 hours of treatment, Dr. Eikelboom reported. Every patient included in the analysis had more than 50% reversal.
The study followed patients to 12-24 hours after they received idarucizumab, and 55% of patients with severe renal dysfunction showed a plasma dabigatran level that crept back toward a clinically meaningful level and so might need a second idarucizumab dose. In contrast, this happened in 8% of patients with normal renal function.
In patients with severe renal dysfunction given idarucizumab, “be alert for a recurrent bleed,” which could require a second dose of idarucizumab, Dr. Eikelboom suggested.
SOURCE: Eikelboom JW et al. ACC 18, Abstract 1231M-11.
ORLANDO – Idarucizumab, the reversal agent for the anticoagulant dabigatran, appeared as effective in quickly reversing dabigatran’s effects in patients with severe renal dysfunction as in patients with normally working kidneys, in a post hoc analysis of data collected in the drug’s pivotal trial.
A standard dose of idarucizumab “works just as well in patients with bad kidney function as it does in patients with preserved kidney function,” John W. Eikelboom, MD, said at the annual meeting of the American College of Cardiology. “The time to cessation of bleeding and the degree of normal hemostasis achieved was consistent” across the entire range of renal function examined, from severe renal dysfunction, with a creatinine clearance rate of less than 30 mL/min, to normal function, with an estimated rate of 80 mL/min or greater.
The ability of idarucizumab (Praxbind), conditionally approved by the Food and Drug Administration in 2015 and then fully approved in April 2018, to work in patients with impaired renal function has been an open question and concern because dabigatran (Pradaxa) is excreted renally, so it builds to unusually high levels in patients with poor kidney function. “Plasma dabigatran levels might be sky high, so a standard dose of idarucizumab might not work. That’s been a fear of clinicians,” explained Dr. Eikelboom, a hematologist at McMaster University in Hamilton, Ont.
To examine whether idarucizumab’s activity varied by renal function he used data from the patients enrolled in the RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran) study, the pivotal dataset that led to idarucizumab’s U.S. approval. The new, post hoc analysis divided patients into four subgroups based on their kidney function, and focused on the 489 patients for whom renal data were available out of the 503 patients in the study (N Engl J Med. 2017 Aug 3;377[5]:431-41). The subgroups included 91 patients with severe dysfunction with a creatinine clearance rate of less than 30 mL/min; 127 with moderate dysfunction and a clearance rate of 30-49 mL/min; 163 with mild dysfunction and a clearance rate of 50-79 mL/min; and 108 with normal function and a creatinine clearance of at least 80 mL/min.
Patients in the subgroup with severe renal dysfunction had the worst clinical profile overall, and as predicted, had a markedly elevated average plasma level of dabigatran, 231 ng/mL, nearly five times higher than the 47-ng/mL average level in patients with normal renal function.
The ability of a single, standard dose of idarucizumab to reverse the anticoagulant effects of dabigatran were essentially identical across the four strata of renal activity, with 98% of patients in both the severely impaired subgroup and the normal subgroup having 100% reversal within 4 hours of treatment, Dr. Eikelboom reported. Every patient included in the analysis had more than 50% reversal.
The study followed patients to 12-24 hours after they received idarucizumab, and 55% of patients with severe renal dysfunction showed a plasma dabigatran level that crept back toward a clinically meaningful level and so might need a second idarucizumab dose. In contrast, this happened in 8% of patients with normal renal function.
In patients with severe renal dysfunction given idarucizumab, “be alert for a recurrent bleed,” which could require a second dose of idarucizumab, Dr. Eikelboom suggested.
SOURCE: Eikelboom JW et al. ACC 18, Abstract 1231M-11.
REPORTING FROM ACC 18
Key clinical point: Renal function had no impact on idarucizumab’s efficacy for dabigatran reversal.
Major finding: Complete dabigatran reversal occurred in 98% of patients with severe renal dysfunction who received idarucizumab.
Study details: Post hoc analysis of data from RE-VERSE AD, idarucizumab’s pivotal trial with 503 patients.
Disclosures: RE-VERSE AD was funded by Boehringer Ingelheim, the company that markets idarucizumab (Praxbind) and dabigatran (Pradaxa). Dr. Eikelboom has been a consultant to and has received research support from Boehringer Ingelheim, as well as from Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, and Pfizer.
Source: Eikelboom JW et al. ACC 18, Abstract 1231M-11.
Sodium bicarbonate and acetylcysteine for prevention of contrast-related morbidity and mortality in CKD patients
Clinical question: Do either intravenous sodium bicarbonate or oral acetylcysteine prevent renal morbidity and mortality in patients with chronic kidney disease (CKD) undergoing angiography?
Background: Both intravenous sodium bicarbonate and acetylcysteine are commonly used therapies aimed at preventing contrast-induced nephropathy. However, data regarding their efficacy are controversial, and prior studies have largely included patients with normal renal function.
Setting: Medical centers (53) throughout the United States, Australia, New Zealand, and Malaysia.
Synopsis: This study included 4,993 patients with CKD, stage III and IV, who were scheduled for angiography. The study population was predominately male (93.6%) and had diabetes (80.9%). Patients were randomized to receive either sodium bicarbonate or normal saline infusion, and oral acetylcysteine or placebo. The primary outcome was a composite of death, dialysis, or a sustained increase in creatinine by 50% at 90 days, and the secondary outcome was contrast-associated acute kidney injury. There was no interaction between sodium bicarbonate and acetylcysteine. Neither therapy prevented the primary or secondary outcome. The main limitations to this study included a very narrow demographic making the results hard to extrapolate beyond male diabetes patients receiving contrast for angiography. Overall, this study suggests that treatment with sodium bicarbonate or acetylcysteine does not improve the contrast-related morbidity and mortality in patients with CKD III and IV.
Bottom line: Neither intravenous sodium bicarbonate nor acetylcysteine led to improved renal outcomes in predominantly male patients with diabetes and baseline renal dysfunction undergoing angiography.
Citation: Weisbord SD et al. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med. 2017 Nov 12. doi: 10.1056/NEJMal1710933.
Dr. Lusa is assistant professor of medicine, division of hospital medicine, University of Virginia.
Clinical question: Do either intravenous sodium bicarbonate or oral acetylcysteine prevent renal morbidity and mortality in patients with chronic kidney disease (CKD) undergoing angiography?
Background: Both intravenous sodium bicarbonate and acetylcysteine are commonly used therapies aimed at preventing contrast-induced nephropathy. However, data regarding their efficacy are controversial, and prior studies have largely included patients with normal renal function.
Setting: Medical centers (53) throughout the United States, Australia, New Zealand, and Malaysia.
Synopsis: This study included 4,993 patients with CKD, stage III and IV, who were scheduled for angiography. The study population was predominately male (93.6%) and had diabetes (80.9%). Patients were randomized to receive either sodium bicarbonate or normal saline infusion, and oral acetylcysteine or placebo. The primary outcome was a composite of death, dialysis, or a sustained increase in creatinine by 50% at 90 days, and the secondary outcome was contrast-associated acute kidney injury. There was no interaction between sodium bicarbonate and acetylcysteine. Neither therapy prevented the primary or secondary outcome. The main limitations to this study included a very narrow demographic making the results hard to extrapolate beyond male diabetes patients receiving contrast for angiography. Overall, this study suggests that treatment with sodium bicarbonate or acetylcysteine does not improve the contrast-related morbidity and mortality in patients with CKD III and IV.
Bottom line: Neither intravenous sodium bicarbonate nor acetylcysteine led to improved renal outcomes in predominantly male patients with diabetes and baseline renal dysfunction undergoing angiography.
Citation: Weisbord SD et al. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med. 2017 Nov 12. doi: 10.1056/NEJMal1710933.
Dr. Lusa is assistant professor of medicine, division of hospital medicine, University of Virginia.
Clinical question: Do either intravenous sodium bicarbonate or oral acetylcysteine prevent renal morbidity and mortality in patients with chronic kidney disease (CKD) undergoing angiography?
Background: Both intravenous sodium bicarbonate and acetylcysteine are commonly used therapies aimed at preventing contrast-induced nephropathy. However, data regarding their efficacy are controversial, and prior studies have largely included patients with normal renal function.
Setting: Medical centers (53) throughout the United States, Australia, New Zealand, and Malaysia.
Synopsis: This study included 4,993 patients with CKD, stage III and IV, who were scheduled for angiography. The study population was predominately male (93.6%) and had diabetes (80.9%). Patients were randomized to receive either sodium bicarbonate or normal saline infusion, and oral acetylcysteine or placebo. The primary outcome was a composite of death, dialysis, or a sustained increase in creatinine by 50% at 90 days, and the secondary outcome was contrast-associated acute kidney injury. There was no interaction between sodium bicarbonate and acetylcysteine. Neither therapy prevented the primary or secondary outcome. The main limitations to this study included a very narrow demographic making the results hard to extrapolate beyond male diabetes patients receiving contrast for angiography. Overall, this study suggests that treatment with sodium bicarbonate or acetylcysteine does not improve the contrast-related morbidity and mortality in patients with CKD III and IV.
Bottom line: Neither intravenous sodium bicarbonate nor acetylcysteine led to improved renal outcomes in predominantly male patients with diabetes and baseline renal dysfunction undergoing angiography.
Citation: Weisbord SD et al. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med. 2017 Nov 12. doi: 10.1056/NEJMal1710933.
Dr. Lusa is assistant professor of medicine, division of hospital medicine, University of Virginia.
Can African-American Patients Take Metoprolol?
Q) One of the physicians in my practice won't use metoprolol in African-American patients. He says it causes kidney disease. Is it right, or is this an old wives' tale?
There are multiple concerns with the use of metoprolol specifically—this does not apply to all ß-blockers—in the African-American population. The main concerns are
- Lack of effective blood pressure control, compared to angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs)
- No observable reduction in proteinuria
- The possibility of a significant increase in uric acid.
Most of the evidence-based guidelines for care of hypertensive nephrosclerosis in the African-American population were derived from the African-American Study of Kidney Disease and Hypertension (AASK) trial. This large-scale, multicenter, randomized, double-blinded study from the National Institute of Health had multiple arms to compare an ACE inhibitor (ramipril) to a CCB (amlodipine) or a ß-blocker (metoprolol) in the nondiabetic African-American population.1
In a subgroup analysis, more than 1,000 subjects with hypertensive nephrosclerosis were followed for four years, with serial glomerular filtration rate (GFR) measurements taken. Treatment with ACE inhibitors was shown to be superior to CCB and ß-blockers for hypertension and proteinuria control.1
One important take-away from the AASK trial has been that strict blood pressure control is not enough to improve kidney outcomes. Proteinuria (albuminuria) must also be controlled.1
Continue to: In a subsequent secondary analysis
In a subsequent secondary analysis of data from the AASK study, Juraschek et al showed that metoprolol significantly increased serum uric acid in African-American adults.2 It is known that hyperuricemia (> 6 mg/dL) can cause a decline in kidney function.3
Furthermore, uric acid may be a strong prognostic factor for chronic kidney disease (CKD) progression. (This association, however, remains controversial. One recent study showed that, while hyperuricemia is associated with higher risk for kidney failure, the relationship was not parallel in CKD stage 3 or 4 [GFR ≤ 60 mL/min]).4 In fact, taking uric acid–lowering medications did not slow progression of kidney disease.
In other words, your colleague seems to believe that since A (metoprolol) leads to B (hyperuricemia) and B (hyperuricemia) leads to C (kidney disease), then A leads to C. While the theory is undoubtedly logical, we have no proof that metoprolol causes increased kidney disease in African-American patients.
What we do know, thanks to AASK, is that an African-American patient with kidney disease should be treated with a diuretic and/or an ACE inhibitor as initial therapy. Furthermore, we have a blood pressure goal: < 130/80 mm Hg. And we know that CCBs are most effective for African-American patients who do not have kidney disease.5—BWM
Barbara Weis Malone, DNP, FNP-C, FNKF
Assistant Professor
Adult/Gerontology NP Program, College of Nursing
Nurse Practitioner
School of Medicine, University of Colorado Anschutz Medical Campus
1. Toto RD. Lessons from the African-American Study of Kidney Disease and Hypertension: an update. Curr Hypertens Rep. 2006;8(5):409-412.
2. Juraschek SP, Appel LJ, Miller ER III. Metoprolol increases uric acid and risk of gout in African Americans with chronic kidney disease attributed to hypertension. Am J Hypertens. 2017; 30(9):871-875.
3. Tsai C-W, Lin S-Y, Kuo C-C, Huang C-C. Serum uric acid and progression of kidney disease: a longitudinal analysis and mini-review. PLoS One. 2017;12(1):e0170393.
4. Rincon-Choles H, Jolly SE, Arrigain S, et al. Impact of uric acid levels on kidney disease progression. Am J Nephrol. 2017;46(4):315-322.
5. Armstrong C. JNC8 guidelines for the management of hypertension in adults. Am Fam Physician. 2014;90(7):503-504.
Clinician Reviews in partnership with
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National Kidney Foundation's Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a semi-retired PA who works with the American Academy of Nephrology PAs and is a past chair of the NKF-CAP. This month's responses were authored by Danielle S. Wentworth, MSN, FNP-BC, who practices in the Division of Nephrology at the University of Virginia Health System in Charlottesville, and Barbara Weis Malone, DNP, FNP-C, FNKF, who is an Assistant Professor in the Adult/Gerontology NP Program in the College of Nursing, and a Nurse Practitioner in the School of Medicine, at the University of Colorado Anschutz Medical Campus.
Clinician Reviews in partnership with
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National Kidney Foundation's Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a semi-retired PA who works with the American Academy of Nephrology PAs and is a past chair of the NKF-CAP. This month's responses were authored by Danielle S. Wentworth, MSN, FNP-BC, who practices in the Division of Nephrology at the University of Virginia Health System in Charlottesville, and Barbara Weis Malone, DNP, FNP-C, FNKF, who is an Assistant Professor in the Adult/Gerontology NP Program in the College of Nursing, and a Nurse Practitioner in the School of Medicine, at the University of Colorado Anschutz Medical Campus.
Clinician Reviews in partnership with
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National Kidney Foundation's Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a semi-retired PA who works with the American Academy of Nephrology PAs and is a past chair of the NKF-CAP. This month's responses were authored by Danielle S. Wentworth, MSN, FNP-BC, who practices in the Division of Nephrology at the University of Virginia Health System in Charlottesville, and Barbara Weis Malone, DNP, FNP-C, FNKF, who is an Assistant Professor in the Adult/Gerontology NP Program in the College of Nursing, and a Nurse Practitioner in the School of Medicine, at the University of Colorado Anschutz Medical Campus.
Q) One of the physicians in my practice won't use metoprolol in African-American patients. He says it causes kidney disease. Is it right, or is this an old wives' tale?
There are multiple concerns with the use of metoprolol specifically—this does not apply to all ß-blockers—in the African-American population. The main concerns are
- Lack of effective blood pressure control, compared to angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs)
- No observable reduction in proteinuria
- The possibility of a significant increase in uric acid.
Most of the evidence-based guidelines for care of hypertensive nephrosclerosis in the African-American population were derived from the African-American Study of Kidney Disease and Hypertension (AASK) trial. This large-scale, multicenter, randomized, double-blinded study from the National Institute of Health had multiple arms to compare an ACE inhibitor (ramipril) to a CCB (amlodipine) or a ß-blocker (metoprolol) in the nondiabetic African-American population.1
In a subgroup analysis, more than 1,000 subjects with hypertensive nephrosclerosis were followed for four years, with serial glomerular filtration rate (GFR) measurements taken. Treatment with ACE inhibitors was shown to be superior to CCB and ß-blockers for hypertension and proteinuria control.1
One important take-away from the AASK trial has been that strict blood pressure control is not enough to improve kidney outcomes. Proteinuria (albuminuria) must also be controlled.1
Continue to: In a subsequent secondary analysis
In a subsequent secondary analysis of data from the AASK study, Juraschek et al showed that metoprolol significantly increased serum uric acid in African-American adults.2 It is known that hyperuricemia (> 6 mg/dL) can cause a decline in kidney function.3
Furthermore, uric acid may be a strong prognostic factor for chronic kidney disease (CKD) progression. (This association, however, remains controversial. One recent study showed that, while hyperuricemia is associated with higher risk for kidney failure, the relationship was not parallel in CKD stage 3 or 4 [GFR ≤ 60 mL/min]).4 In fact, taking uric acid–lowering medications did not slow progression of kidney disease.
In other words, your colleague seems to believe that since A (metoprolol) leads to B (hyperuricemia) and B (hyperuricemia) leads to C (kidney disease), then A leads to C. While the theory is undoubtedly logical, we have no proof that metoprolol causes increased kidney disease in African-American patients.
What we do know, thanks to AASK, is that an African-American patient with kidney disease should be treated with a diuretic and/or an ACE inhibitor as initial therapy. Furthermore, we have a blood pressure goal: < 130/80 mm Hg. And we know that CCBs are most effective for African-American patients who do not have kidney disease.5—BWM
Barbara Weis Malone, DNP, FNP-C, FNKF
Assistant Professor
Adult/Gerontology NP Program, College of Nursing
Nurse Practitioner
School of Medicine, University of Colorado Anschutz Medical Campus
Q) One of the physicians in my practice won't use metoprolol in African-American patients. He says it causes kidney disease. Is it right, or is this an old wives' tale?
There are multiple concerns with the use of metoprolol specifically—this does not apply to all ß-blockers—in the African-American population. The main concerns are
- Lack of effective blood pressure control, compared to angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs)
- No observable reduction in proteinuria
- The possibility of a significant increase in uric acid.
Most of the evidence-based guidelines for care of hypertensive nephrosclerosis in the African-American population were derived from the African-American Study of Kidney Disease and Hypertension (AASK) trial. This large-scale, multicenter, randomized, double-blinded study from the National Institute of Health had multiple arms to compare an ACE inhibitor (ramipril) to a CCB (amlodipine) or a ß-blocker (metoprolol) in the nondiabetic African-American population.1
In a subgroup analysis, more than 1,000 subjects with hypertensive nephrosclerosis were followed for four years, with serial glomerular filtration rate (GFR) measurements taken. Treatment with ACE inhibitors was shown to be superior to CCB and ß-blockers for hypertension and proteinuria control.1
One important take-away from the AASK trial has been that strict blood pressure control is not enough to improve kidney outcomes. Proteinuria (albuminuria) must also be controlled.1
Continue to: In a subsequent secondary analysis
In a subsequent secondary analysis of data from the AASK study, Juraschek et al showed that metoprolol significantly increased serum uric acid in African-American adults.2 It is known that hyperuricemia (> 6 mg/dL) can cause a decline in kidney function.3
Furthermore, uric acid may be a strong prognostic factor for chronic kidney disease (CKD) progression. (This association, however, remains controversial. One recent study showed that, while hyperuricemia is associated with higher risk for kidney failure, the relationship was not parallel in CKD stage 3 or 4 [GFR ≤ 60 mL/min]).4 In fact, taking uric acid–lowering medications did not slow progression of kidney disease.
In other words, your colleague seems to believe that since A (metoprolol) leads to B (hyperuricemia) and B (hyperuricemia) leads to C (kidney disease), then A leads to C. While the theory is undoubtedly logical, we have no proof that metoprolol causes increased kidney disease in African-American patients.
What we do know, thanks to AASK, is that an African-American patient with kidney disease should be treated with a diuretic and/or an ACE inhibitor as initial therapy. Furthermore, we have a blood pressure goal: < 130/80 mm Hg. And we know that CCBs are most effective for African-American patients who do not have kidney disease.5—BWM
Barbara Weis Malone, DNP, FNP-C, FNKF
Assistant Professor
Adult/Gerontology NP Program, College of Nursing
Nurse Practitioner
School of Medicine, University of Colorado Anschutz Medical Campus
1. Toto RD. Lessons from the African-American Study of Kidney Disease and Hypertension: an update. Curr Hypertens Rep. 2006;8(5):409-412.
2. Juraschek SP, Appel LJ, Miller ER III. Metoprolol increases uric acid and risk of gout in African Americans with chronic kidney disease attributed to hypertension. Am J Hypertens. 2017; 30(9):871-875.
3. Tsai C-W, Lin S-Y, Kuo C-C, Huang C-C. Serum uric acid and progression of kidney disease: a longitudinal analysis and mini-review. PLoS One. 2017;12(1):e0170393.
4. Rincon-Choles H, Jolly SE, Arrigain S, et al. Impact of uric acid levels on kidney disease progression. Am J Nephrol. 2017;46(4):315-322.
5. Armstrong C. JNC8 guidelines for the management of hypertension in adults. Am Fam Physician. 2014;90(7):503-504.
1. Toto RD. Lessons from the African-American Study of Kidney Disease and Hypertension: an update. Curr Hypertens Rep. 2006;8(5):409-412.
2. Juraschek SP, Appel LJ, Miller ER III. Metoprolol increases uric acid and risk of gout in African Americans with chronic kidney disease attributed to hypertension. Am J Hypertens. 2017; 30(9):871-875.
3. Tsai C-W, Lin S-Y, Kuo C-C, Huang C-C. Serum uric acid and progression of kidney disease: a longitudinal analysis and mini-review. PLoS One. 2017;12(1):e0170393.
4. Rincon-Choles H, Jolly SE, Arrigain S, et al. Impact of uric acid levels on kidney disease progression. Am J Nephrol. 2017;46(4):315-322.
5. Armstrong C. JNC8 guidelines for the management of hypertension in adults. Am Fam Physician. 2014;90(7):503-504.
Is “Runner’s Kidney” a Thing?
Q) Many of my patients are athletes. I recall reading something about kidney disease in marathon runners. Am I remembering correctly?
Although data on acute kidney injury (AKI) in marathon runners are limited, two recent studies have added to our knowledge. In 2017, Mansour et al studied 22 marathon runners, collecting urine and blood samples 24 hours before, immediately after, and 24 hours after a race. The results showed that in 82% of the subjects, serum creatinine increased to a level correlated with stage 1 or 2 AKI (as defined by the Acute Kidney Injury Network criteria).1
Based on urine microscopy results, as well as serum creatinine and novel biomarker levels, the researchers concluded that the runners’ AKI was caused by acute tubular injury—likely induced by ischemia. However, the subjects did not show any evidence of chronic kidney disease (CKD), despite years of running and intensive training. One theory: Habitual running might condition the kidneys to transient ischemic conditions—in other words, they build tolerance to repetitive injury over time.1
Continue to: The other recent study
The other recent study examined use of NSAIDs by ultramarathon
In summary: While marathon runners are prone to AKI, the injury seems to be transient and does not progress to CKD. Furthermore, use of NSAIDs during endurance running may contribute to AKI development, so patients should be advised to use caution with these analgesics. Finally, remind your endurance runners to stay hydrated, since it may help to limit kidney damage. As for the casual runner? The impact on the kidney remains unclear and needs further investigation. —DSW
Danielle S. Wentworth, MSN, FNP-BC
Division of Nephrology, University of Viriginia Health System, Charlottesville
1. Mansour SG, Verma G, Pata RW, et al. Kidney injury and repair biomarkers in marathon runners. Am J Kidney Dis. 2017;70(2):252-261.
2. Lipman GS, Shea K, Christensen M, et al. Ibuprofen versus placebo effect on acute kidney injury in ultramarathons: a randomised controlled trial. Emerg Med J. 2017;34(10):637-642.
Clinician Reviews in partnership with
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National Kidney Foundation's Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a semi-retired PA who works with the American Academy of Nephrology PAs and is a past chair of the NKF-CAP. This month's responses were authored by Danielle S. Wentworth, MSN, FNP-BC, who practices in the Division of Nephrology at the University of Virginia Health System in Charlottesville, and Barbara Weis Malone, DNP, FNP-C, FNKF, who is an Assistant Professor in the Adult/Gerontology NP Program in the College of Nursing, and a Nurse Practitioner in the School of Medicine, at the University of Colorado Anschutz Medical Campus.
Clinician Reviews in partnership with
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National Kidney Foundation's Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a semi-retired PA who works with the American Academy of Nephrology PAs and is a past chair of the NKF-CAP. This month's responses were authored by Danielle S. Wentworth, MSN, FNP-BC, who practices in the Division of Nephrology at the University of Virginia Health System in Charlottesville, and Barbara Weis Malone, DNP, FNP-C, FNKF, who is an Assistant Professor in the Adult/Gerontology NP Program in the College of Nursing, and a Nurse Practitioner in the School of Medicine, at the University of Colorado Anschutz Medical Campus.
Clinician Reviews in partnership with
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National Kidney Foundation's Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a semi-retired PA who works with the American Academy of Nephrology PAs and is a past chair of the NKF-CAP. This month's responses were authored by Danielle S. Wentworth, MSN, FNP-BC, who practices in the Division of Nephrology at the University of Virginia Health System in Charlottesville, and Barbara Weis Malone, DNP, FNP-C, FNKF, who is an Assistant Professor in the Adult/Gerontology NP Program in the College of Nursing, and a Nurse Practitioner in the School of Medicine, at the University of Colorado Anschutz Medical Campus.
Q) Many of my patients are athletes. I recall reading something about kidney disease in marathon runners. Am I remembering correctly?
Although data on acute kidney injury (AKI) in marathon runners are limited, two recent studies have added to our knowledge. In 2017, Mansour et al studied 22 marathon runners, collecting urine and blood samples 24 hours before, immediately after, and 24 hours after a race. The results showed that in 82% of the subjects, serum creatinine increased to a level correlated with stage 1 or 2 AKI (as defined by the Acute Kidney Injury Network criteria).1
Based on urine microscopy results, as well as serum creatinine and novel biomarker levels, the researchers concluded that the runners’ AKI was caused by acute tubular injury—likely induced by ischemia. However, the subjects did not show any evidence of chronic kidney disease (CKD), despite years of running and intensive training. One theory: Habitual running might condition the kidneys to transient ischemic conditions—in other words, they build tolerance to repetitive injury over time.1
Continue to: The other recent study
The other recent study examined use of NSAIDs by ultramarathon
In summary: While marathon runners are prone to AKI, the injury seems to be transient and does not progress to CKD. Furthermore, use of NSAIDs during endurance running may contribute to AKI development, so patients should be advised to use caution with these analgesics. Finally, remind your endurance runners to stay hydrated, since it may help to limit kidney damage. As for the casual runner? The impact on the kidney remains unclear and needs further investigation. —DSW
Danielle S. Wentworth, MSN, FNP-BC
Division of Nephrology, University of Viriginia Health System, Charlottesville
Q) Many of my patients are athletes. I recall reading something about kidney disease in marathon runners. Am I remembering correctly?
Although data on acute kidney injury (AKI) in marathon runners are limited, two recent studies have added to our knowledge. In 2017, Mansour et al studied 22 marathon runners, collecting urine and blood samples 24 hours before, immediately after, and 24 hours after a race. The results showed that in 82% of the subjects, serum creatinine increased to a level correlated with stage 1 or 2 AKI (as defined by the Acute Kidney Injury Network criteria).1
Based on urine microscopy results, as well as serum creatinine and novel biomarker levels, the researchers concluded that the runners’ AKI was caused by acute tubular injury—likely induced by ischemia. However, the subjects did not show any evidence of chronic kidney disease (CKD), despite years of running and intensive training. One theory: Habitual running might condition the kidneys to transient ischemic conditions—in other words, they build tolerance to repetitive injury over time.1
Continue to: The other recent study
The other recent study examined use of NSAIDs by ultramarathon
In summary: While marathon runners are prone to AKI, the injury seems to be transient and does not progress to CKD. Furthermore, use of NSAIDs during endurance running may contribute to AKI development, so patients should be advised to use caution with these analgesics. Finally, remind your endurance runners to stay hydrated, since it may help to limit kidney damage. As for the casual runner? The impact on the kidney remains unclear and needs further investigation. —DSW
Danielle S. Wentworth, MSN, FNP-BC
Division of Nephrology, University of Viriginia Health System, Charlottesville
1. Mansour SG, Verma G, Pata RW, et al. Kidney injury and repair biomarkers in marathon runners. Am J Kidney Dis. 2017;70(2):252-261.
2. Lipman GS, Shea K, Christensen M, et al. Ibuprofen versus placebo effect on acute kidney injury in ultramarathons: a randomised controlled trial. Emerg Med J. 2017;34(10):637-642.
1. Mansour SG, Verma G, Pata RW, et al. Kidney injury and repair biomarkers in marathon runners. Am J Kidney Dis. 2017;70(2):252-261.
2. Lipman GS, Shea K, Christensen M, et al. Ibuprofen versus placebo effect on acute kidney injury in ultramarathons: a randomised controlled trial. Emerg Med J. 2017;34(10):637-642.
Clearer picture emerging of renal impact of SGLT2s
LOS ANGELES – Results from recent trials suggest that
“Despite optimal care around blood pressure control, glycemic control, and control of other risk factors, our patients still have a significant risk of both cardiovascular disease progression and renal disease progression,” David Cherney, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “In fact, when we have a narrow focus on glycemia, there is a lot of additional residual risk, and that A1c lowering by itself does not negate that risk and in fact has very little effect on clinical outcomes. That brings us to the newer hyperglycemic therapies, including the SGLT2 inhibitors. While these agents do indeed block the reabsorption of glucose in the kidney, they also have an effect on other nonglycemic risk factors.”
“Inside the kidney, there are direct effects on reducing intraglomerular hypertension, leading to reductions in proteinuria,” he said. “These agents are interesting because of the way that they influence how the kidney handles sodium. As a consequence, they impact on glomerular hypertension.”
Under normal physiological conditions, humans who become volume depleted or hypotensive experience a reduction in sodium delivery to the kidney by the afferent arteriole, he explained. If less sodium is delivered to the afferent arteriole, less is filtered and delivered to the macula densa, which is the sodium-sensing area of the kidney.
“If less sodium is delivered to the macula densa, less sodium will be reabsorbed, which is an energy-requiring process that leads to the breakdown of ATP [adenosine triphosphate],” Dr. Cherney said. “If less ATP is broken down to adenosine, then less adenosine is produced. Adenosine is a vasoconstrictor in this area. So, under conditions of hypervolemia or hypotension, that’s great, because we want to maintain blood flow to the kidney; that’s a protective autoregulatory response that all of us have called tubular glomerular feedback. It’s through sodium delivery to the macula densa.”
He went on to note that hyperglycemic patients who are not taking an SGLT2 inhibitor experience an increase in sodium absorption proximally, which decreases sodium delivery to the macula densa. As a result, this causes afferent dilation, which leads to a rise in glomerular pressure, glomerular hypertension, hyperfiltration, and an increased risk of renal disease progression.
“This leads to all the effects that we see clinically, including the GFR [glomerular filtration rate] dip and the reduction in proteinuria that these agents cause either when used alone or with an ACE or ARB [angiotensin II receptor blocker],” Dr. Cherney said. “SGLT2s constrict the afferent arterial and reduce glomerular hypertension and proteinuria, whereas ACE inhibitors dilate the efferent arterial, which also reduces glomerular hypertension and proteinuria.”
An analysis of renal data from the multicenter EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) found that the use of empagliflozin was associated with slower progression of kidney disease than was placebo when added to standard care. Empagliflozin was also associated with a significantly lower risk of clinically relevant renal events, including a 40%-50% reduction in microalbuminuria in patients with micro- or macroalbuminuria (N Engl J Med. 2016 Jul 28;375:323-34).
In a recent study of EMPA-REG OUTCOME patients, Dr. Cherney and his associates examined the effects of empagliflozin on the urinary albumin to creatinine ratio in patients with type 2 diabetes and established cardiovascular disease (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). They found that even in patients with normal albuminuria at baseline, by the end of the trial at about 3 years there was a modest but statistically significant 15% reduction in urinary albumin secretion. “That reduction was greater in patients with microalbuminuria at baseline,” Dr. Cherney said. “There was a more than 40% reduction in microalbuminuric patients, and almost a 50% in patients who had macroalbuminuria at baseline, suggesting that the effect is greater in patients with higher levels of albuminuria.”
Meanwhile, results from the CANVAS program, which integrated data from two trials of more than 10,000 patients with type 2 diabetes and high cardiovascular disease risk, showed that those who received canagliflozin had a 14% reduced risk of 3-point major adverse cardiovascular events (3P-MACE), compared with those who received placebo. (N Engl J Med. 2017 Aug;377:644-57). “There was a curious increased risk of amputation and fracture in the canagliflozin group, which has not been seen in other trials,” Dr. Cherney said. “That certainly merits further thought and investigation, to better understand how significant this risk is.”
Upcoming trials of renal endpoints to look out for, he said, include the CREDENCE study (results expected in 2019), DAPA-CKD, which is in the recruitment stage, and a new outcome study to evaluate the effect of empagliflozin for the treatment of people with chronic kidney disease. “This is an expanding area in the renal and cardiovascular world that we will hear a lot more about in the next 3-5 years,” he said.
Dr. Cherney reported consulting fees and/or honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe, and Sanofi.
LOS ANGELES – Results from recent trials suggest that
“Despite optimal care around blood pressure control, glycemic control, and control of other risk factors, our patients still have a significant risk of both cardiovascular disease progression and renal disease progression,” David Cherney, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “In fact, when we have a narrow focus on glycemia, there is a lot of additional residual risk, and that A1c lowering by itself does not negate that risk and in fact has very little effect on clinical outcomes. That brings us to the newer hyperglycemic therapies, including the SGLT2 inhibitors. While these agents do indeed block the reabsorption of glucose in the kidney, they also have an effect on other nonglycemic risk factors.”
“Inside the kidney, there are direct effects on reducing intraglomerular hypertension, leading to reductions in proteinuria,” he said. “These agents are interesting because of the way that they influence how the kidney handles sodium. As a consequence, they impact on glomerular hypertension.”
Under normal physiological conditions, humans who become volume depleted or hypotensive experience a reduction in sodium delivery to the kidney by the afferent arteriole, he explained. If less sodium is delivered to the afferent arteriole, less is filtered and delivered to the macula densa, which is the sodium-sensing area of the kidney.
“If less sodium is delivered to the macula densa, less sodium will be reabsorbed, which is an energy-requiring process that leads to the breakdown of ATP [adenosine triphosphate],” Dr. Cherney said. “If less ATP is broken down to adenosine, then less adenosine is produced. Adenosine is a vasoconstrictor in this area. So, under conditions of hypervolemia or hypotension, that’s great, because we want to maintain blood flow to the kidney; that’s a protective autoregulatory response that all of us have called tubular glomerular feedback. It’s through sodium delivery to the macula densa.”
He went on to note that hyperglycemic patients who are not taking an SGLT2 inhibitor experience an increase in sodium absorption proximally, which decreases sodium delivery to the macula densa. As a result, this causes afferent dilation, which leads to a rise in glomerular pressure, glomerular hypertension, hyperfiltration, and an increased risk of renal disease progression.
“This leads to all the effects that we see clinically, including the GFR [glomerular filtration rate] dip and the reduction in proteinuria that these agents cause either when used alone or with an ACE or ARB [angiotensin II receptor blocker],” Dr. Cherney said. “SGLT2s constrict the afferent arterial and reduce glomerular hypertension and proteinuria, whereas ACE inhibitors dilate the efferent arterial, which also reduces glomerular hypertension and proteinuria.”
An analysis of renal data from the multicenter EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) found that the use of empagliflozin was associated with slower progression of kidney disease than was placebo when added to standard care. Empagliflozin was also associated with a significantly lower risk of clinically relevant renal events, including a 40%-50% reduction in microalbuminuria in patients with micro- or macroalbuminuria (N Engl J Med. 2016 Jul 28;375:323-34).
In a recent study of EMPA-REG OUTCOME patients, Dr. Cherney and his associates examined the effects of empagliflozin on the urinary albumin to creatinine ratio in patients with type 2 diabetes and established cardiovascular disease (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). They found that even in patients with normal albuminuria at baseline, by the end of the trial at about 3 years there was a modest but statistically significant 15% reduction in urinary albumin secretion. “That reduction was greater in patients with microalbuminuria at baseline,” Dr. Cherney said. “There was a more than 40% reduction in microalbuminuric patients, and almost a 50% in patients who had macroalbuminuria at baseline, suggesting that the effect is greater in patients with higher levels of albuminuria.”
Meanwhile, results from the CANVAS program, which integrated data from two trials of more than 10,000 patients with type 2 diabetes and high cardiovascular disease risk, showed that those who received canagliflozin had a 14% reduced risk of 3-point major adverse cardiovascular events (3P-MACE), compared with those who received placebo. (N Engl J Med. 2017 Aug;377:644-57). “There was a curious increased risk of amputation and fracture in the canagliflozin group, which has not been seen in other trials,” Dr. Cherney said. “That certainly merits further thought and investigation, to better understand how significant this risk is.”
Upcoming trials of renal endpoints to look out for, he said, include the CREDENCE study (results expected in 2019), DAPA-CKD, which is in the recruitment stage, and a new outcome study to evaluate the effect of empagliflozin for the treatment of people with chronic kidney disease. “This is an expanding area in the renal and cardiovascular world that we will hear a lot more about in the next 3-5 years,” he said.
Dr. Cherney reported consulting fees and/or honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe, and Sanofi.
LOS ANGELES – Results from recent trials suggest that
“Despite optimal care around blood pressure control, glycemic control, and control of other risk factors, our patients still have a significant risk of both cardiovascular disease progression and renal disease progression,” David Cherney, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “In fact, when we have a narrow focus on glycemia, there is a lot of additional residual risk, and that A1c lowering by itself does not negate that risk and in fact has very little effect on clinical outcomes. That brings us to the newer hyperglycemic therapies, including the SGLT2 inhibitors. While these agents do indeed block the reabsorption of glucose in the kidney, they also have an effect on other nonglycemic risk factors.”
“Inside the kidney, there are direct effects on reducing intraglomerular hypertension, leading to reductions in proteinuria,” he said. “These agents are interesting because of the way that they influence how the kidney handles sodium. As a consequence, they impact on glomerular hypertension.”
Under normal physiological conditions, humans who become volume depleted or hypotensive experience a reduction in sodium delivery to the kidney by the afferent arteriole, he explained. If less sodium is delivered to the afferent arteriole, less is filtered and delivered to the macula densa, which is the sodium-sensing area of the kidney.
“If less sodium is delivered to the macula densa, less sodium will be reabsorbed, which is an energy-requiring process that leads to the breakdown of ATP [adenosine triphosphate],” Dr. Cherney said. “If less ATP is broken down to adenosine, then less adenosine is produced. Adenosine is a vasoconstrictor in this area. So, under conditions of hypervolemia or hypotension, that’s great, because we want to maintain blood flow to the kidney; that’s a protective autoregulatory response that all of us have called tubular glomerular feedback. It’s through sodium delivery to the macula densa.”
He went on to note that hyperglycemic patients who are not taking an SGLT2 inhibitor experience an increase in sodium absorption proximally, which decreases sodium delivery to the macula densa. As a result, this causes afferent dilation, which leads to a rise in glomerular pressure, glomerular hypertension, hyperfiltration, and an increased risk of renal disease progression.
“This leads to all the effects that we see clinically, including the GFR [glomerular filtration rate] dip and the reduction in proteinuria that these agents cause either when used alone or with an ACE or ARB [angiotensin II receptor blocker],” Dr. Cherney said. “SGLT2s constrict the afferent arterial and reduce glomerular hypertension and proteinuria, whereas ACE inhibitors dilate the efferent arterial, which also reduces glomerular hypertension and proteinuria.”
An analysis of renal data from the multicenter EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) found that the use of empagliflozin was associated with slower progression of kidney disease than was placebo when added to standard care. Empagliflozin was also associated with a significantly lower risk of clinically relevant renal events, including a 40%-50% reduction in microalbuminuria in patients with micro- or macroalbuminuria (N Engl J Med. 2016 Jul 28;375:323-34).
In a recent study of EMPA-REG OUTCOME patients, Dr. Cherney and his associates examined the effects of empagliflozin on the urinary albumin to creatinine ratio in patients with type 2 diabetes and established cardiovascular disease (Lancet Diabetes Endocrinol. 2017 Aug;5[8]:610-21). They found that even in patients with normal albuminuria at baseline, by the end of the trial at about 3 years there was a modest but statistically significant 15% reduction in urinary albumin secretion. “That reduction was greater in patients with microalbuminuria at baseline,” Dr. Cherney said. “There was a more than 40% reduction in microalbuminuric patients, and almost a 50% in patients who had macroalbuminuria at baseline, suggesting that the effect is greater in patients with higher levels of albuminuria.”
Meanwhile, results from the CANVAS program, which integrated data from two trials of more than 10,000 patients with type 2 diabetes and high cardiovascular disease risk, showed that those who received canagliflozin had a 14% reduced risk of 3-point major adverse cardiovascular events (3P-MACE), compared with those who received placebo. (N Engl J Med. 2017 Aug;377:644-57). “There was a curious increased risk of amputation and fracture in the canagliflozin group, which has not been seen in other trials,” Dr. Cherney said. “That certainly merits further thought and investigation, to better understand how significant this risk is.”
Upcoming trials of renal endpoints to look out for, he said, include the CREDENCE study (results expected in 2019), DAPA-CKD, which is in the recruitment stage, and a new outcome study to evaluate the effect of empagliflozin for the treatment of people with chronic kidney disease. “This is an expanding area in the renal and cardiovascular world that we will hear a lot more about in the next 3-5 years,” he said.
Dr. Cherney reported consulting fees and/or honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe, and Sanofi.
EXPERT ANALYSIS FROM WCIRDC 2017
Always get culture in symptomatic children with neurogenic bladder
In the symptomatic child with neurogenic bladder at risk for urinary tract infection (UTI), urine culture should be performed regardless of the results of urinalysis, recommended Catherine S. Forster, MD, of Cincinnati Children’s Hospital Medical Center, and her associates.
In a general pediatric population, studies have found that certain uropathogens – such as Enterococcus species, Klebsiella species, and Pseudomonas aeruginosa – are less likely to be associated with pyuria than Escherichia coli.
According to the guidelines of the Infectious Disease Society of America guidelines for the diagnosis of catheter-associated UTI, pyuria is not considered diagnostic of UTI in patients who require CIC.
Children with neurogenic bladder requiring CIC often have bacteriuria and often undergo urinalyses to determine if empirical antibiotics are warranted until urine culture results are available. “Although timely initiation of antibiotics can prevent the progression of infection and decrease the risk of renal scars, unnecessary antimicrobial agents contribute to the emergence of bacterial resistance,” Dr. Forster and her associates said.
So the researchers designed a study to find out if the presence of pyuria was associated with particular uropathogens in children with neurogenic bladders.
In an analysis of 2,420 urinalysis and urine culture results from EHRs between Jan.1, 2008, and Dec. 31, 2014, for patients aged 18 years and younger with neurogenic bladders requiring CIC, the most frequently isolated uropathogen was E. coli (37%), followed by Enterococcus species (14%), Klebsiella species (11%), and various other uropathogen species (38%).
In children needing CIC for neurogenic bladder, growth of Enterococcus species on urine culture was linked with lower odds of both microscopic pyuria (0.44) and leukocyte esterase (0.45).
“With these results, we suggest that the current markers of UTI evidenced on urinalysis and urine microscopy are insufficient for predicting bacteriuria in this population,” Dr. Forster and her colleagues said, leading to their recommendation to perform a culture in symptomatic children with neurogenic bladders irrespective of urinalysis results.
Dr. Forster received a research grant from the National Institutes of Health. The investigators said they had no relevant conflicts of interest.
SOURCE: Forster CS et al. Pediatrics. 2018;141(5):e20173006.
In the symptomatic child with neurogenic bladder at risk for urinary tract infection (UTI), urine culture should be performed regardless of the results of urinalysis, recommended Catherine S. Forster, MD, of Cincinnati Children’s Hospital Medical Center, and her associates.
In a general pediatric population, studies have found that certain uropathogens – such as Enterococcus species, Klebsiella species, and Pseudomonas aeruginosa – are less likely to be associated with pyuria than Escherichia coli.
According to the guidelines of the Infectious Disease Society of America guidelines for the diagnosis of catheter-associated UTI, pyuria is not considered diagnostic of UTI in patients who require CIC.
Children with neurogenic bladder requiring CIC often have bacteriuria and often undergo urinalyses to determine if empirical antibiotics are warranted until urine culture results are available. “Although timely initiation of antibiotics can prevent the progression of infection and decrease the risk of renal scars, unnecessary antimicrobial agents contribute to the emergence of bacterial resistance,” Dr. Forster and her associates said.
So the researchers designed a study to find out if the presence of pyuria was associated with particular uropathogens in children with neurogenic bladders.
In an analysis of 2,420 urinalysis and urine culture results from EHRs between Jan.1, 2008, and Dec. 31, 2014, for patients aged 18 years and younger with neurogenic bladders requiring CIC, the most frequently isolated uropathogen was E. coli (37%), followed by Enterococcus species (14%), Klebsiella species (11%), and various other uropathogen species (38%).
In children needing CIC for neurogenic bladder, growth of Enterococcus species on urine culture was linked with lower odds of both microscopic pyuria (0.44) and leukocyte esterase (0.45).
“With these results, we suggest that the current markers of UTI evidenced on urinalysis and urine microscopy are insufficient for predicting bacteriuria in this population,” Dr. Forster and her colleagues said, leading to their recommendation to perform a culture in symptomatic children with neurogenic bladders irrespective of urinalysis results.
Dr. Forster received a research grant from the National Institutes of Health. The investigators said they had no relevant conflicts of interest.
SOURCE: Forster CS et al. Pediatrics. 2018;141(5):e20173006.
In the symptomatic child with neurogenic bladder at risk for urinary tract infection (UTI), urine culture should be performed regardless of the results of urinalysis, recommended Catherine S. Forster, MD, of Cincinnati Children’s Hospital Medical Center, and her associates.
In a general pediatric population, studies have found that certain uropathogens – such as Enterococcus species, Klebsiella species, and Pseudomonas aeruginosa – are less likely to be associated with pyuria than Escherichia coli.
According to the guidelines of the Infectious Disease Society of America guidelines for the diagnosis of catheter-associated UTI, pyuria is not considered diagnostic of UTI in patients who require CIC.
Children with neurogenic bladder requiring CIC often have bacteriuria and often undergo urinalyses to determine if empirical antibiotics are warranted until urine culture results are available. “Although timely initiation of antibiotics can prevent the progression of infection and decrease the risk of renal scars, unnecessary antimicrobial agents contribute to the emergence of bacterial resistance,” Dr. Forster and her associates said.
So the researchers designed a study to find out if the presence of pyuria was associated with particular uropathogens in children with neurogenic bladders.
In an analysis of 2,420 urinalysis and urine culture results from EHRs between Jan.1, 2008, and Dec. 31, 2014, for patients aged 18 years and younger with neurogenic bladders requiring CIC, the most frequently isolated uropathogen was E. coli (37%), followed by Enterococcus species (14%), Klebsiella species (11%), and various other uropathogen species (38%).
In children needing CIC for neurogenic bladder, growth of Enterococcus species on urine culture was linked with lower odds of both microscopic pyuria (0.44) and leukocyte esterase (0.45).
“With these results, we suggest that the current markers of UTI evidenced on urinalysis and urine microscopy are insufficient for predicting bacteriuria in this population,” Dr. Forster and her colleagues said, leading to their recommendation to perform a culture in symptomatic children with neurogenic bladders irrespective of urinalysis results.
Dr. Forster received a research grant from the National Institutes of Health. The investigators said they had no relevant conflicts of interest.
SOURCE: Forster CS et al. Pediatrics. 2018;141(5):e20173006.
FROM PEDIATRICS
Key clinical point:
Major finding: In children needing CIC for neurogenic bladder, growth of Enterococcus species on urine culture was linked with lower odds of both microscopic pyuria (0.44) and leukocyte esterase (0.45).
Study details: Assessment of 2,420 urinalyses and urine cultures in children with neurogenic bladders.
Disclosures: Dr. Forster received a research grant from the National Institutes of Health. The investigators said they had no relevant conflicts of interest.
Source: Forster CS et al. Pediatrics. 2018;141(5):e20173006.
Acute cardiorenal syndrome: Mechanisms and clinical implications
As the heart goes, so go the kidneys—and vice versa. Cardiac and renal function are intricately interdependent, and failure of either organ causes injury to the other in a vicious circle of worsening function.1
Here, we discuss acute cardiorenal syndrome, ie, acute exacerbation of heart failure leading to acute kidney injury, a common cause of hospitalization and admission to the intensive care unit. We examine its clinical definition, pathophysiology, hemodynamic derangements, clues that help in diagnosing it, and its treatment.
A GROUP OF LINKED DISORDERS
Two types of acute cardiac dysfunction
Although these definitions offer a good general description, further clarification of the nature of organ dysfunction is needed. Acute renal dysfunction can be unambiguously defined using the AKIN (Acute Kidney Injury Network) and RIFLE (risk, injury, failure, loss of kidney function, and end-stage kidney disease) classifications.3 Acute cardiac dysfunction, on the other hand, is an ambiguous term that encompasses 2 clinically and pathophysiologically distinct conditions: cardiogenic shock and acute heart failure.
Cardiogenic shock is characterized by a catastrophic compromise of cardiac pump function leading to global hypoperfusion severe enough to cause systemic organ damage.4 The cardiac index at which organs start to fail varies in different cases, but a value of less than 1.8 L/min/m2 is typically used to define cardiogenic shock.4
Acute heart failure, on the other hand, is defined as gradually or rapidly worsening signs and symptoms of congestive heart failure due to worsening pulmonary or systemic congestion.5 Hypervolemia is the hallmark of acute heart failure, whereas patients with cardiogenic shock may be hypervolemic, normovolemic, or hypovolemic. Although cardiac output may be mildly reduced in some cases of acute heart failure, systemic perfusion is enough to maintain organ function.
These two conditions cause renal injury by distinct mechanisms and have entirely different therapeutic implications. As we discuss later, reduced renal perfusion due to renal venous congestion is now believed to be the major hemodynamic mechanism of renal injury in acute heart failure. On the other hand, in cardiogenic shock, renal perfusion is reduced due to a critical decline of cardiac pump function.
The ideal definition of acute cardiorenal syndrome should describe a distinct pathophysiology of the syndrome and offer distinct therapeutic options that counteract it. Hence, we propose that renal injury from cardiogenic shock should not be included in its definition, an approach that has been adopted in some of the recent reviews as well.6 Our discussion of acute cardiorenal syndrome is restricted to renal injury caused by acute heart failure.
PATHOPHYSIOLOGY OF ACUTE CARDIORENAL SYNDROME
Multiple mechanisms have been implicated in the pathophysiology of cardiorenal syndrome.7,8
Sympathetic hyperactivity is a compensatory mechanism in heart failure and may be aggravated if cardiac output is further reduced. Its effects include constriction of afferent and efferent arterioles, causing reduced renal perfusion and increased tubular sodium and water reabsorption.7
The renin-angiotensin-aldosterone system is activated in patients with stable congestive heart failure and may be further stimulated in a state of reduced renal perfusion, which is a hallmark of acute cardiorenal syndrome. Its activation can cause further salt and water retention.
However, direct hemodynamic mechanisms likely play the most important role and have obvious diagnostic and therapeutic implications.
Elevated venous pressure, not reduced cardiac output, drives kidney injury
The classic view was that renal dysfunction in acute heart failure is caused by reduced renal blood flow due to failing cardiac pump function. Cardiac output may be reduced in acute heart failure for various reasons, such as atrial fibrillation, myocardial infarction, or other processes, but reduced cardiac output has a minimal role, if any, in the pathogenesis of renal injury in acute heart failure.
As evidence of this, acute heart failure is not always associated with reduced cardiac output.5 Even if the cardiac index (cardiac output divided by body surface area) is mildly reduced, renal blood flow is largely unaffected, thanks to effective renal autoregulatory mechanisms. Not until the mean arterial pressure falls below 70 mm Hg do these mechanisms fail and renal blood flow starts to drop.9 Hence, unless cardiac performance is compromised enough to cause cardiogenic shock, renal blood flow usually does not change significantly with mild reduction in cardiac output.
Hanberg et al10 performed a post hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial, in which 525 patients with advanced heart failure underwent pulmonary artery catheterization to measure their cardiac index. The authors found no association between the cardiac index and renal function in these patients.
How venous congestion impairs the kidney
In view of the current clinical evidence, the focus has shifted to renal venous congestion. According to Poiseuille’s law, blood flow through the kidneys depends on the pressure gradient—high pressure on the arterial side, low pressure on the venous side.8 Increased renal venous pressure causes reduced renal perfusion pressure, thereby affecting renal perfusion. This is now recognized as an important hemodynamic mechanism of acute cardiorenal syndrome.
Renal congestion can also affect renal function through indirect mechanisms. For example, it can cause renal interstitial edema that may then increase the intratubular pressure, thereby reducing the transglomerular pressure gradient.11
Firth et al,14 in experiments in animals, found that increasing the renal venous pressure above 18.75 mm Hg significantly reduced the glomerular filtration rate, which completely resolved when renal venous pressure was restored to basal levels.
Mullens et al,15 in a study of 145 patients admitted with acute heart failure, reported that 58 (40%) developed acute kidney injury. Pulmonary artery catheterization revealed that elevated central venous pressure, rather than reduced cardiac index, was the primary hemodynamic factor driving renal dysfunction.
DIAGNOSIS AND CLINICAL ASSESSMENT
Patients with acute cardiorenal syndrome present with clinical features of pulmonary or systemic congestion (or both) and acute kidney injury.
Elevated left-sided pressures are usually but not always associated with elevated right-sided pressures. In a study of 1,000 patients with advanced heart failure, a pulmonary capillary wedge pressure of 22 mm Hg or higher had a positive predictive value of 88% for a right atrial pressure of 10 mm Hg or higher.16 Hence, the clinical presentation may vary depending on the location (pulmonary, systemic, or both) and degree of congestion.
Symptoms of pulmonary congestion include worsening exertional dyspnea and orthopnea; bilateral crackles may be heard on physical examination if pulmonary edema is present.
Systemic congestion can cause significant peripheral edema and weight gain. Jugular venous distention may be noted. Oliguria may be present due to renal dysfunction; patients on maintenance diuretic therapy often note its lack of efficacy.
Signs of acute heart failure
Wang et al,17 in a meta-analysis of 22 studies, concluded that the features that most strongly suggested acute heart failure were:
- History of paroxysmal nocturnal dyspnea
- A third heart sound
- Evidence of pulmonary venous congestion on chest radiography.
Features that most strongly suggested the patient did not have acute heart failure were:
- Absence of exertional dyspnea
- Absence of rales
- Absence of radiographic evidence of cardiomegaly.
Patients may present without some of these classic clinical features, and the diagnosis of acute heart failure may be challenging. For example, even if left-sided pressures are very high, pulmonary edema may be absent because of pulmonary vascular remodeling in chronic heart failure.18 Pulmonary artery catheterization reveals elevated cardiac filling pressures and can be used to guide therapy, but clinical evidence argues against its routine use.19
Urine electrolytes (fractional excretion of sodium < 1% and fractional excretion of urea < 35%) often suggest a prerenal form of acute kidney injury, since the hemodynamic derangements in acute cardiorenal syndrome reduce renal perfusion.
Biomarkers of cell-cycle arrest such as urine insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinase 2 have recently been shown to identify patients with acute heart failure at risk of developing acute cardiorenal syndrome.20
Acute cardiorenal syndrome vs renal injury due to hypovolemia
The major alternative in the differential diagnosis of acute cardiorenal syndrome is renal injury due to hypovolemia. Patients with stable heart failure usually have mild hypervolemia at baseline, but they can become hypovolemic due to overaggressive diuretic therapy, severe diarrhea, or other causes.
Although the fluid status of patients in these 2 conditions is opposite, they can be difficult to distinguish. In both conditions, urine electrolytes suggest a prerenal acute kidney injury. A history of recent fluid losses or diuretic overuse may help identify hypovolemia. If available, analysis of the recent trend in weight can be vital in making the right diagnosis.
Misdiagnosis of acute cardiorenal syndrome as hypovolemia-induced acute kidney injury can be catastrophic. If volume depletion is erroneously judged to be the cause of acute kidney injury, fluid administration can further worsen both cardiac and renal function. This can perpetuate the vicious circle that is already in play. Lack of renal recovery may invite further fluid administration.
TREATMENT
Fluid removal with diuresis or ultrafiltration is the cornerstone of treatment. Other treatments such as inotropes are reserved for patients with resistant disease.
Diuretics
The goal of therapy in acute cardiorenal syndrome is to achieve aggressive diuresis, typically using intravenous diuretics. Loop diuretics are the most potent class of diuretics and are the first-line drugs for this purpose. Other classes of diuretics can be used in conjunction with loop diuretics; however, using them by themselves is neither effective nor recommended.
Resistance to diuretics at usual doses is common in patients with acute cardiorenal syndrome. Several mechanisms contribute to diuretic resistance in these patients.21
Oral bioavailability of diuretics may be reduced due to intestinal edema.
Diuretic pharmacokinetics are significantly deranged in cardiorenal syndrome. All diuretics except mineralocorticoid antagonists (ie, spironolactone and eplerenone) act on targets on the luminal side of renal tubules, but are highly protein-bound and are hence not filtered at the glomerulus. Loop diuretics, thiazides, and carbonic anhydrase inhibitors are secreted in the proximal convoluted tubule via the organic anion transporter,22 whereas epithelial sodium channel inhibitors (amiloride and triamterene) are secreted via the organic cation transporter 2.23 In renal dysfunction, various uremic toxins accumulate in the body and compete with diuretics for secretion into the proximal convoluted tubule via these transporters.24
Finally, activation of the sympathetic nervous system and renin-angiotensin-aldosterone system leads to increased tubular sodium and water retention, thereby also blunting the diuretic response.
Diuretic dosage. In patients whose creatinine clearance is less than 15 mL/min, only 10% to 20% as much loop diuretic is secreted into the renal tubule as in normal individuals.25 This effect warrants dose adjustment of diuretics during uremia.
Continuous infusion or bolus? Continuous infusion of loop diuretics is another strategy to optimize drug delivery. Compared with bolus therapy, continuous infusion provides more sustained and uniform drug delivery and prevents postdiuretic sodium retention.
The Diuretic Optimization Strategies Evaluation (DOSE) trial compared the efficacy and safety of continuous vs bolus furosemide therapy in 308 patients admitted with acute decompensated heart failure.26 There was no difference in symptom control or net fluid loss at 72 hours in either group. Other studies have shown more diuresis with continuous infusion than with a similarly dosed bolus regimen.27 However, definitive clinical evidence is lacking at this point to support routine use of continuous loop diuretic therapy.
Combination diuretic therapy. Sequential nephron blockade with combination diuretic therapy is an important therapeutic strategy against diuretic resistance. Notably, urine output-guided diuretic therapy has been shown to be superior to standard diuretic therapy.28 Such therapeutic protocols may employ combination diuretic therapy as a next step when the desired diuretic response is not obtained with high doses of loop diuretic monotherapy.
The desired diuretic response depends on the clinical situation. For example, in patients with severe congestion, we would like the net fluid output to be at least 2 to 3 L more than the fluid intake after the first 24 hours. Sometimes, patients in the intensive care unit are on several essential drug infusions, so that their net intake amounts to 1 to 2 L. In these patients, the desired urine output would be even more than in patients not on these drug infusions.
Loop diuretics block sodium reabsorption at the thick ascending loop of Henle. This disrupts the countercurrent exchange mechanism and reduces renal medullary interstitial osmolarity; these effects prevent water reabsorption. However, the unresorbed sodium can be taken up by the sodium-chloride cotransporter and the epithelial sodium channel in the distal nephron, thereby blunting the diuretic effect. This is the rationale for combining loop diuretics with thiazides or potassium-sparing diuretics.
Similarly, carbonic anhydrase inhibitors (eg, acetazolamide) reduce sodium reabsorption from the proximal convoluted tubule, but most of this sodium is then reabsorbed distally. Hence, the combination of a loop diuretic and acetazolamide can also have a synergistic diuretic effect.
The most popular combination is a loop diuretic plus a thiazide, although no large-scale placebo-controlled trials have been performed.29 Metolazone (a thiazidelike diuretic) is typically used due to its low cost and availability.30 Metolazone has also been shown to block sodium reabsorption at the proximal tubule, which may contribute to its synergistic effect. Chlorothiazide is available in an intravenous formulation and has a faster onset of action than metolazone. However, studies have failed to detect any benefit of one over the other.31
The potential benefit of combining a loop diuretic with acetazolamide is a lower tendency to develop metabolic alkalosis, a potential side effect of loop diuretics and thiazides. Although data are limited, a recent study showed that adding acetazolamide to bumetanide led to significantly increased natriuresis.32
In the Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) trial, adding spironolactone in high doses to usual therapy was not found to cause any significant change in N-terminal pro-B-type natriuretic peptide level or net urine output.33
Ultrafiltration
Venovenous ultrafiltration (or aquapheresis) employs an extracorporeal circuit, similar to the one used in hemodialysis, which removes iso-osmolar fluid at a fixed rate.34 Newer ultrafiltration systems are more portable, can be used with peripheral venous access, and require minimal nursing supervision.35
Although ultrafiltration seems an attractive alternative to diuresis in acute heart failure, studies have been inconclusive. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial compared ultrafiltration and diuresis in 188 patients with acute heart failure and acute cardiorenal syndrome.36 Diuresis, performed according to an algorithm, was found to be superior to ultrafiltration in terms of a bivariate end point of change in weight and change in serum creatinine level at 96 hours. However, the level of cystatin C is thought to be a more accurate indicator of renal function, and the change in cystatin C level from baseline did not differ between the two treatment groups. Also, the ultrafiltration rate was 200 mL per hour, which, some argue, may have been excessive and may have caused intravascular depletion.
Although the ideal rate of fluid removal is unknown, it should be individualized and adjusted based on the patient’s renal function, volume status, and hemodynamic status. The initial rate should be based on the degree of fluid overload and the anticipated plasma refill rate from the interstitial fluid.37 For example, a malnourished patient may have low serum oncotic pressure and hence have low plasma refill upon ultrafiltration. Disturbance of this delicate balance between the rates of ultrafiltration and plasma refill may lead to intravascular volume contraction.
In summary, although ultrafiltration is a valuable alternative to diuretics in resistant cases, its use as a primary decongestive therapy cannot be endorsed in view of the current data.
Inotropes
Inotropes such as dobutamine and milrinone are typically used in cases of cardiogenic shock to maintain organ perfusion. There is a physiologic rationale to using inotropes in acute cardiorenal syndrome as well, especially when the aforementioned strategies fail to overcome diuretic resistance.7
Inotropes increase cardiac output, improve renal blood flow, improve right ventricular output, and thereby relieve systemic congestion. These hemodynamic effects may improve renal perfusion and response to diuretics. However, clinical evidence to support this is lacking.
The Renal Optimization Strategies Evaluation (ROSE) trial enrolled 360 patients with acute heart failure and renal dysfunction. Adding dopamine in a low dose (2 μg/kg/min) to diuretic therapy had no significant effect on 72-hour cumulative urine output or renal function as measured by cystatin C levels.38 However, acute kidney injury was not identified in this trial, and the renal function of many of these patients may have been at its baseline when they were admitted. In other words, this trial did not necessarily include patients with acute kidney injury along with acute heart failure. Hence, it did not necessarily include patients with acute cardiorenal syndrome.
Vasodilators
Vasodilators such as nitroglycerin, sodium nitroprusside, and hydralazine are commonly used in patients with acute heart failure, although the clinical evidence supporting their use is weak.
Physiologically, arterial dilation reduces afterload and can help relieve pulmonary congestion, and venodilation increases capacitance and reduces preload. In theory, venodilators such as nitroglycerin can relieve renal venous congestion in patients with acute cardiorenal syndrome, thereby improving renal perfusion.
However, the use of vasodilators is often limited by their adverse effects, the most important being hypotension. This is especially relevant in light of recent data identifying reduction in blood pressure during treatment of acute heart failure as an independent risk factor for worsening renal function.39,40 It is important to note that in these studies, changes in cardiac index did not affect the propensity for developing worsening renal function. The precise mechanism of this finding is unclear but it is plausible that systemic vasodilation redistributes the cardiac output to nonrenal tissues, thereby overriding the renal autoregulatory mechanisms that are normally employed in low output states.
Preventive strategies
Various strategies can be used to prevent acute cardiorenal syndrome. An optimal outpatient diuretic regimen to avoid hypervolemia is essential. Patients with advanced congestive heart failure should be followed up closely in dedicated heart failure clinics until their diuretic regimen is optimized. Patients should be advised to check their weight on a regular basis and seek medical advice if they notice an increase in their weight or a reduction in their urine output.
TAKE-HOME POINTS
- A robust clinical definition of cardiorenal syndrome is lacking. Hence, recognition of this condition can be challenging.
- Volume overload is central to its pathogenesis, and accurate assessment of volume status is critical.
- Renal venous congestion is the major mechanism of type 1 cardiorenal syndrome.
- Misdiagnosis can have devastating consequences, as it may lead to an opposite therapeutic approach.
- Fluid removal by various strategies is the mainstay of treatment.
- Temporary inotropic support should be saved for the last resort.
- Geisberg C, Butler J. Addressing the challenges of cardiorenal syndrome. Cleve Clin J Med 2006; 73:485–491.
- House AA, Anand I, Bellomo R, et al. Definition and classification of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant 2010; 25:1416–1420.
- Chang CH, Lin CY, Tian YC, et al. Acute kidney injury classification: comparison of AKIN and RIFLE criteria. Shock 2010; 33:247-252.
- Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation 2008; 117:686–697.
- Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009; 53:557–573.
- ter Maaten JM, Valente MA, Damman K, et al. Diuretic response in acute heart failure—pathophysiology, evaluation, and therapy. Nat Rev Cardiol 2015; 12:184–192.
- Hatamizadeh P, Fonarow GC, Budoff MJ, Darabian S, Kovesdy CP, Kalantar-Zadeh K. Cardiorenal syndrome: pathophysiology and potential targets for clinical management. Nat Rev Nephrol 2013; 9:99–111.
- Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation 2010; 121:2592–2600.
- Burke M, Pabbidi MR, Farley J, et al. Molecular mechanisms of renal blood flow autoregulation. Curr Vasc Pharmacol 2014; 12:845–858.
- 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.
- Afsar B, Ortiz A, Covic A, et al. Focus on renal congestion in heart failure. Clin Kidney J 2016; 9:39–47.
- Verbrugge FH, Dupont M, Steels P, et al. Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J Am Coll Cardiol 2013; 62:485–495.
- 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.
- Firth JD, Raine AE, Ledingham JG. Raised venous pressure: a direct cause of renal sodium retention in oedema? Lancet 1988; 1:1033–1035.
- 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.
- Drazner MH, Hamilton MA, Fonarow G, et al. Relationship between right and left-sided filling pressures in 1000 patients with advanced heart failure. J Heart Lung Transplant 1999; 18:1126–1132.
- Wang CS, FitzGerald JM, Schulzer M, et al. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA 2005; 294:1944–1956.
- Gehlbach BK, Geppert E. The pulmonary manifestations of left heart failure. Chest 2004; 125:669–682.
- Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 2005; 294:1625–1633.
- Schanz M, Shi J , Wasser C , Alscher MD, Kimmel M. Urinary [TIMP-2] × [IGFBP7] for risk prediction of acute kidney injury in decompensated heart failure. Clin Cardiol 2017; doi.org/10.1002/clc.22683.
- Bowman BN, Nawarskas JJ, Anderson JR. Treating diuretic resistance: an overview. Cardiol Rev 2016; 24:256–260.
- Uwai Y, Saito H, Hashimoto Y, Inui KI. Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1. J Pharmacol Exp Ther 2000; 295:261–265.
- Hacker K, Maas R, Kornhuber J, et al. Substrate-dependent inhibition of the human organic cation transporter OCT2: a comparison of metformin with experimental substrates. PLoS One 2015; 10:e0136451.
- Schophuizen CM, Wilmer MJ, Jansen J, et al. Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter. Pflugers Arch 2013; 465:1701–1714.
- Brater DC. Diuretic therapy. N Engl J Med 1998; 339:387–395.
- Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011; 364:797–805.
- Thomson MR, Nappi JM, Dunn SP, Hollis IB, Rodgers JE, Van Bakel AB. Continuous versus intermittent infusion of furosemide in acute decompensated heart failure. J Card Fail 2010; 16:188–193.
- Grodin JL, Stevens SR, de Las Fuentes L, et al. Intensification of medication therapy for cardiorenal syndrome in acute decompensated heart failure. J Card Fail 2016; 22:26–32.
- Ng TM, Konopka E, Hyderi AF, et al. Comparison of bumetanide- and metolazone-based diuretic regimens to furosemide in acute heart failure. J Cardiovasc Pharmacol Ther 2013; 18:345–353.
- Sica DA. Metolazone and its role in edema management. Congest Heart Fail 2003; 9:100–105.
- Moranville MP, Choi S, Hogg J, Anderson AS, Rich JD. Comparison of metolazone versus chlorothiazide in acute decompensated heart failure with diuretic resistance. Cardiovasc Ther 2015; 33:42–49.
- Verbrugge FH, Dupont M, Bertrand PB, et al. Determinants and impact of the natriuretic response to diuretic therapy in heart failure with reduced ejection fraction and volume overload. Acta Cardiol 2015; 70:265–373.
- Butler J, Anstrom KJ, Felker GM, et al. Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial. JAMA Cardiol 2017 Jul 12. doi: 10.1001/jamacardio.2017.2198. [Epub ahead of print]
- Pourafshar N, Karimi A, Kazory A. Extracorporeal ultrafiltration therapy for acute decompensated heart failure. Expert Rev Cardiovasc Ther 2016; 14:5–13.
- Jaski BE, Ha J, Denys BG, et al. Peripherally inserted veno-venous ultrafiltration for rapid treatment of volume overloaded patients. J Card Fail 2003; 9:227–231.
- Jaski BE, Ha J, Denys BG, Lamba S, Trupp RJ, Abraham WT. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012; 367:2296–2304.
- Kazory A. Cardiorenal syndrome: ultrafiltration therapy for heart failure—trials and tribulations. Clin J Am Soc Nephrol 2013; 8:1816–1828.
- Chen HH, Anstrom KJ, Givertz MM, et al. 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.
- Testani JM, Coca SG, McCauley BD, et al. Impact of changes in blood pressure during the treatment of acute decompensated heart failure on renal and clinical outcomes. Eur J Heart Fail 2011; 13:877–884.
- Dupont M, Mullens W, Finucan M, et al. Determinants of dynamic changes in serum creatinine in acute decompensated heart failure: the importance of blood pressure reduction during treatment. Eur J Heart Fail 2013; 15:433–440.
As the heart goes, so go the kidneys—and vice versa. Cardiac and renal function are intricately interdependent, and failure of either organ causes injury to the other in a vicious circle of worsening function.1
Here, we discuss acute cardiorenal syndrome, ie, acute exacerbation of heart failure leading to acute kidney injury, a common cause of hospitalization and admission to the intensive care unit. We examine its clinical definition, pathophysiology, hemodynamic derangements, clues that help in diagnosing it, and its treatment.
A GROUP OF LINKED DISORDERS
Two types of acute cardiac dysfunction
Although these definitions offer a good general description, further clarification of the nature of organ dysfunction is needed. Acute renal dysfunction can be unambiguously defined using the AKIN (Acute Kidney Injury Network) and RIFLE (risk, injury, failure, loss of kidney function, and end-stage kidney disease) classifications.3 Acute cardiac dysfunction, on the other hand, is an ambiguous term that encompasses 2 clinically and pathophysiologically distinct conditions: cardiogenic shock and acute heart failure.
Cardiogenic shock is characterized by a catastrophic compromise of cardiac pump function leading to global hypoperfusion severe enough to cause systemic organ damage.4 The cardiac index at which organs start to fail varies in different cases, but a value of less than 1.8 L/min/m2 is typically used to define cardiogenic shock.4
Acute heart failure, on the other hand, is defined as gradually or rapidly worsening signs and symptoms of congestive heart failure due to worsening pulmonary or systemic congestion.5 Hypervolemia is the hallmark of acute heart failure, whereas patients with cardiogenic shock may be hypervolemic, normovolemic, or hypovolemic. Although cardiac output may be mildly reduced in some cases of acute heart failure, systemic perfusion is enough to maintain organ function.
These two conditions cause renal injury by distinct mechanisms and have entirely different therapeutic implications. As we discuss later, reduced renal perfusion due to renal venous congestion is now believed to be the major hemodynamic mechanism of renal injury in acute heart failure. On the other hand, in cardiogenic shock, renal perfusion is reduced due to a critical decline of cardiac pump function.
The ideal definition of acute cardiorenal syndrome should describe a distinct pathophysiology of the syndrome and offer distinct therapeutic options that counteract it. Hence, we propose that renal injury from cardiogenic shock should not be included in its definition, an approach that has been adopted in some of the recent reviews as well.6 Our discussion of acute cardiorenal syndrome is restricted to renal injury caused by acute heart failure.
PATHOPHYSIOLOGY OF ACUTE CARDIORENAL SYNDROME
Multiple mechanisms have been implicated in the pathophysiology of cardiorenal syndrome.7,8
Sympathetic hyperactivity is a compensatory mechanism in heart failure and may be aggravated if cardiac output is further reduced. Its effects include constriction of afferent and efferent arterioles, causing reduced renal perfusion and increased tubular sodium and water reabsorption.7
The renin-angiotensin-aldosterone system is activated in patients with stable congestive heart failure and may be further stimulated in a state of reduced renal perfusion, which is a hallmark of acute cardiorenal syndrome. Its activation can cause further salt and water retention.
However, direct hemodynamic mechanisms likely play the most important role and have obvious diagnostic and therapeutic implications.
Elevated venous pressure, not reduced cardiac output, drives kidney injury
The classic view was that renal dysfunction in acute heart failure is caused by reduced renal blood flow due to failing cardiac pump function. Cardiac output may be reduced in acute heart failure for various reasons, such as atrial fibrillation, myocardial infarction, or other processes, but reduced cardiac output has a minimal role, if any, in the pathogenesis of renal injury in acute heart failure.
As evidence of this, acute heart failure is not always associated with reduced cardiac output.5 Even if the cardiac index (cardiac output divided by body surface area) is mildly reduced, renal blood flow is largely unaffected, thanks to effective renal autoregulatory mechanisms. Not until the mean arterial pressure falls below 70 mm Hg do these mechanisms fail and renal blood flow starts to drop.9 Hence, unless cardiac performance is compromised enough to cause cardiogenic shock, renal blood flow usually does not change significantly with mild reduction in cardiac output.
Hanberg et al10 performed a post hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial, in which 525 patients with advanced heart failure underwent pulmonary artery catheterization to measure their cardiac index. The authors found no association between the cardiac index and renal function in these patients.
How venous congestion impairs the kidney
In view of the current clinical evidence, the focus has shifted to renal venous congestion. According to Poiseuille’s law, blood flow through the kidneys depends on the pressure gradient—high pressure on the arterial side, low pressure on the venous side.8 Increased renal venous pressure causes reduced renal perfusion pressure, thereby affecting renal perfusion. This is now recognized as an important hemodynamic mechanism of acute cardiorenal syndrome.
Renal congestion can also affect renal function through indirect mechanisms. For example, it can cause renal interstitial edema that may then increase the intratubular pressure, thereby reducing the transglomerular pressure gradient.11
Firth et al,14 in experiments in animals, found that increasing the renal venous pressure above 18.75 mm Hg significantly reduced the glomerular filtration rate, which completely resolved when renal venous pressure was restored to basal levels.
Mullens et al,15 in a study of 145 patients admitted with acute heart failure, reported that 58 (40%) developed acute kidney injury. Pulmonary artery catheterization revealed that elevated central venous pressure, rather than reduced cardiac index, was the primary hemodynamic factor driving renal dysfunction.
DIAGNOSIS AND CLINICAL ASSESSMENT
Patients with acute cardiorenal syndrome present with clinical features of pulmonary or systemic congestion (or both) and acute kidney injury.
Elevated left-sided pressures are usually but not always associated with elevated right-sided pressures. In a study of 1,000 patients with advanced heart failure, a pulmonary capillary wedge pressure of 22 mm Hg or higher had a positive predictive value of 88% for a right atrial pressure of 10 mm Hg or higher.16 Hence, the clinical presentation may vary depending on the location (pulmonary, systemic, or both) and degree of congestion.
Symptoms of pulmonary congestion include worsening exertional dyspnea and orthopnea; bilateral crackles may be heard on physical examination if pulmonary edema is present.
Systemic congestion can cause significant peripheral edema and weight gain. Jugular venous distention may be noted. Oliguria may be present due to renal dysfunction; patients on maintenance diuretic therapy often note its lack of efficacy.
Signs of acute heart failure
Wang et al,17 in a meta-analysis of 22 studies, concluded that the features that most strongly suggested acute heart failure were:
- History of paroxysmal nocturnal dyspnea
- A third heart sound
- Evidence of pulmonary venous congestion on chest radiography.
Features that most strongly suggested the patient did not have acute heart failure were:
- Absence of exertional dyspnea
- Absence of rales
- Absence of radiographic evidence of cardiomegaly.
Patients may present without some of these classic clinical features, and the diagnosis of acute heart failure may be challenging. For example, even if left-sided pressures are very high, pulmonary edema may be absent because of pulmonary vascular remodeling in chronic heart failure.18 Pulmonary artery catheterization reveals elevated cardiac filling pressures and can be used to guide therapy, but clinical evidence argues against its routine use.19
Urine electrolytes (fractional excretion of sodium < 1% and fractional excretion of urea < 35%) often suggest a prerenal form of acute kidney injury, since the hemodynamic derangements in acute cardiorenal syndrome reduce renal perfusion.
Biomarkers of cell-cycle arrest such as urine insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinase 2 have recently been shown to identify patients with acute heart failure at risk of developing acute cardiorenal syndrome.20
Acute cardiorenal syndrome vs renal injury due to hypovolemia
The major alternative in the differential diagnosis of acute cardiorenal syndrome is renal injury due to hypovolemia. Patients with stable heart failure usually have mild hypervolemia at baseline, but they can become hypovolemic due to overaggressive diuretic therapy, severe diarrhea, or other causes.
Although the fluid status of patients in these 2 conditions is opposite, they can be difficult to distinguish. In both conditions, urine electrolytes suggest a prerenal acute kidney injury. A history of recent fluid losses or diuretic overuse may help identify hypovolemia. If available, analysis of the recent trend in weight can be vital in making the right diagnosis.
Misdiagnosis of acute cardiorenal syndrome as hypovolemia-induced acute kidney injury can be catastrophic. If volume depletion is erroneously judged to be the cause of acute kidney injury, fluid administration can further worsen both cardiac and renal function. This can perpetuate the vicious circle that is already in play. Lack of renal recovery may invite further fluid administration.
TREATMENT
Fluid removal with diuresis or ultrafiltration is the cornerstone of treatment. Other treatments such as inotropes are reserved for patients with resistant disease.
Diuretics
The goal of therapy in acute cardiorenal syndrome is to achieve aggressive diuresis, typically using intravenous diuretics. Loop diuretics are the most potent class of diuretics and are the first-line drugs for this purpose. Other classes of diuretics can be used in conjunction with loop diuretics; however, using them by themselves is neither effective nor recommended.
Resistance to diuretics at usual doses is common in patients with acute cardiorenal syndrome. Several mechanisms contribute to diuretic resistance in these patients.21
Oral bioavailability of diuretics may be reduced due to intestinal edema.
Diuretic pharmacokinetics are significantly deranged in cardiorenal syndrome. All diuretics except mineralocorticoid antagonists (ie, spironolactone and eplerenone) act on targets on the luminal side of renal tubules, but are highly protein-bound and are hence not filtered at the glomerulus. Loop diuretics, thiazides, and carbonic anhydrase inhibitors are secreted in the proximal convoluted tubule via the organic anion transporter,22 whereas epithelial sodium channel inhibitors (amiloride and triamterene) are secreted via the organic cation transporter 2.23 In renal dysfunction, various uremic toxins accumulate in the body and compete with diuretics for secretion into the proximal convoluted tubule via these transporters.24
Finally, activation of the sympathetic nervous system and renin-angiotensin-aldosterone system leads to increased tubular sodium and water retention, thereby also blunting the diuretic response.
Diuretic dosage. In patients whose creatinine clearance is less than 15 mL/min, only 10% to 20% as much loop diuretic is secreted into the renal tubule as in normal individuals.25 This effect warrants dose adjustment of diuretics during uremia.
Continuous infusion or bolus? Continuous infusion of loop diuretics is another strategy to optimize drug delivery. Compared with bolus therapy, continuous infusion provides more sustained and uniform drug delivery and prevents postdiuretic sodium retention.
The Diuretic Optimization Strategies Evaluation (DOSE) trial compared the efficacy and safety of continuous vs bolus furosemide therapy in 308 patients admitted with acute decompensated heart failure.26 There was no difference in symptom control or net fluid loss at 72 hours in either group. Other studies have shown more diuresis with continuous infusion than with a similarly dosed bolus regimen.27 However, definitive clinical evidence is lacking at this point to support routine use of continuous loop diuretic therapy.
Combination diuretic therapy. Sequential nephron blockade with combination diuretic therapy is an important therapeutic strategy against diuretic resistance. Notably, urine output-guided diuretic therapy has been shown to be superior to standard diuretic therapy.28 Such therapeutic protocols may employ combination diuretic therapy as a next step when the desired diuretic response is not obtained with high doses of loop diuretic monotherapy.
The desired diuretic response depends on the clinical situation. For example, in patients with severe congestion, we would like the net fluid output to be at least 2 to 3 L more than the fluid intake after the first 24 hours. Sometimes, patients in the intensive care unit are on several essential drug infusions, so that their net intake amounts to 1 to 2 L. In these patients, the desired urine output would be even more than in patients not on these drug infusions.
Loop diuretics block sodium reabsorption at the thick ascending loop of Henle. This disrupts the countercurrent exchange mechanism and reduces renal medullary interstitial osmolarity; these effects prevent water reabsorption. However, the unresorbed sodium can be taken up by the sodium-chloride cotransporter and the epithelial sodium channel in the distal nephron, thereby blunting the diuretic effect. This is the rationale for combining loop diuretics with thiazides or potassium-sparing diuretics.
Similarly, carbonic anhydrase inhibitors (eg, acetazolamide) reduce sodium reabsorption from the proximal convoluted tubule, but most of this sodium is then reabsorbed distally. Hence, the combination of a loop diuretic and acetazolamide can also have a synergistic diuretic effect.
The most popular combination is a loop diuretic plus a thiazide, although no large-scale placebo-controlled trials have been performed.29 Metolazone (a thiazidelike diuretic) is typically used due to its low cost and availability.30 Metolazone has also been shown to block sodium reabsorption at the proximal tubule, which may contribute to its synergistic effect. Chlorothiazide is available in an intravenous formulation and has a faster onset of action than metolazone. However, studies have failed to detect any benefit of one over the other.31
The potential benefit of combining a loop diuretic with acetazolamide is a lower tendency to develop metabolic alkalosis, a potential side effect of loop diuretics and thiazides. Although data are limited, a recent study showed that adding acetazolamide to bumetanide led to significantly increased natriuresis.32
In the Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) trial, adding spironolactone in high doses to usual therapy was not found to cause any significant change in N-terminal pro-B-type natriuretic peptide level or net urine output.33
Ultrafiltration
Venovenous ultrafiltration (or aquapheresis) employs an extracorporeal circuit, similar to the one used in hemodialysis, which removes iso-osmolar fluid at a fixed rate.34 Newer ultrafiltration systems are more portable, can be used with peripheral venous access, and require minimal nursing supervision.35
Although ultrafiltration seems an attractive alternative to diuresis in acute heart failure, studies have been inconclusive. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial compared ultrafiltration and diuresis in 188 patients with acute heart failure and acute cardiorenal syndrome.36 Diuresis, performed according to an algorithm, was found to be superior to ultrafiltration in terms of a bivariate end point of change in weight and change in serum creatinine level at 96 hours. However, the level of cystatin C is thought to be a more accurate indicator of renal function, and the change in cystatin C level from baseline did not differ between the two treatment groups. Also, the ultrafiltration rate was 200 mL per hour, which, some argue, may have been excessive and may have caused intravascular depletion.
Although the ideal rate of fluid removal is unknown, it should be individualized and adjusted based on the patient’s renal function, volume status, and hemodynamic status. The initial rate should be based on the degree of fluid overload and the anticipated plasma refill rate from the interstitial fluid.37 For example, a malnourished patient may have low serum oncotic pressure and hence have low plasma refill upon ultrafiltration. Disturbance of this delicate balance between the rates of ultrafiltration and plasma refill may lead to intravascular volume contraction.
In summary, although ultrafiltration is a valuable alternative to diuretics in resistant cases, its use as a primary decongestive therapy cannot be endorsed in view of the current data.
Inotropes
Inotropes such as dobutamine and milrinone are typically used in cases of cardiogenic shock to maintain organ perfusion. There is a physiologic rationale to using inotropes in acute cardiorenal syndrome as well, especially when the aforementioned strategies fail to overcome diuretic resistance.7
Inotropes increase cardiac output, improve renal blood flow, improve right ventricular output, and thereby relieve systemic congestion. These hemodynamic effects may improve renal perfusion and response to diuretics. However, clinical evidence to support this is lacking.
The Renal Optimization Strategies Evaluation (ROSE) trial enrolled 360 patients with acute heart failure and renal dysfunction. Adding dopamine in a low dose (2 μg/kg/min) to diuretic therapy had no significant effect on 72-hour cumulative urine output or renal function as measured by cystatin C levels.38 However, acute kidney injury was not identified in this trial, and the renal function of many of these patients may have been at its baseline when they were admitted. In other words, this trial did not necessarily include patients with acute kidney injury along with acute heart failure. Hence, it did not necessarily include patients with acute cardiorenal syndrome.
Vasodilators
Vasodilators such as nitroglycerin, sodium nitroprusside, and hydralazine are commonly used in patients with acute heart failure, although the clinical evidence supporting their use is weak.
Physiologically, arterial dilation reduces afterload and can help relieve pulmonary congestion, and venodilation increases capacitance and reduces preload. In theory, venodilators such as nitroglycerin can relieve renal venous congestion in patients with acute cardiorenal syndrome, thereby improving renal perfusion.
However, the use of vasodilators is often limited by their adverse effects, the most important being hypotension. This is especially relevant in light of recent data identifying reduction in blood pressure during treatment of acute heart failure as an independent risk factor for worsening renal function.39,40 It is important to note that in these studies, changes in cardiac index did not affect the propensity for developing worsening renal function. The precise mechanism of this finding is unclear but it is plausible that systemic vasodilation redistributes the cardiac output to nonrenal tissues, thereby overriding the renal autoregulatory mechanisms that are normally employed in low output states.
Preventive strategies
Various strategies can be used to prevent acute cardiorenal syndrome. An optimal outpatient diuretic regimen to avoid hypervolemia is essential. Patients with advanced congestive heart failure should be followed up closely in dedicated heart failure clinics until their diuretic regimen is optimized. Patients should be advised to check their weight on a regular basis and seek medical advice if they notice an increase in their weight or a reduction in their urine output.
TAKE-HOME POINTS
- A robust clinical definition of cardiorenal syndrome is lacking. Hence, recognition of this condition can be challenging.
- Volume overload is central to its pathogenesis, and accurate assessment of volume status is critical.
- Renal venous congestion is the major mechanism of type 1 cardiorenal syndrome.
- Misdiagnosis can have devastating consequences, as it may lead to an opposite therapeutic approach.
- Fluid removal by various strategies is the mainstay of treatment.
- Temporary inotropic support should be saved for the last resort.
As the heart goes, so go the kidneys—and vice versa. Cardiac and renal function are intricately interdependent, and failure of either organ causes injury to the other in a vicious circle of worsening function.1
Here, we discuss acute cardiorenal syndrome, ie, acute exacerbation of heart failure leading to acute kidney injury, a common cause of hospitalization and admission to the intensive care unit. We examine its clinical definition, pathophysiology, hemodynamic derangements, clues that help in diagnosing it, and its treatment.
A GROUP OF LINKED DISORDERS
Two types of acute cardiac dysfunction
Although these definitions offer a good general description, further clarification of the nature of organ dysfunction is needed. Acute renal dysfunction can be unambiguously defined using the AKIN (Acute Kidney Injury Network) and RIFLE (risk, injury, failure, loss of kidney function, and end-stage kidney disease) classifications.3 Acute cardiac dysfunction, on the other hand, is an ambiguous term that encompasses 2 clinically and pathophysiologically distinct conditions: cardiogenic shock and acute heart failure.
Cardiogenic shock is characterized by a catastrophic compromise of cardiac pump function leading to global hypoperfusion severe enough to cause systemic organ damage.4 The cardiac index at which organs start to fail varies in different cases, but a value of less than 1.8 L/min/m2 is typically used to define cardiogenic shock.4
Acute heart failure, on the other hand, is defined as gradually or rapidly worsening signs and symptoms of congestive heart failure due to worsening pulmonary or systemic congestion.5 Hypervolemia is the hallmark of acute heart failure, whereas patients with cardiogenic shock may be hypervolemic, normovolemic, or hypovolemic. Although cardiac output may be mildly reduced in some cases of acute heart failure, systemic perfusion is enough to maintain organ function.
These two conditions cause renal injury by distinct mechanisms and have entirely different therapeutic implications. As we discuss later, reduced renal perfusion due to renal venous congestion is now believed to be the major hemodynamic mechanism of renal injury in acute heart failure. On the other hand, in cardiogenic shock, renal perfusion is reduced due to a critical decline of cardiac pump function.
The ideal definition of acute cardiorenal syndrome should describe a distinct pathophysiology of the syndrome and offer distinct therapeutic options that counteract it. Hence, we propose that renal injury from cardiogenic shock should not be included in its definition, an approach that has been adopted in some of the recent reviews as well.6 Our discussion of acute cardiorenal syndrome is restricted to renal injury caused by acute heart failure.
PATHOPHYSIOLOGY OF ACUTE CARDIORENAL SYNDROME
Multiple mechanisms have been implicated in the pathophysiology of cardiorenal syndrome.7,8
Sympathetic hyperactivity is a compensatory mechanism in heart failure and may be aggravated if cardiac output is further reduced. Its effects include constriction of afferent and efferent arterioles, causing reduced renal perfusion and increased tubular sodium and water reabsorption.7
The renin-angiotensin-aldosterone system is activated in patients with stable congestive heart failure and may be further stimulated in a state of reduced renal perfusion, which is a hallmark of acute cardiorenal syndrome. Its activation can cause further salt and water retention.
However, direct hemodynamic mechanisms likely play the most important role and have obvious diagnostic and therapeutic implications.
Elevated venous pressure, not reduced cardiac output, drives kidney injury
The classic view was that renal dysfunction in acute heart failure is caused by reduced renal blood flow due to failing cardiac pump function. Cardiac output may be reduced in acute heart failure for various reasons, such as atrial fibrillation, myocardial infarction, or other processes, but reduced cardiac output has a minimal role, if any, in the pathogenesis of renal injury in acute heart failure.
As evidence of this, acute heart failure is not always associated with reduced cardiac output.5 Even if the cardiac index (cardiac output divided by body surface area) is mildly reduced, renal blood flow is largely unaffected, thanks to effective renal autoregulatory mechanisms. Not until the mean arterial pressure falls below 70 mm Hg do these mechanisms fail and renal blood flow starts to drop.9 Hence, unless cardiac performance is compromised enough to cause cardiogenic shock, renal blood flow usually does not change significantly with mild reduction in cardiac output.
Hanberg et al10 performed a post hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness (ESCAPE) trial, in which 525 patients with advanced heart failure underwent pulmonary artery catheterization to measure their cardiac index. The authors found no association between the cardiac index and renal function in these patients.
How venous congestion impairs the kidney
In view of the current clinical evidence, the focus has shifted to renal venous congestion. According to Poiseuille’s law, blood flow through the kidneys depends on the pressure gradient—high pressure on the arterial side, low pressure on the venous side.8 Increased renal venous pressure causes reduced renal perfusion pressure, thereby affecting renal perfusion. This is now recognized as an important hemodynamic mechanism of acute cardiorenal syndrome.
Renal congestion can also affect renal function through indirect mechanisms. For example, it can cause renal interstitial edema that may then increase the intratubular pressure, thereby reducing the transglomerular pressure gradient.11
Firth et al,14 in experiments in animals, found that increasing the renal venous pressure above 18.75 mm Hg significantly reduced the glomerular filtration rate, which completely resolved when renal venous pressure was restored to basal levels.
Mullens et al,15 in a study of 145 patients admitted with acute heart failure, reported that 58 (40%) developed acute kidney injury. Pulmonary artery catheterization revealed that elevated central venous pressure, rather than reduced cardiac index, was the primary hemodynamic factor driving renal dysfunction.
DIAGNOSIS AND CLINICAL ASSESSMENT
Patients with acute cardiorenal syndrome present with clinical features of pulmonary or systemic congestion (or both) and acute kidney injury.
Elevated left-sided pressures are usually but not always associated with elevated right-sided pressures. In a study of 1,000 patients with advanced heart failure, a pulmonary capillary wedge pressure of 22 mm Hg or higher had a positive predictive value of 88% for a right atrial pressure of 10 mm Hg or higher.16 Hence, the clinical presentation may vary depending on the location (pulmonary, systemic, or both) and degree of congestion.
Symptoms of pulmonary congestion include worsening exertional dyspnea and orthopnea; bilateral crackles may be heard on physical examination if pulmonary edema is present.
Systemic congestion can cause significant peripheral edema and weight gain. Jugular venous distention may be noted. Oliguria may be present due to renal dysfunction; patients on maintenance diuretic therapy often note its lack of efficacy.
Signs of acute heart failure
Wang et al,17 in a meta-analysis of 22 studies, concluded that the features that most strongly suggested acute heart failure were:
- History of paroxysmal nocturnal dyspnea
- A third heart sound
- Evidence of pulmonary venous congestion on chest radiography.
Features that most strongly suggested the patient did not have acute heart failure were:
- Absence of exertional dyspnea
- Absence of rales
- Absence of radiographic evidence of cardiomegaly.
Patients may present without some of these classic clinical features, and the diagnosis of acute heart failure may be challenging. For example, even if left-sided pressures are very high, pulmonary edema may be absent because of pulmonary vascular remodeling in chronic heart failure.18 Pulmonary artery catheterization reveals elevated cardiac filling pressures and can be used to guide therapy, but clinical evidence argues against its routine use.19
Urine electrolytes (fractional excretion of sodium < 1% and fractional excretion of urea < 35%) often suggest a prerenal form of acute kidney injury, since the hemodynamic derangements in acute cardiorenal syndrome reduce renal perfusion.
Biomarkers of cell-cycle arrest such as urine insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinase 2 have recently been shown to identify patients with acute heart failure at risk of developing acute cardiorenal syndrome.20
Acute cardiorenal syndrome vs renal injury due to hypovolemia
The major alternative in the differential diagnosis of acute cardiorenal syndrome is renal injury due to hypovolemia. Patients with stable heart failure usually have mild hypervolemia at baseline, but they can become hypovolemic due to overaggressive diuretic therapy, severe diarrhea, or other causes.
Although the fluid status of patients in these 2 conditions is opposite, they can be difficult to distinguish. In both conditions, urine electrolytes suggest a prerenal acute kidney injury. A history of recent fluid losses or diuretic overuse may help identify hypovolemia. If available, analysis of the recent trend in weight can be vital in making the right diagnosis.
Misdiagnosis of acute cardiorenal syndrome as hypovolemia-induced acute kidney injury can be catastrophic. If volume depletion is erroneously judged to be the cause of acute kidney injury, fluid administration can further worsen both cardiac and renal function. This can perpetuate the vicious circle that is already in play. Lack of renal recovery may invite further fluid administration.
TREATMENT
Fluid removal with diuresis or ultrafiltration is the cornerstone of treatment. Other treatments such as inotropes are reserved for patients with resistant disease.
Diuretics
The goal of therapy in acute cardiorenal syndrome is to achieve aggressive diuresis, typically using intravenous diuretics. Loop diuretics are the most potent class of diuretics and are the first-line drugs for this purpose. Other classes of diuretics can be used in conjunction with loop diuretics; however, using them by themselves is neither effective nor recommended.
Resistance to diuretics at usual doses is common in patients with acute cardiorenal syndrome. Several mechanisms contribute to diuretic resistance in these patients.21
Oral bioavailability of diuretics may be reduced due to intestinal edema.
Diuretic pharmacokinetics are significantly deranged in cardiorenal syndrome. All diuretics except mineralocorticoid antagonists (ie, spironolactone and eplerenone) act on targets on the luminal side of renal tubules, but are highly protein-bound and are hence not filtered at the glomerulus. Loop diuretics, thiazides, and carbonic anhydrase inhibitors are secreted in the proximal convoluted tubule via the organic anion transporter,22 whereas epithelial sodium channel inhibitors (amiloride and triamterene) are secreted via the organic cation transporter 2.23 In renal dysfunction, various uremic toxins accumulate in the body and compete with diuretics for secretion into the proximal convoluted tubule via these transporters.24
Finally, activation of the sympathetic nervous system and renin-angiotensin-aldosterone system leads to increased tubular sodium and water retention, thereby also blunting the diuretic response.
Diuretic dosage. In patients whose creatinine clearance is less than 15 mL/min, only 10% to 20% as much loop diuretic is secreted into the renal tubule as in normal individuals.25 This effect warrants dose adjustment of diuretics during uremia.
Continuous infusion or bolus? Continuous infusion of loop diuretics is another strategy to optimize drug delivery. Compared with bolus therapy, continuous infusion provides more sustained and uniform drug delivery and prevents postdiuretic sodium retention.
The Diuretic Optimization Strategies Evaluation (DOSE) trial compared the efficacy and safety of continuous vs bolus furosemide therapy in 308 patients admitted with acute decompensated heart failure.26 There was no difference in symptom control or net fluid loss at 72 hours in either group. Other studies have shown more diuresis with continuous infusion than with a similarly dosed bolus regimen.27 However, definitive clinical evidence is lacking at this point to support routine use of continuous loop diuretic therapy.
Combination diuretic therapy. Sequential nephron blockade with combination diuretic therapy is an important therapeutic strategy against diuretic resistance. Notably, urine output-guided diuretic therapy has been shown to be superior to standard diuretic therapy.28 Such therapeutic protocols may employ combination diuretic therapy as a next step when the desired diuretic response is not obtained with high doses of loop diuretic monotherapy.
The desired diuretic response depends on the clinical situation. For example, in patients with severe congestion, we would like the net fluid output to be at least 2 to 3 L more than the fluid intake after the first 24 hours. Sometimes, patients in the intensive care unit are on several essential drug infusions, so that their net intake amounts to 1 to 2 L. In these patients, the desired urine output would be even more than in patients not on these drug infusions.
Loop diuretics block sodium reabsorption at the thick ascending loop of Henle. This disrupts the countercurrent exchange mechanism and reduces renal medullary interstitial osmolarity; these effects prevent water reabsorption. However, the unresorbed sodium can be taken up by the sodium-chloride cotransporter and the epithelial sodium channel in the distal nephron, thereby blunting the diuretic effect. This is the rationale for combining loop diuretics with thiazides or potassium-sparing diuretics.
Similarly, carbonic anhydrase inhibitors (eg, acetazolamide) reduce sodium reabsorption from the proximal convoluted tubule, but most of this sodium is then reabsorbed distally. Hence, the combination of a loop diuretic and acetazolamide can also have a synergistic diuretic effect.
The most popular combination is a loop diuretic plus a thiazide, although no large-scale placebo-controlled trials have been performed.29 Metolazone (a thiazidelike diuretic) is typically used due to its low cost and availability.30 Metolazone has also been shown to block sodium reabsorption at the proximal tubule, which may contribute to its synergistic effect. Chlorothiazide is available in an intravenous formulation and has a faster onset of action than metolazone. However, studies have failed to detect any benefit of one over the other.31
The potential benefit of combining a loop diuretic with acetazolamide is a lower tendency to develop metabolic alkalosis, a potential side effect of loop diuretics and thiazides. Although data are limited, a recent study showed that adding acetazolamide to bumetanide led to significantly increased natriuresis.32
In the Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) trial, adding spironolactone in high doses to usual therapy was not found to cause any significant change in N-terminal pro-B-type natriuretic peptide level or net urine output.33
Ultrafiltration
Venovenous ultrafiltration (or aquapheresis) employs an extracorporeal circuit, similar to the one used in hemodialysis, which removes iso-osmolar fluid at a fixed rate.34 Newer ultrafiltration systems are more portable, can be used with peripheral venous access, and require minimal nursing supervision.35
Although ultrafiltration seems an attractive alternative to diuresis in acute heart failure, studies have been inconclusive. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial compared ultrafiltration and diuresis in 188 patients with acute heart failure and acute cardiorenal syndrome.36 Diuresis, performed according to an algorithm, was found to be superior to ultrafiltration in terms of a bivariate end point of change in weight and change in serum creatinine level at 96 hours. However, the level of cystatin C is thought to be a more accurate indicator of renal function, and the change in cystatin C level from baseline did not differ between the two treatment groups. Also, the ultrafiltration rate was 200 mL per hour, which, some argue, may have been excessive and may have caused intravascular depletion.
Although the ideal rate of fluid removal is unknown, it should be individualized and adjusted based on the patient’s renal function, volume status, and hemodynamic status. The initial rate should be based on the degree of fluid overload and the anticipated plasma refill rate from the interstitial fluid.37 For example, a malnourished patient may have low serum oncotic pressure and hence have low plasma refill upon ultrafiltration. Disturbance of this delicate balance between the rates of ultrafiltration and plasma refill may lead to intravascular volume contraction.
In summary, although ultrafiltration is a valuable alternative to diuretics in resistant cases, its use as a primary decongestive therapy cannot be endorsed in view of the current data.
Inotropes
Inotropes such as dobutamine and milrinone are typically used in cases of cardiogenic shock to maintain organ perfusion. There is a physiologic rationale to using inotropes in acute cardiorenal syndrome as well, especially when the aforementioned strategies fail to overcome diuretic resistance.7
Inotropes increase cardiac output, improve renal blood flow, improve right ventricular output, and thereby relieve systemic congestion. These hemodynamic effects may improve renal perfusion and response to diuretics. However, clinical evidence to support this is lacking.
The Renal Optimization Strategies Evaluation (ROSE) trial enrolled 360 patients with acute heart failure and renal dysfunction. Adding dopamine in a low dose (2 μg/kg/min) to diuretic therapy had no significant effect on 72-hour cumulative urine output or renal function as measured by cystatin C levels.38 However, acute kidney injury was not identified in this trial, and the renal function of many of these patients may have been at its baseline when they were admitted. In other words, this trial did not necessarily include patients with acute kidney injury along with acute heart failure. Hence, it did not necessarily include patients with acute cardiorenal syndrome.
Vasodilators
Vasodilators such as nitroglycerin, sodium nitroprusside, and hydralazine are commonly used in patients with acute heart failure, although the clinical evidence supporting their use is weak.
Physiologically, arterial dilation reduces afterload and can help relieve pulmonary congestion, and venodilation increases capacitance and reduces preload. In theory, venodilators such as nitroglycerin can relieve renal venous congestion in patients with acute cardiorenal syndrome, thereby improving renal perfusion.
However, the use of vasodilators is often limited by their adverse effects, the most important being hypotension. This is especially relevant in light of recent data identifying reduction in blood pressure during treatment of acute heart failure as an independent risk factor for worsening renal function.39,40 It is important to note that in these studies, changes in cardiac index did not affect the propensity for developing worsening renal function. The precise mechanism of this finding is unclear but it is plausible that systemic vasodilation redistributes the cardiac output to nonrenal tissues, thereby overriding the renal autoregulatory mechanisms that are normally employed in low output states.
Preventive strategies
Various strategies can be used to prevent acute cardiorenal syndrome. An optimal outpatient diuretic regimen to avoid hypervolemia is essential. Patients with advanced congestive heart failure should be followed up closely in dedicated heart failure clinics until their diuretic regimen is optimized. Patients should be advised to check their weight on a regular basis and seek medical advice if they notice an increase in their weight or a reduction in their urine output.
TAKE-HOME POINTS
- A robust clinical definition of cardiorenal syndrome is lacking. Hence, recognition of this condition can be challenging.
- Volume overload is central to its pathogenesis, and accurate assessment of volume status is critical.
- Renal venous congestion is the major mechanism of type 1 cardiorenal syndrome.
- Misdiagnosis can have devastating consequences, as it may lead to an opposite therapeutic approach.
- Fluid removal by various strategies is the mainstay of treatment.
- Temporary inotropic support should be saved for the last resort.
- Geisberg C, Butler J. Addressing the challenges of cardiorenal syndrome. Cleve Clin J Med 2006; 73:485–491.
- House AA, Anand I, Bellomo R, et al. Definition and classification of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant 2010; 25:1416–1420.
- Chang CH, Lin CY, Tian YC, et al. Acute kidney injury classification: comparison of AKIN and RIFLE criteria. Shock 2010; 33:247-252.
- Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation 2008; 117:686–697.
- Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009; 53:557–573.
- ter Maaten JM, Valente MA, Damman K, et al. Diuretic response in acute heart failure—pathophysiology, evaluation, and therapy. Nat Rev Cardiol 2015; 12:184–192.
- Hatamizadeh P, Fonarow GC, Budoff MJ, Darabian S, Kovesdy CP, Kalantar-Zadeh K. Cardiorenal syndrome: pathophysiology and potential targets for clinical management. Nat Rev Nephrol 2013; 9:99–111.
- Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation 2010; 121:2592–2600.
- Burke M, Pabbidi MR, Farley J, et al. Molecular mechanisms of renal blood flow autoregulation. Curr Vasc Pharmacol 2014; 12:845–858.
- 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.
- Afsar B, Ortiz A, Covic A, et al. Focus on renal congestion in heart failure. Clin Kidney J 2016; 9:39–47.
- Verbrugge FH, Dupont M, Steels P, et al. Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J Am Coll Cardiol 2013; 62:485–495.
- 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.
- Firth JD, Raine AE, Ledingham JG. Raised venous pressure: a direct cause of renal sodium retention in oedema? Lancet 1988; 1:1033–1035.
- 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.
- Drazner MH, Hamilton MA, Fonarow G, et al. Relationship between right and left-sided filling pressures in 1000 patients with advanced heart failure. J Heart Lung Transplant 1999; 18:1126–1132.
- Wang CS, FitzGerald JM, Schulzer M, et al. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA 2005; 294:1944–1956.
- Gehlbach BK, Geppert E. The pulmonary manifestations of left heart failure. Chest 2004; 125:669–682.
- Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 2005; 294:1625–1633.
- Schanz M, Shi J , Wasser C , Alscher MD, Kimmel M. Urinary [TIMP-2] × [IGFBP7] for risk prediction of acute kidney injury in decompensated heart failure. Clin Cardiol 2017; doi.org/10.1002/clc.22683.
- Bowman BN, Nawarskas JJ, Anderson JR. Treating diuretic resistance: an overview. Cardiol Rev 2016; 24:256–260.
- Uwai Y, Saito H, Hashimoto Y, Inui KI. Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1. J Pharmacol Exp Ther 2000; 295:261–265.
- Hacker K, Maas R, Kornhuber J, et al. Substrate-dependent inhibition of the human organic cation transporter OCT2: a comparison of metformin with experimental substrates. PLoS One 2015; 10:e0136451.
- Schophuizen CM, Wilmer MJ, Jansen J, et al. Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter. Pflugers Arch 2013; 465:1701–1714.
- Brater DC. Diuretic therapy. N Engl J Med 1998; 339:387–395.
- Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011; 364:797–805.
- Thomson MR, Nappi JM, Dunn SP, Hollis IB, Rodgers JE, Van Bakel AB. Continuous versus intermittent infusion of furosemide in acute decompensated heart failure. J Card Fail 2010; 16:188–193.
- Grodin JL, Stevens SR, de Las Fuentes L, et al. Intensification of medication therapy for cardiorenal syndrome in acute decompensated heart failure. J Card Fail 2016; 22:26–32.
- Ng TM, Konopka E, Hyderi AF, et al. Comparison of bumetanide- and metolazone-based diuretic regimens to furosemide in acute heart failure. J Cardiovasc Pharmacol Ther 2013; 18:345–353.
- Sica DA. Metolazone and its role in edema management. Congest Heart Fail 2003; 9:100–105.
- Moranville MP, Choi S, Hogg J, Anderson AS, Rich JD. Comparison of metolazone versus chlorothiazide in acute decompensated heart failure with diuretic resistance. Cardiovasc Ther 2015; 33:42–49.
- Verbrugge FH, Dupont M, Bertrand PB, et al. Determinants and impact of the natriuretic response to diuretic therapy in heart failure with reduced ejection fraction and volume overload. Acta Cardiol 2015; 70:265–373.
- Butler J, Anstrom KJ, Felker GM, et al. Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial. JAMA Cardiol 2017 Jul 12. doi: 10.1001/jamacardio.2017.2198. [Epub ahead of print]
- Pourafshar N, Karimi A, Kazory A. Extracorporeal ultrafiltration therapy for acute decompensated heart failure. Expert Rev Cardiovasc Ther 2016; 14:5–13.
- Jaski BE, Ha J, Denys BG, et al. Peripherally inserted veno-venous ultrafiltration for rapid treatment of volume overloaded patients. J Card Fail 2003; 9:227–231.
- Jaski BE, Ha J, Denys BG, Lamba S, Trupp RJ, Abraham WT. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012; 367:2296–2304.
- Kazory A. Cardiorenal syndrome: ultrafiltration therapy for heart failure—trials and tribulations. Clin J Am Soc Nephrol 2013; 8:1816–1828.
- Chen HH, Anstrom KJ, Givertz MM, et al. 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.
- Testani JM, Coca SG, McCauley BD, et al. Impact of changes in blood pressure during the treatment of acute decompensated heart failure on renal and clinical outcomes. Eur J Heart Fail 2011; 13:877–884.
- Dupont M, Mullens W, Finucan M, et al. Determinants of dynamic changes in serum creatinine in acute decompensated heart failure: the importance of blood pressure reduction during treatment. Eur J Heart Fail 2013; 15:433–440.
- Geisberg C, Butler J. Addressing the challenges of cardiorenal syndrome. Cleve Clin J Med 2006; 73:485–491.
- House AA, Anand I, Bellomo R, et al. Definition and classification of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant 2010; 25:1416–1420.
- Chang CH, Lin CY, Tian YC, et al. Acute kidney injury classification: comparison of AKIN and RIFLE criteria. Shock 2010; 33:247-252.
- Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation 2008; 117:686–697.
- Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009; 53:557–573.
- ter Maaten JM, Valente MA, Damman K, et al. Diuretic response in acute heart failure—pathophysiology, evaluation, and therapy. Nat Rev Cardiol 2015; 12:184–192.
- Hatamizadeh P, Fonarow GC, Budoff MJ, Darabian S, Kovesdy CP, Kalantar-Zadeh K. Cardiorenal syndrome: pathophysiology and potential targets for clinical management. Nat Rev Nephrol 2013; 9:99–111.
- Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation 2010; 121:2592–2600.
- Burke M, Pabbidi MR, Farley J, et al. Molecular mechanisms of renal blood flow autoregulation. Curr Vasc Pharmacol 2014; 12:845–858.
- 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.
- Afsar B, Ortiz A, Covic A, et al. Focus on renal congestion in heart failure. Clin Kidney J 2016; 9:39–47.
- Verbrugge FH, Dupont M, Steels P, et al. Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J Am Coll Cardiol 2013; 62:485–495.
- 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.
- Firth JD, Raine AE, Ledingham JG. Raised venous pressure: a direct cause of renal sodium retention in oedema? Lancet 1988; 1:1033–1035.
- 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.
- Drazner MH, Hamilton MA, Fonarow G, et al. Relationship between right and left-sided filling pressures in 1000 patients with advanced heart failure. J Heart Lung Transplant 1999; 18:1126–1132.
- Wang CS, FitzGerald JM, Schulzer M, et al. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA 2005; 294:1944–1956.
- Gehlbach BK, Geppert E. The pulmonary manifestations of left heart failure. Chest 2004; 125:669–682.
- Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 2005; 294:1625–1633.
- Schanz M, Shi J , Wasser C , Alscher MD, Kimmel M. Urinary [TIMP-2] × [IGFBP7] for risk prediction of acute kidney injury in decompensated heart failure. Clin Cardiol 2017; doi.org/10.1002/clc.22683.
- Bowman BN, Nawarskas JJ, Anderson JR. Treating diuretic resistance: an overview. Cardiol Rev 2016; 24:256–260.
- Uwai Y, Saito H, Hashimoto Y, Inui KI. Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1. J Pharmacol Exp Ther 2000; 295:261–265.
- Hacker K, Maas R, Kornhuber J, et al. Substrate-dependent inhibition of the human organic cation transporter OCT2: a comparison of metformin with experimental substrates. PLoS One 2015; 10:e0136451.
- Schophuizen CM, Wilmer MJ, Jansen J, et al. Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter. Pflugers Arch 2013; 465:1701–1714.
- Brater DC. Diuretic therapy. N Engl J Med 1998; 339:387–395.
- Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011; 364:797–805.
- Thomson MR, Nappi JM, Dunn SP, Hollis IB, Rodgers JE, Van Bakel AB. Continuous versus intermittent infusion of furosemide in acute decompensated heart failure. J Card Fail 2010; 16:188–193.
- Grodin JL, Stevens SR, de Las Fuentes L, et al. Intensification of medication therapy for cardiorenal syndrome in acute decompensated heart failure. J Card Fail 2016; 22:26–32.
- Ng TM, Konopka E, Hyderi AF, et al. Comparison of bumetanide- and metolazone-based diuretic regimens to furosemide in acute heart failure. J Cardiovasc Pharmacol Ther 2013; 18:345–353.
- Sica DA. Metolazone and its role in edema management. Congest Heart Fail 2003; 9:100–105.
- Moranville MP, Choi S, Hogg J, Anderson AS, Rich JD. Comparison of metolazone versus chlorothiazide in acute decompensated heart failure with diuretic resistance. Cardiovasc Ther 2015; 33:42–49.
- Verbrugge FH, Dupont M, Bertrand PB, et al. Determinants and impact of the natriuretic response to diuretic therapy in heart failure with reduced ejection fraction and volume overload. Acta Cardiol 2015; 70:265–373.
- Butler J, Anstrom KJ, Felker GM, et al. Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial. JAMA Cardiol 2017 Jul 12. doi: 10.1001/jamacardio.2017.2198. [Epub ahead of print]
- Pourafshar N, Karimi A, Kazory A. Extracorporeal ultrafiltration therapy for acute decompensated heart failure. Expert Rev Cardiovasc Ther 2016; 14:5–13.
- Jaski BE, Ha J, Denys BG, et al. Peripherally inserted veno-venous ultrafiltration for rapid treatment of volume overloaded patients. J Card Fail 2003; 9:227–231.
- Jaski BE, Ha J, Denys BG, Lamba S, Trupp RJ, Abraham WT. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012; 367:2296–2304.
- Kazory A. Cardiorenal syndrome: ultrafiltration therapy for heart failure—trials and tribulations. Clin J Am Soc Nephrol 2013; 8:1816–1828.
- Chen HH, Anstrom KJ, Givertz MM, et al. 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.
- Testani JM, Coca SG, McCauley BD, et al. Impact of changes in blood pressure during the treatment of acute decompensated heart failure on renal and clinical outcomes. Eur J Heart Fail 2011; 13:877–884.
- Dupont M, Mullens W, Finucan M, et al. Determinants of dynamic changes in serum creatinine in acute decompensated heart failure: the importance of blood pressure reduction during treatment. Eur J Heart Fail 2013; 15:433–440.
KEY POINTS
- Acute cardiorenal syndrome is the acute worsening of renal function due to acute decompensated heart failure.
- The most important mechanism of acute cardiorenal syndrome is now believed to be systemic congestion leading to increased renal venous pressure, which in turn reduces renal perfusion.
- The major alternative in the differential diagnosis of acute cardiorenal syndrome is renal injury due to hypovolemia. Differentiating the 2 may be challenging if signs of systemic and pulmonary congestion are not obvious.
- Diuretic resistance is common in acute cardiorenal syndrome but may be overcome by using higher doses of diuretics and combinations of diuretics that block reabsorption at different segments of the renal tubules.
