A 60-year-old woman was referred for pharmacologic nuclear stress testing before treatment for breast cancer. She had hypertension, diabetes mellitus, coronary artery disease, and a remote history of stroke, and she was taking clonidine (Catapres), labetalol (Normodyne, Trandate), furosemide (Lasix), hydralazine, valsartan (Diovan), insulin, and the aspirin-dipyridamole combination Aggrenox. Her vital signs and electrocardiogram before the stress test were normal.

The stress test was started with a standard protocol of adenosine (Adenoscan) infused intravenously over 4 minutes. For the first 2 minutes, she was stable and had no symptoms, but then sinus pauses and second-degree atrioventricular block type 2 developed, after which her heart stopped beating (Figure 1). The infusion was immediately stopped, but she became unresponsive and remained pulseless.

Cardiopulmonary resuscitation was started, aminophylline 100 mg was given intravenously, and she regained a pulse and blood pressure within a few minutes. She was then transferred to the emergency room, where she returned to her baseline clinical and neurologic status without symptoms.

AN UNRECOGNIZED DRUG INTERACTION

Asystole occurred in this patient because of the interaction of intravenous adenosine with the dipyridamole in the medication Aggrenox. Although adenosine, given during pharmacologic stress testing, is known to interact with various medications, the potential for this interaction may be overlooked if the culprit is present in a combination drug. Aggrenox is commonly given for secondary stroke prevention and should be discontinued before pharmacologic nuclear stress testing.

Pharmacologic stress testing involves two commonly used stress agents, adenosine and regadenoson (Lexiscan), which cause coronary vasodilation through their action on A2A receptors in the heart. Coronary vasodilation results in flow heterogeneity in the region of a stenotic artery, which can be detected with nuclear perfusion agents. In addition, adenosine has a short-lived effect on the A1 receptors that block atrioventricular conduction.¹

Dipyridamole (Persantine) is contraindicated when either adenosine or regadenoson is used. Dipyridamole enhances the effect of exogenous and endogenous adenosine by inhibiting its uptake by cardiac cells, thus enhancing the action of these coronary vasodilators.² Atrioventricular block is common during adenosine stress testing but is transient because adenosine has a short half-life (< 10 seconds), and complete heart block or asystole, as seen in this patient, is rare. Giving intravenous adenosine or regadenoson to patients on dipyridamole may have a marked effect on adenosine receptors, so that profound bradycardia and even asystole leading to cardiac collapse may occur. No data are available on the specific interaction of dipyridamole and regadenoson.

Even though the pharmacodynamics of the interaction between dipyridamole and adenosine are known,³ few reports are available detailing serious adverse events. The contraindication to pharmacologic stress testing in patients taking dipyridamole is noted in the American Society of Nuclear Cardiology Guidelines for stress protocols,⁴ which advise discontinuing dipyridamole-containing drugs at least 48 hours before the use of adenosine or regadenoson. Similarly, the American Heart Association guidelines⁵ for the management of supraventricular tachycardia recommend an initial dose of 3 mg of adenosine rather than 6 mg in patients who have been taking dipyridamole.

The dose of aminophylline for reversing the adverse effects of adenosine or regadenoson is 50 to 250 mg intravenously over 30 to 60 seconds. But since these adverse effects are short-lived once the infusion is stopped, aminophylline is usually given only if the adverse effects are severe, as in this patient.

Pharmacologic nuclear stress testing with adenosine receptor agonists (eg, adenosine or regadenoson) is contraindicated in patients taking dipyridamole or the combination pill Aggrenox because of the potential for profound bradyarrhythmias or asystole.

A 60-year-old woman was referred for pharmacologic nuclear stress testing before treatment for breast cancer. She had hypertension, diabetes mellitus, coronary artery disease, and a remote history of stroke, and she was taking clonidine (Catapres), labetalol (Normodyne, Trandate), furosemide (Lasix), hydralazine, valsartan (Diovan), insulin, and the aspirin-dipyridamole combination Aggrenox. Her vital signs and electrocardiogram before the stress test were normal.

The stress test was started with a standard protocol of adenosine (Adenoscan) infused intravenously over 4 minutes. For the first 2 minutes, she was stable and had no symptoms, but then sinus pauses and second-degree atrioventricular block type 2 developed, after which her heart stopped beating (Figure 1). The infusion was immediately stopped, but she became unresponsive and remained pulseless.

Cardiopulmonary resuscitation was started, aminophylline 100 mg was given intravenously, and she regained a pulse and blood pressure within a few minutes. She was then transferred to the emergency room, where she returned to her baseline clinical and neurologic status without symptoms.

AN UNRECOGNIZED DRUG INTERACTION

Asystole occurred in this patient because of the interaction of intravenous adenosine with the dipyridamole in the medication Aggrenox. Although adenosine, given during pharmacologic stress testing, is known to interact with various medications, the potential for this interaction may be overlooked if the culprit is present in a combination drug. Aggrenox is commonly given for secondary stroke prevention and should be discontinued before pharmacologic nuclear stress testing.

Pharmacologic stress testing involves two commonly used stress agents, adenosine and regadenoson (Lexiscan), which cause coronary vasodilation through their action on A2A receptors in the heart. Coronary vasodilation results in flow heterogeneity in the region of a stenotic artery, which can be detected with nuclear perfusion agents. In addition, adenosine has a short-lived effect on the A1 receptors that block atrioventricular conduction.¹

Dipyridamole (Persantine) is contraindicated when either adenosine or regadenoson is used. Dipyridamole enhances the effect of exogenous and endogenous adenosine by inhibiting its uptake by cardiac cells, thus enhancing the action of these coronary vasodilators.² Atrioventricular block is common during adenosine stress testing but is transient because adenosine has a short half-life (< 10 seconds), and complete heart block or asystole, as seen in this patient, is rare. Giving intravenous adenosine or regadenoson to patients on dipyridamole may have a marked effect on adenosine receptors, so that profound bradycardia and even asystole leading to cardiac collapse may occur. No data are available on the specific interaction of dipyridamole and regadenoson.

Even though the pharmacodynamics of the interaction between dipyridamole and adenosine are known,³ few reports are available detailing serious adverse events. The contraindication to pharmacologic stress testing in patients taking dipyridamole is noted in the American Society of Nuclear Cardiology Guidelines for stress protocols,⁴ which advise discontinuing dipyridamole-containing drugs at least 48 hours before the use of adenosine or regadenoson. Similarly, the American Heart Association guidelines⁵ for the management of supraventricular tachycardia recommend an initial dose of 3 mg of adenosine rather than 6 mg in patients who have been taking dipyridamole.

The dose of aminophylline for reversing the adverse effects of adenosine or regadenoson is 50 to 250 mg intravenously over 30 to 60 seconds. But since these adverse effects are short-lived once the infusion is stopped, aminophylline is usually given only if the adverse effects are severe, as in this patient.

Pharmacologic nuclear stress testing with adenosine receptor agonists (eg, adenosine or regadenoson) is contraindicated in patients taking dipyridamole or the combination pill Aggrenox because of the potential for profound bradyarrhythmias or asystole.

A 60-year-old woman was referred for pharmacologic nuclear stress testing before treatment for breast cancer. She had hypertension, diabetes mellitus, coronary artery disease, and a remote history of stroke, and she was taking clonidine (Catapres), labetalol (Normodyne, Trandate), furosemide (Lasix), hydralazine, valsartan (Diovan), insulin, and the aspirin-dipyridamole combination Aggrenox. Her vital signs and electrocardiogram before the stress test were normal.

The stress test was started with a standard protocol of adenosine (Adenoscan) infused intravenously over 4 minutes. For the first 2 minutes, she was stable and had no symptoms, but then sinus pauses and second-degree atrioventricular block type 2 developed, after which her heart stopped beating (Figure 1). The infusion was immediately stopped, but she became unresponsive and remained pulseless.

Cardiopulmonary resuscitation was started, aminophylline 100 mg was given intravenously, and she regained a pulse and blood pressure within a few minutes. She was then transferred to the emergency room, where she returned to her baseline clinical and neurologic status without symptoms.

AN UNRECOGNIZED DRUG INTERACTION

Asystole occurred in this patient because of the interaction of intravenous adenosine with the dipyridamole in the medication Aggrenox. Although adenosine, given during pharmacologic stress testing, is known to interact with various medications, the potential for this interaction may be overlooked if the culprit is present in a combination drug. Aggrenox is commonly given for secondary stroke prevention and should be discontinued before pharmacologic nuclear stress testing.

Pharmacologic stress testing involves two commonly used stress agents, adenosine and regadenoson (Lexiscan), which cause coronary vasodilation through their action on A2A receptors in the heart. Coronary vasodilation results in flow heterogeneity in the region of a stenotic artery, which can be detected with nuclear perfusion agents. In addition, adenosine has a short-lived effect on the A1 receptors that block atrioventricular conduction.¹

Dipyridamole (Persantine) is contraindicated when either adenosine or regadenoson is used. Dipyridamole enhances the effect of exogenous and endogenous adenosine by inhibiting its uptake by cardiac cells, thus enhancing the action of these coronary vasodilators.² Atrioventricular block is common during adenosine stress testing but is transient because adenosine has a short half-life (< 10 seconds), and complete heart block or asystole, as seen in this patient, is rare. Giving intravenous adenosine or regadenoson to patients on dipyridamole may have a marked effect on adenosine receptors, so that profound bradycardia and even asystole leading to cardiac collapse may occur. No data are available on the specific interaction of dipyridamole and regadenoson.

Even though the pharmacodynamics of the interaction between dipyridamole and adenosine are known,³ few reports are available detailing serious adverse events. The contraindication to pharmacologic stress testing in patients taking dipyridamole is noted in the American Society of Nuclear Cardiology Guidelines for stress protocols,⁴ which advise discontinuing dipyridamole-containing drugs at least 48 hours before the use of adenosine or regadenoson. Similarly, the American Heart Association guidelines⁵ for the management of supraventricular tachycardia recommend an initial dose of 3 mg of adenosine rather than 6 mg in patients who have been taking dipyridamole.

The dose of aminophylline for reversing the adverse effects of adenosine or regadenoson is 50 to 250 mg intravenously over 30 to 60 seconds. But since these adverse effects are short-lived once the infusion is stopped, aminophylline is usually given only if the adverse effects are severe, as in this patient.

Pharmacologic nuclear stress testing with adenosine receptor agonists (eg, adenosine or regadenoson) is contraindicated in patients taking dipyridamole or the combination pill Aggrenox because of the potential for profound bradyarrhythmias or asystole.

Randomized controlled trials have unequivocally shown that lowering levels of low-density lipoprotein cholesterol (LDL-C) with statins reduces the rate of cardiovascular events.^1–3 Yet many patients still have heart attacks even though they are on statins, so the search continues for other agents to lower cardiovascular risk.⁴

Niacin has been used for its lipid-modifying effects for more than 50 years. In addition to being the most potent agent for raising the level of high-density lipoprotein cholesterol (HDL-C), niacin decreases the atherogenic lipids triglyceride, LDL-C, and lipoprotein (a)⁵ and can be very effective in treating mixed dyslipidemias such as hypertriglyceridemia and low HDL-C. This is particularly important for the challenging patients seen in preventive cardiology clinics.

In 1986, before statins were available, the Coronary Drug Project⁶ showed that immediate-release forms of niacin lowered the rates of nonfatal myocardial infarction and long-term mortality. Later, imaging studies demonstrated that niacin slows progression of carotid intima-medial thickness and coronary atherosclerosis.^7–9 Furthermore, meta-analyses of these studies suggest cardiovascular benefit for patients at high vascular risk.¹⁰

However, niacin is difficult to use in clinical practice. The near-ubiquitous experience of flushing has limited our ability to give doses high enough to modify plasma lipid levels and rates of clinical events.

To try to mitigate this side effect, investigators developed extended-release formulations and agents such as laropiprant, a chemical antagonist of the interaction between niacin and epidermal prostanoid receptors implicated as the mechanism behind flushing. Although these innovations do not eliminate flushing, they reduce it, and thus have prompted hopes of using niacin more widely in statin-treated patients. However, whether widespread use of niacin on a background of statin therapy would have an impact on cardiovascular events remained to be established.

WHAT WE HAVE LEARNED LATELY ABOUT NIACIN?

More-tolerable formulations of niacin prompted interest in its potential to lower the residual cardiovascular risk observed in statin-treated patients. Two large clinical trials attempted to determine its impact on cardiovascular events in the contemporary era.

The AIM-HIGH study

In the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) study,¹¹ 3,414 patients at high vascular risk with low HDL-C were treated with niacin or placebo. The trial was stopped early because of no evidence of clinical benefit with niacin and because of concern about an increased risk of stroke, a finding ultimately not observed on a complete review of the data.

I reviewed the limitations of this study earlier in this journal.¹² The study was small, use of low-dose niacin was allowed in the placebo group, and physicians could treat high LDL-C as they saw fit during the study, so that more patients in the placebo group received high-dose statin therapy and ezetimibe. All of this likely limited the study’s ability to measure the clinical impact of niacin. As a result, this study was not a pure evaluation of the benefits of niacin vs placebo in addition to standard medical therapy. Hope remained that a much larger study with greater statistical power and a simpler design would provide a definitive answer.

HPS2–THRIVE

The Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), with more than 40,000 patients, was the largest cardiovascular outcomes trial of lipid-modifying therapy to date.¹³ Its purpose was to determine whether extended-release niacin plus the prostanoid receptor antagonist laropiprant would reduce the rate of cardiovascular events in patients with clinically established vascular disease.

Patients age 50 to 80 with a history of myocardial infarction, ischemic stroke, transient ischemic attack, peripheral arterial disease, or diabetes with other forms of coronary heart disease received a standardized LDL-C-lowering regimen with simvastatin 40 mg daily, with or without ezetimibe 10 mg daily, to achieve a total cholesterol target of 135 mg/dL or below. All were treated with extended-release niacin 2 g daily plus laropiprant 40 mg daily for 1 month to assess compliance. They were then randomized to treatment with extended-release niacin 2 g plus laropiprant 40 mg or placebo daily. At baseline, the mean lipid values were LDL-C 63 mg/dL, HDL-C 44 mg/dL, and triglyceride 125 mg/dL.

Before the end of the trial, the investigators reported a high rate of myopathy-related adverse events in the niacin group, particularly in Chinese patients.¹³ This contributed to a high dropout rate in the niacin group, in which one quarter of patients stopped taking the study drug.

During the study, niacin lowered the LDL-C level by a mean of 10 mg/dL, lowered triglycerides by 33 mg/dL, and raised HDL-C by 6 mg/dL. On the basis of previous observational studies and randomized clinical trials, the authors calculated that such lipid changes should translate to a 10% to 15% reduction in vascular events. However, no reduction was observed in the primary end point of major vascular events, which included nonfatal myocardial infarction, coronary death, any nonfatal or fatal stroke, and any arterial revascularization, including amputation. The rates were 15% in the placebo group vs 14.5% in the niacin group (P = .96).

A statistically significant 10% reduction in the rate of arterial revascularization was observed in the niacin group, perhaps consistent with earlier observations of an antiatherosclerotic effect.

Subgroup analyses, while always to be interpreted with caution, also provide some interesting findings for consideration. A significant interaction was observed between treatment and baseline LDL-C, with those in the highest LDL-C tertile (> 77 mg/dL) demonstrating a potential reduction in the primary end point with niacin treatment. In addition, a trend toward potential benefit with niacin in patients in Europe, but not in China, was also observed; however, this just failed to meet statistical significance.

HPS2-THRIVE provided important information about the safety of extended-release niacin in combination with laropiprant. The niacin group experienced higher rates not only of myopathy but also of diabetic complications, new diagnosis of diabetes, serious infections, and bleeding. Whether these observations were related to niacin or to laropiprant is unknown. In fact, recent reports suggest laropiprant has adverse effects that may have substantially reduced the potential benefits of niacin.

The overall conclusion of HPS2-THRIVE was that there was no widespread clinical benefit from the combination of niacin and laropiprant in statin-treated patients with vascular disease, and that there was a potential increase in adverse events. Accordingly, the combination treatment will not be integrated into clinical practice.

WHERE DO WE GO FROM HERE?

Despite their limitations, these two large trials suggest that niacin does not reduce cardiovascular risk in patients already receiving a statin.

Might some subgroups be more likely to benefit from niacin? The finding of potential benefit in patients with higher baseline LDL-C suggests this may be true. At baseline, the HPS2-THRIVE patients had very good LDL-C control and had HDL-C levels within the normal range, not necessarily reflecting the patients we see in daily practice, who require more effective reductions in vascular risk. Furthermore, failure of both fibrates and niacin to reduce risk may have reflected the attempt to study these agents in broad patient populations as opposed to focusing on specific cohorts, such as patients with mixed dyslipidemia, for which there is suggestion of benefit.¹⁴ It seems unlikely that such a study will be performed in a clinical setting in which niacin may be of greater utility. The experience of adverse events would appear to make that a certainty.

For now, niacin will remain useful in lipid clinics for managing refractory dyslipidemia. Specifically, its ability to lower triglyceride and lipoprotein (a) and to raise HDL-C will continue to be of interest in the clinical management of patients and in the formulation of treatment guidelines. Another reason to use it is to lower LDL-C in patients who cannot tolerate statins. However, there is currently no evidence from randomized controlled trials to support its broader use.

While registry information could provide some sense of real-world effects of niacin’s use, this is a suboptimal way to evaluate the potential efficacy of a therapy—randomized controlled trials are the gold standard. The major flaws of both of the large trials of niacin point out the need for thoughtful study design to avoid incorrectly dismissing potentially useful therapies. But for now, the renaissance of niacin as a means of lowering cardiovascular risk is only wishful thinking.

Randomized controlled trials have unequivocally shown that lowering levels of low-density lipoprotein cholesterol (LDL-C) with statins reduces the rate of cardiovascular events.^1–3 Yet many patients still have heart attacks even though they are on statins, so the search continues for other agents to lower cardiovascular risk.⁴

Niacin has been used for its lipid-modifying effects for more than 50 years. In addition to being the most potent agent for raising the level of high-density lipoprotein cholesterol (HDL-C), niacin decreases the atherogenic lipids triglyceride, LDL-C, and lipoprotein (a)⁵ and can be very effective in treating mixed dyslipidemias such as hypertriglyceridemia and low HDL-C. This is particularly important for the challenging patients seen in preventive cardiology clinics.

In 1986, before statins were available, the Coronary Drug Project⁶ showed that immediate-release forms of niacin lowered the rates of nonfatal myocardial infarction and long-term mortality. Later, imaging studies demonstrated that niacin slows progression of carotid intima-medial thickness and coronary atherosclerosis.^7–9 Furthermore, meta-analyses of these studies suggest cardiovascular benefit for patients at high vascular risk.¹⁰

However, niacin is difficult to use in clinical practice. The near-ubiquitous experience of flushing has limited our ability to give doses high enough to modify plasma lipid levels and rates of clinical events.

To try to mitigate this side effect, investigators developed extended-release formulations and agents such as laropiprant, a chemical antagonist of the interaction between niacin and epidermal prostanoid receptors implicated as the mechanism behind flushing. Although these innovations do not eliminate flushing, they reduce it, and thus have prompted hopes of using niacin more widely in statin-treated patients. However, whether widespread use of niacin on a background of statin therapy would have an impact on cardiovascular events remained to be established.

WHAT WE HAVE LEARNED LATELY ABOUT NIACIN?

More-tolerable formulations of niacin prompted interest in its potential to lower the residual cardiovascular risk observed in statin-treated patients. Two large clinical trials attempted to determine its impact on cardiovascular events in the contemporary era.

The AIM-HIGH study

In the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) study,¹¹ 3,414 patients at high vascular risk with low HDL-C were treated with niacin or placebo. The trial was stopped early because of no evidence of clinical benefit with niacin and because of concern about an increased risk of stroke, a finding ultimately not observed on a complete review of the data.

I reviewed the limitations of this study earlier in this journal.¹² The study was small, use of low-dose niacin was allowed in the placebo group, and physicians could treat high LDL-C as they saw fit during the study, so that more patients in the placebo group received high-dose statin therapy and ezetimibe. All of this likely limited the study’s ability to measure the clinical impact of niacin. As a result, this study was not a pure evaluation of the benefits of niacin vs placebo in addition to standard medical therapy. Hope remained that a much larger study with greater statistical power and a simpler design would provide a definitive answer.

HPS2–THRIVE

The Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), with more than 40,000 patients, was the largest cardiovascular outcomes trial of lipid-modifying therapy to date.¹³ Its purpose was to determine whether extended-release niacin plus the prostanoid receptor antagonist laropiprant would reduce the rate of cardiovascular events in patients with clinically established vascular disease.

Patients age 50 to 80 with a history of myocardial infarction, ischemic stroke, transient ischemic attack, peripheral arterial disease, or diabetes with other forms of coronary heart disease received a standardized LDL-C-lowering regimen with simvastatin 40 mg daily, with or without ezetimibe 10 mg daily, to achieve a total cholesterol target of 135 mg/dL or below. All were treated with extended-release niacin 2 g daily plus laropiprant 40 mg daily for 1 month to assess compliance. They were then randomized to treatment with extended-release niacin 2 g plus laropiprant 40 mg or placebo daily. At baseline, the mean lipid values were LDL-C 63 mg/dL, HDL-C 44 mg/dL, and triglyceride 125 mg/dL.

Before the end of the trial, the investigators reported a high rate of myopathy-related adverse events in the niacin group, particularly in Chinese patients.¹³ This contributed to a high dropout rate in the niacin group, in which one quarter of patients stopped taking the study drug.

During the study, niacin lowered the LDL-C level by a mean of 10 mg/dL, lowered triglycerides by 33 mg/dL, and raised HDL-C by 6 mg/dL. On the basis of previous observational studies and randomized clinical trials, the authors calculated that such lipid changes should translate to a 10% to 15% reduction in vascular events. However, no reduction was observed in the primary end point of major vascular events, which included nonfatal myocardial infarction, coronary death, any nonfatal or fatal stroke, and any arterial revascularization, including amputation. The rates were 15% in the placebo group vs 14.5% in the niacin group (P = .96).

A statistically significant 10% reduction in the rate of arterial revascularization was observed in the niacin group, perhaps consistent with earlier observations of an antiatherosclerotic effect.

Subgroup analyses, while always to be interpreted with caution, also provide some interesting findings for consideration. A significant interaction was observed between treatment and baseline LDL-C, with those in the highest LDL-C tertile (> 77 mg/dL) demonstrating a potential reduction in the primary end point with niacin treatment. In addition, a trend toward potential benefit with niacin in patients in Europe, but not in China, was also observed; however, this just failed to meet statistical significance.

HPS2-THRIVE provided important information about the safety of extended-release niacin in combination with laropiprant. The niacin group experienced higher rates not only of myopathy but also of diabetic complications, new diagnosis of diabetes, serious infections, and bleeding. Whether these observations were related to niacin or to laropiprant is unknown. In fact, recent reports suggest laropiprant has adverse effects that may have substantially reduced the potential benefits of niacin.

The overall conclusion of HPS2-THRIVE was that there was no widespread clinical benefit from the combination of niacin and laropiprant in statin-treated patients with vascular disease, and that there was a potential increase in adverse events. Accordingly, the combination treatment will not be integrated into clinical practice.

WHERE DO WE GO FROM HERE?

Despite their limitations, these two large trials suggest that niacin does not reduce cardiovascular risk in patients already receiving a statin.

Might some subgroups be more likely to benefit from niacin? The finding of potential benefit in patients with higher baseline LDL-C suggests this may be true. At baseline, the HPS2-THRIVE patients had very good LDL-C control and had HDL-C levels within the normal range, not necessarily reflecting the patients we see in daily practice, who require more effective reductions in vascular risk. Furthermore, failure of both fibrates and niacin to reduce risk may have reflected the attempt to study these agents in broad patient populations as opposed to focusing on specific cohorts, such as patients with mixed dyslipidemia, for which there is suggestion of benefit.¹⁴ It seems unlikely that such a study will be performed in a clinical setting in which niacin may be of greater utility. The experience of adverse events would appear to make that a certainty.

For now, niacin will remain useful in lipid clinics for managing refractory dyslipidemia. Specifically, its ability to lower triglyceride and lipoprotein (a) and to raise HDL-C will continue to be of interest in the clinical management of patients and in the formulation of treatment guidelines. Another reason to use it is to lower LDL-C in patients who cannot tolerate statins. However, there is currently no evidence from randomized controlled trials to support its broader use.

While registry information could provide some sense of real-world effects of niacin’s use, this is a suboptimal way to evaluate the potential efficacy of a therapy—randomized controlled trials are the gold standard. The major flaws of both of the large trials of niacin point out the need for thoughtful study design to avoid incorrectly dismissing potentially useful therapies. But for now, the renaissance of niacin as a means of lowering cardiovascular risk is only wishful thinking.

Randomized controlled trials have unequivocally shown that lowering levels of low-density lipoprotein cholesterol (LDL-C) with statins reduces the rate of cardiovascular events.^1–3 Yet many patients still have heart attacks even though they are on statins, so the search continues for other agents to lower cardiovascular risk.⁴

Niacin has been used for its lipid-modifying effects for more than 50 years. In addition to being the most potent agent for raising the level of high-density lipoprotein cholesterol (HDL-C), niacin decreases the atherogenic lipids triglyceride, LDL-C, and lipoprotein (a)⁵ and can be very effective in treating mixed dyslipidemias such as hypertriglyceridemia and low HDL-C. This is particularly important for the challenging patients seen in preventive cardiology clinics.

In 1986, before statins were available, the Coronary Drug Project⁶ showed that immediate-release forms of niacin lowered the rates of nonfatal myocardial infarction and long-term mortality. Later, imaging studies demonstrated that niacin slows progression of carotid intima-medial thickness and coronary atherosclerosis.^7–9 Furthermore, meta-analyses of these studies suggest cardiovascular benefit for patients at high vascular risk.¹⁰

However, niacin is difficult to use in clinical practice. The near-ubiquitous experience of flushing has limited our ability to give doses high enough to modify plasma lipid levels and rates of clinical events.

To try to mitigate this side effect, investigators developed extended-release formulations and agents such as laropiprant, a chemical antagonist of the interaction between niacin and epidermal prostanoid receptors implicated as the mechanism behind flushing. Although these innovations do not eliminate flushing, they reduce it, and thus have prompted hopes of using niacin more widely in statin-treated patients. However, whether widespread use of niacin on a background of statin therapy would have an impact on cardiovascular events remained to be established.

WHAT WE HAVE LEARNED LATELY ABOUT NIACIN?

More-tolerable formulations of niacin prompted interest in its potential to lower the residual cardiovascular risk observed in statin-treated patients. Two large clinical trials attempted to determine its impact on cardiovascular events in the contemporary era.

The AIM-HIGH study

In the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) study,¹¹ 3,414 patients at high vascular risk with low HDL-C were treated with niacin or placebo. The trial was stopped early because of no evidence of clinical benefit with niacin and because of concern about an increased risk of stroke, a finding ultimately not observed on a complete review of the data.

I reviewed the limitations of this study earlier in this journal.¹² The study was small, use of low-dose niacin was allowed in the placebo group, and physicians could treat high LDL-C as they saw fit during the study, so that more patients in the placebo group received high-dose statin therapy and ezetimibe. All of this likely limited the study’s ability to measure the clinical impact of niacin. As a result, this study was not a pure evaluation of the benefits of niacin vs placebo in addition to standard medical therapy. Hope remained that a much larger study with greater statistical power and a simpler design would provide a definitive answer.

HPS2–THRIVE

The Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), with more than 40,000 patients, was the largest cardiovascular outcomes trial of lipid-modifying therapy to date.¹³ Its purpose was to determine whether extended-release niacin plus the prostanoid receptor antagonist laropiprant would reduce the rate of cardiovascular events in patients with clinically established vascular disease.

Patients age 50 to 80 with a history of myocardial infarction, ischemic stroke, transient ischemic attack, peripheral arterial disease, or diabetes with other forms of coronary heart disease received a standardized LDL-C-lowering regimen with simvastatin 40 mg daily, with or without ezetimibe 10 mg daily, to achieve a total cholesterol target of 135 mg/dL or below. All were treated with extended-release niacin 2 g daily plus laropiprant 40 mg daily for 1 month to assess compliance. They were then randomized to treatment with extended-release niacin 2 g plus laropiprant 40 mg or placebo daily. At baseline, the mean lipid values were LDL-C 63 mg/dL, HDL-C 44 mg/dL, and triglyceride 125 mg/dL.

Before the end of the trial, the investigators reported a high rate of myopathy-related adverse events in the niacin group, particularly in Chinese patients.¹³ This contributed to a high dropout rate in the niacin group, in which one quarter of patients stopped taking the study drug.

During the study, niacin lowered the LDL-C level by a mean of 10 mg/dL, lowered triglycerides by 33 mg/dL, and raised HDL-C by 6 mg/dL. On the basis of previous observational studies and randomized clinical trials, the authors calculated that such lipid changes should translate to a 10% to 15% reduction in vascular events. However, no reduction was observed in the primary end point of major vascular events, which included nonfatal myocardial infarction, coronary death, any nonfatal or fatal stroke, and any arterial revascularization, including amputation. The rates were 15% in the placebo group vs 14.5% in the niacin group (P = .96).

A statistically significant 10% reduction in the rate of arterial revascularization was observed in the niacin group, perhaps consistent with earlier observations of an antiatherosclerotic effect.

Subgroup analyses, while always to be interpreted with caution, also provide some interesting findings for consideration. A significant interaction was observed between treatment and baseline LDL-C, with those in the highest LDL-C tertile (> 77 mg/dL) demonstrating a potential reduction in the primary end point with niacin treatment. In addition, a trend toward potential benefit with niacin in patients in Europe, but not in China, was also observed; however, this just failed to meet statistical significance.

HPS2-THRIVE provided important information about the safety of extended-release niacin in combination with laropiprant. The niacin group experienced higher rates not only of myopathy but also of diabetic complications, new diagnosis of diabetes, serious infections, and bleeding. Whether these observations were related to niacin or to laropiprant is unknown. In fact, recent reports suggest laropiprant has adverse effects that may have substantially reduced the potential benefits of niacin.

The overall conclusion of HPS2-THRIVE was that there was no widespread clinical benefit from the combination of niacin and laropiprant in statin-treated patients with vascular disease, and that there was a potential increase in adverse events. Accordingly, the combination treatment will not be integrated into clinical practice.

WHERE DO WE GO FROM HERE?

Despite their limitations, these two large trials suggest that niacin does not reduce cardiovascular risk in patients already receiving a statin.

Might some subgroups be more likely to benefit from niacin? The finding of potential benefit in patients with higher baseline LDL-C suggests this may be true. At baseline, the HPS2-THRIVE patients had very good LDL-C control and had HDL-C levels within the normal range, not necessarily reflecting the patients we see in daily practice, who require more effective reductions in vascular risk. Furthermore, failure of both fibrates and niacin to reduce risk may have reflected the attempt to study these agents in broad patient populations as opposed to focusing on specific cohorts, such as patients with mixed dyslipidemia, for which there is suggestion of benefit.¹⁴ It seems unlikely that such a study will be performed in a clinical setting in which niacin may be of greater utility. The experience of adverse events would appear to make that a certainty.

For now, niacin will remain useful in lipid clinics for managing refractory dyslipidemia. Specifically, its ability to lower triglyceride and lipoprotein (a) and to raise HDL-C will continue to be of interest in the clinical management of patients and in the formulation of treatment guidelines. Another reason to use it is to lower LDL-C in patients who cannot tolerate statins. However, there is currently no evidence from randomized controlled trials to support its broader use.

While registry information could provide some sense of real-world effects of niacin’s use, this is a suboptimal way to evaluate the potential efficacy of a therapy—randomized controlled trials are the gold standard. The major flaws of both of the large trials of niacin point out the need for thoughtful study design to avoid incorrectly dismissing potentially useful therapies. But for now, the renaissance of niacin as a means of lowering cardiovascular risk is only wishful thinking.

A key part of medical practice is managing professional relationships. This includes effective communication with each other: primary care provider, specialist, and patient in all permutations. I have previously written about how technologic advances both facilitate and hamper interphysician communication. But as payment models morph, as health systems become more complex and insulated, and as the medicine subspecialty workforce changes, the relationship between generalist and nonprocedural specialist will continue to evolve. I can offer personal testimony to the enormous value of sharing our electronic medical record with my nephrology colleagues within the institution; online (nondisruptive) management “conversation” is common in real time while I am with a patient in the office.

Gone is the time when referral was a necessary mechanism to build a practice, when a primary care physician would send everyone with an elevated alkaline phosphatase to the neighboring gastroenterologist, who in turn would send everyone without a primary care doctor to him or her. But there has always been the potential for professional, ego-based tension between primary care and nonprocedural specialist physicians, although this tension is rarely discussed. When does referral to a specialist by a general internist imply a lack of appropriate knowledge or an unwillingness to do an appropriate literature review? When should a specialist be concerned about “interfering” in primary care—by initiating more aggressive blood pressure control, or by giving the patient a needed vaccination? And what should be done if the patient decides to change the captain of the medical team? Maybe in the new medical care arena we will indeed function and be judged as a team, physician communication and transitions will be seamless, and all that matters will be the patient. Time will tell.

For now, the comanagement of patients with a chronic disease is often a challenge. The discussion by Sakhuja et al of patients with chronic kidney disease (CKD) highlights important clinical issues faced by primary care providers and nephrologists. With the increased diagnosis of early CKD, there may not be enough consulting nephrologists to see all these patients. And when CKD is diagnosed at an early stage, not all patients may warrant a specialist consultation. Yet the gaps in clinical care are clear. Too many patients with “a little” proteinuria or microhematuria do not get an adequate microscopic urinalysis to look for a treatable inflammatory renal disorder. Too many patients with a “slightly” elevated creatinine and blood pressure do not have their pressure aggressively treated, despite evidence that a systolic blood pressure in the high 130s is associated with more rapid progression of CKD. Should we establish expectations for ourselves, or should we just take a step back and refer all these patients to a nephrologist and await guidance? This is where I believe that a few clearly written and widely disseminated guidelines would help. Knowledge of appropriate and basic guidelines for diagnosing and managing common disorders (not just CKD) should be the focus of continuing medical education and should be required for maintaining certification for all internists, including specialists. But, as always, guidelines often need to be tailored for the patient in our examining room.

There are nuances in the care of patients with CKD that, as a nonspecialist, I will not automatically know need to be implemented. As an internist, I should know the value of starting inhibition of the angiotensin pathway in patients with proteinuria, but as CKD progresses in a specific patient, should this be decreased? Should I initiate urate-lowering therapy,¹ hoping to slow the rate of my patient’s renal demise?

When do we know enough to know that we do not need to ask for a specialist’s input? How well do we self-assess our clinical knowledge and skills? How can we achieve the right balance between referral and self-management? We try to save our patient the cost of the time and the copayment to see a specialist, and with bundled care we try to minimize consultant fees and time. But in the meantime, are we ordering unnecessary tests or delaying appropriate therapy?

As we think about the comanagement of patients with CKD, we need to recognize and utilize the nuanced improvements in care that our nephrology colleagues can provide. As non-nephrologists, we should be able to start a thoughtful diagnostic evaluation. For example, an antinuclear antibody test in the absence of evidence of glomerulonephritis is not likely to be informative in determining the cause of an isolated elevated creatinine; a urinalysis is. We should be able to recognize potential renal injury (proteinuria, decreased glomerular filtration rate, microhematuria, hypertension), and initiate aggressive mitigation of factors that are known to enhance progression of the CKD (proteinuria, hypertension) and contribute to the significant morbidity and mortality of CKD-associated cardiovascular disease.

We should already be managing hypertension, diabetes, and hyperlipidemia, but CKD should be a red flag, driving us to more aggressively control these comorbidities, and driving us to do better than control only the estimated 46.4% of hypertensive patients in 2009 and 2010 whose hypertension was adequately controlled.² There is no reason for us to step back and wait for direction in addressing these most common issues. And our specialist colleagues will be there to efficiently assist in refining the nuances of care.

A key part of medical practice is managing professional relationships. This includes effective communication with each other: primary care provider, specialist, and patient in all permutations. I have previously written about how technologic advances both facilitate and hamper interphysician communication. But as payment models morph, as health systems become more complex and insulated, and as the medicine subspecialty workforce changes, the relationship between generalist and nonprocedural specialist will continue to evolve. I can offer personal testimony to the enormous value of sharing our electronic medical record with my nephrology colleagues within the institution; online (nondisruptive) management “conversation” is common in real time while I am with a patient in the office.

Gone is the time when referral was a necessary mechanism to build a practice, when a primary care physician would send everyone with an elevated alkaline phosphatase to the neighboring gastroenterologist, who in turn would send everyone without a primary care doctor to him or her. But there has always been the potential for professional, ego-based tension between primary care and nonprocedural specialist physicians, although this tension is rarely discussed. When does referral to a specialist by a general internist imply a lack of appropriate knowledge or an unwillingness to do an appropriate literature review? When should a specialist be concerned about “interfering” in primary care—by initiating more aggressive blood pressure control, or by giving the patient a needed vaccination? And what should be done if the patient decides to change the captain of the medical team? Maybe in the new medical care arena we will indeed function and be judged as a team, physician communication and transitions will be seamless, and all that matters will be the patient. Time will tell.

For now, the comanagement of patients with a chronic disease is often a challenge. The discussion by Sakhuja et al of patients with chronic kidney disease (CKD) highlights important clinical issues faced by primary care providers and nephrologists. With the increased diagnosis of early CKD, there may not be enough consulting nephrologists to see all these patients. And when CKD is diagnosed at an early stage, not all patients may warrant a specialist consultation. Yet the gaps in clinical care are clear. Too many patients with “a little” proteinuria or microhematuria do not get an adequate microscopic urinalysis to look for a treatable inflammatory renal disorder. Too many patients with a “slightly” elevated creatinine and blood pressure do not have their pressure aggressively treated, despite evidence that a systolic blood pressure in the high 130s is associated with more rapid progression of CKD. Should we establish expectations for ourselves, or should we just take a step back and refer all these patients to a nephrologist and await guidance? This is where I believe that a few clearly written and widely disseminated guidelines would help. Knowledge of appropriate and basic guidelines for diagnosing and managing common disorders (not just CKD) should be the focus of continuing medical education and should be required for maintaining certification for all internists, including specialists. But, as always, guidelines often need to be tailored for the patient in our examining room.

There are nuances in the care of patients with CKD that, as a nonspecialist, I will not automatically know need to be implemented. As an internist, I should know the value of starting inhibition of the angiotensin pathway in patients with proteinuria, but as CKD progresses in a specific patient, should this be decreased? Should I initiate urate-lowering therapy,¹ hoping to slow the rate of my patient’s renal demise?

When do we know enough to know that we do not need to ask for a specialist’s input? How well do we self-assess our clinical knowledge and skills? How can we achieve the right balance between referral and self-management? We try to save our patient the cost of the time and the copayment to see a specialist, and with bundled care we try to minimize consultant fees and time. But in the meantime, are we ordering unnecessary tests or delaying appropriate therapy?

As we think about the comanagement of patients with CKD, we need to recognize and utilize the nuanced improvements in care that our nephrology colleagues can provide. As non-nephrologists, we should be able to start a thoughtful diagnostic evaluation. For example, an antinuclear antibody test in the absence of evidence of glomerulonephritis is not likely to be informative in determining the cause of an isolated elevated creatinine; a urinalysis is. We should be able to recognize potential renal injury (proteinuria, decreased glomerular filtration rate, microhematuria, hypertension), and initiate aggressive mitigation of factors that are known to enhance progression of the CKD (proteinuria, hypertension) and contribute to the significant morbidity and mortality of CKD-associated cardiovascular disease.

We should already be managing hypertension, diabetes, and hyperlipidemia, but CKD should be a red flag, driving us to more aggressively control these comorbidities, and driving us to do better than control only the estimated 46.4% of hypertensive patients in 2009 and 2010 whose hypertension was adequately controlled.² There is no reason for us to step back and wait for direction in addressing these most common issues. And our specialist colleagues will be there to efficiently assist in refining the nuances of care.

A key part of medical practice is managing professional relationships. This includes effective communication with each other: primary care provider, specialist, and patient in all permutations. I have previously written about how technologic advances both facilitate and hamper interphysician communication. But as payment models morph, as health systems become more complex and insulated, and as the medicine subspecialty workforce changes, the relationship between generalist and nonprocedural specialist will continue to evolve. I can offer personal testimony to the enormous value of sharing our electronic medical record with my nephrology colleagues within the institution; online (nondisruptive) management “conversation” is common in real time while I am with a patient in the office.

Gone is the time when referral was a necessary mechanism to build a practice, when a primary care physician would send everyone with an elevated alkaline phosphatase to the neighboring gastroenterologist, who in turn would send everyone without a primary care doctor to him or her. But there has always been the potential for professional, ego-based tension between primary care and nonprocedural specialist physicians, although this tension is rarely discussed. When does referral to a specialist by a general internist imply a lack of appropriate knowledge or an unwillingness to do an appropriate literature review? When should a specialist be concerned about “interfering” in primary care—by initiating more aggressive blood pressure control, or by giving the patient a needed vaccination? And what should be done if the patient decides to change the captain of the medical team? Maybe in the new medical care arena we will indeed function and be judged as a team, physician communication and transitions will be seamless, and all that matters will be the patient. Time will tell.

For now, the comanagement of patients with a chronic disease is often a challenge. The discussion by Sakhuja et al of patients with chronic kidney disease (CKD) highlights important clinical issues faced by primary care providers and nephrologists. With the increased diagnosis of early CKD, there may not be enough consulting nephrologists to see all these patients. And when CKD is diagnosed at an early stage, not all patients may warrant a specialist consultation. Yet the gaps in clinical care are clear. Too many patients with “a little” proteinuria or microhematuria do not get an adequate microscopic urinalysis to look for a treatable inflammatory renal disorder. Too many patients with a “slightly” elevated creatinine and blood pressure do not have their pressure aggressively treated, despite evidence that a systolic blood pressure in the high 130s is associated with more rapid progression of CKD. Should we establish expectations for ourselves, or should we just take a step back and refer all these patients to a nephrologist and await guidance? This is where I believe that a few clearly written and widely disseminated guidelines would help. Knowledge of appropriate and basic guidelines for diagnosing and managing common disorders (not just CKD) should be the focus of continuing medical education and should be required for maintaining certification for all internists, including specialists. But, as always, guidelines often need to be tailored for the patient in our examining room.

There are nuances in the care of patients with CKD that, as a nonspecialist, I will not automatically know need to be implemented. As an internist, I should know the value of starting inhibition of the angiotensin pathway in patients with proteinuria, but as CKD progresses in a specific patient, should this be decreased? Should I initiate urate-lowering therapy,¹ hoping to slow the rate of my patient’s renal demise?

When do we know enough to know that we do not need to ask for a specialist’s input? How well do we self-assess our clinical knowledge and skills? How can we achieve the right balance between referral and self-management? We try to save our patient the cost of the time and the copayment to see a specialist, and with bundled care we try to minimize consultant fees and time. But in the meantime, are we ordering unnecessary tests or delaying appropriate therapy?

As we think about the comanagement of patients with CKD, we need to recognize and utilize the nuanced improvements in care that our nephrology colleagues can provide. As non-nephrologists, we should be able to start a thoughtful diagnostic evaluation. For example, an antinuclear antibody test in the absence of evidence of glomerulonephritis is not likely to be informative in determining the cause of an isolated elevated creatinine; a urinalysis is. We should be able to recognize potential renal injury (proteinuria, decreased glomerular filtration rate, microhematuria, hypertension), and initiate aggressive mitigation of factors that are known to enhance progression of the CKD (proteinuria, hypertension) and contribute to the significant morbidity and mortality of CKD-associated cardiovascular disease.

We should already be managing hypertension, diabetes, and hyperlipidemia, but CKD should be a red flag, driving us to more aggressively control these comorbidities, and driving us to do better than control only the estimated 46.4% of hypertensive patients in 2009 and 2010 whose hypertension was adequately controlled.² There is no reason for us to step back and wait for direction in addressing these most common issues. And our specialist colleagues will be there to efficiently assist in refining the nuances of care.

Accountable-care organizations are becoming more prominent in the United States, and therefore health care systems in the near future will be reimbursed on the basis of their ability to care for patient populations rather than individual patients. As a result, primary care physicians will need to be well versed in the care of patients with common chronic diseases such as chronic kidney disease (CKD). By one estimate, patients with CKD constitute 14% of the US population age 20 and older, or more than 31 million people.¹

An earlier article in this journal reviewed how to identify patients with CKD and how to interpret the estimated glomerular filtration rate (GFR).² This article examines the care of patients with advanced CKD, how to manage their health risks, and how to optimize their care by coordinating with nephrologists.

GOALS OF CKD CARE

CKD is defined either as renal damage (which is most commonly manifested by proteinuria, but which may include pathologic changes on biopsy or other markers of damage on serum, urine, or imaging studies), or as a GFR less than 60 mL/min/1.73 m² for at least 3 months.³ It is divided into five stages (Table 1).

Since most patients with CKD never reach end-stage renal disease, much of their care is aimed at slowing the progression of renal dysfunction and addressing medical issues that arise as a result of CKD. To these ends, it is important to detect CKD early and refer these patients to a nephrology team in a timely manner. Their care can be separated into several important tasks:

• Identify the cause of CKD, if possible; address potentially reversible causes such as obstruction or medication-related causes. If a primarily glomerular process (marked by heavy proteinuria and dysmorphic red blood cells and red blood cell casts in the urine sediment) or interstitial nephritis (manifested by white blood cells in the urine) is suspected, refer to a nephrologist early.
• Provide treatment to correct the specific cause (if one is present) or slow the deterioration of renal function.
• Address cardiovascular risk factors.
• Address metabolic abnormalities related to CKD.
• If the CKD is advanced, educate the patient about end-stage renal disease and its treatment options, and guide the patient through the transition to end-stage renal disease.

WHEN SHOULD A NEPHROLOGIST BE CONSULTED?

The ideal timing of referral to a nephrologist is not well defined and depends on the comfort level of the primary care provider.

Treatments to slow the progression of CKD and decrease cardiovascular risk should begin early in CKD (ie, in stage 3) and can be managed by the primary care provider with guidance from a nephrologist. Patients referred to a nephrologist while in stage 3 have been shown to go longer without CKD progression than those referred in later stages.⁴ Early referral to a nephrologist has also been associated with a decreased mortality rate.⁵ The studies that found these trends, however, were limited by the fact that patients with stage 3 CKD are less likely to progress to end-stage renal disease or to die of cardiovascular disease than patients with stage 4 or 5 CKD.

Once stage 4 CKD develops, the nephrologist should take a more active role in the care plan. In this stage, cardiovascular risk rises, and the risk of developing end-stage renal disease rises dramatically.⁶ With comprehensive care in a CKD clinic, even patients with advanced CKD are more likely to have a stabilization of renal function.⁷ Kinchen et al⁸ found that patients referred to a nephrologist within 4 months of starting dialysis had a lower survival rate than those referred earlier. Therefore, if a nephrologist was not involved in the patient’s care prior to stage 4, then a referral must be made.

Recommendation. Patients with stage 3 CKD can be referred for an initial evaluation and development of a treatment plan, but most of the responsibility for their care can remain with the primary care provider. Once stage 4 CKD develops, the nephrologist should assume an increasing role. However, if glomerular disease is suspected, we recommend referral to a nephrologist regardless of the estimated GFR.

ELEVATED CARDIOVASCULAR RISK

Patients with stage 3 CKD are 20 times more likely to die of a cardiovascular event than to reach end-stage renal disease.⁶ This increased risk does not quite reach the status of a cardiovascular disease risk equivalent, as does diabetes,^9,10 but cardiovascular risk reduction should be a primary focus of care for the CKD patient.

The cardiovascular risk in part is attributed to a high prevalence of traditional cardiovascular risk factors, including diabetes mellitus, hypertension, and hyperlipidemia.^11,12 About two-thirds of CKD patients have metabolic syndrome, which is a risk factor for cardiovascular disease and is associated with more rapid progression of CKD.¹³ In addition, renal dysfunction, proteinuria, and hyperphosphatemia are also risk factors for cardiovascular disease.^14–19

The risk of death from a cardiovascular event increases as kidney function declines, with reported 5-year death rates of 19.5% in stage 2, 24.3% in stage 3, and 45.7% in stage 4 CKD. However, imbalance between mortality risk and progression to end-stage renal disease may be age-dependent.²⁰ Younger patients (age 45 and younger) are more likely to progress to end-stage renal disease, whereas in older patients (over age 65), the relative risk of dying of cardiovascular disease is higher.

Aggressive lipid management

Hyperlipidemia is a common risk factor for cardiovascular morbidity and mortality in CKD.²¹ However, until recently, all studies of outcomes of patients treated for hyperlipidemia excluded patients with CKD. Post hoc analyses of these studies ^22–27 showed statins to be beneficial in primary and secondary cardiovascular prevention in patents with “normal” serum creatinine values but estimated GFR levels of 50 to 59 mL/min/1.73 m².

The SHARP trial²⁸ was the first prospective trial to study lipid-lowering therapy in patients with CKD. In this trial, patients with various stages of CKD, including advanced CKD, had fewer major vascular events if they received the combination of low-dose simvastatin (Zocor) and ezetimibe (Zetia). However, the evidence does not suggest that statin therapy slows the progression of CKD.^28–31

Recommendation. Manage hyperlipidemia aggressively using statin therapy with or without ezetimibe, with a target low-density lipoprotein cholesterol level below 100 mg/dL.³²

Manage other cardiovascular risk factors

Because hypertension and proteinuria are risk factors not only for cardiovascular disease but also for progression of CKD, they are discussed in the section below.

ATTEMPT TO PREVENT WORSENING OF RENAL FUNCTION

Medications to avoid

It is important to review a CKD patient’s medication list—prescription and over-the-counter drugs—to identify any that may contribute to a worsening of renal function. CKD patients need to be informed about avoiding medications such as nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and herbal supplements because they can cause further renal injury. In addition, other medications (eg, metformin) are contraindicated in CKD because of side effects that may occur in CKD.

Patients should be encouraged to discuss any changes in their medications, including over-the-counter products, with their primary care physicians.

Manage hypertension aggressively

Many patients with CKD also have hypertension,^33,34 possibly because they have a higher frequency of underlying essential hypertension or because CKD often worsens preexisting hypertension. Moreover, uncontrolled hypertension is associated with a further decline in renal function.^35,36

The ACCORD trial³⁷ found no benefit in lowering systolic blood pressure to less than 120 mm Hg compared with less than 140 mm Hg in patients with diabetes mellitus. (The patients in this study did not necessarily have CKD.)

A meta-analysis³⁸ of trials of antihypertensive treatment in patients with CKD found that the optimal target systolic blood pressure for decreasing the progression of CKD was 110 to 129 mm Hg. The relative risk of progression of renal dysfunction was:

• 1.83 (95% confidence interval [CI] 0.97–3.44) at 130 mm to 139 mm Hg, vs
• 3.14 (95% CI 1.64–5.99) at 160 mm Hg or higher.

There is also evidence that blood pressure control can be relaxed as patients age. While the exact age differs among published guidelines, the evidence supports a goal blood pressure of less than 150/90 mm Hg once a patient reaches the age of 70, regardless of CKD or proteinuria.

Recommendation. Current evidence suggests the following blood pressure goals in CKD patients:

• With diabetes mellitus or proteinuria: < 130/80 mm Hg
• Without proteinuria: < 140/90 mm Hg
• Age 70 and older: <150/90 mm Hg.³⁹

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are the preferred antihypertensive drugs in patients with diabetes or proteinuria (see below).

Manage proteinuria

Proteinuria is also associated with progression of CKD. AASK,⁴⁰ a study that included nondiabetic African American patients whose estimated GFRs were between 20 and 60 mL/min/1.73 m², showed that higher levels of proteinuria were associated with a higher risk of decline in GFR and a higher risk of end-stage renal disease. Findings were similar to those in studies of other CKD populations.^41–43 Proteinuria is also an independent risk factor for cardiovascular disease and death. Multiple large studies^16,17,44,45 have found associations between higher levels of albumin excretion and risk of major cardiovascular events, cardiovascular death, and death from any cause in people with and without diabetes.

Reducing proteinuria has been shown to both slow progression of renal dysfunction and reduce the cardiovascular risk.^44,45 In a substudy of the IDNT⁴⁶ in patients with diabetic nephropathy, each 50% reduction in urinary protein excretion was associated with a 56% reduction in risk of progression of CKD. Similar effects have been shown in nondiabetic CKD patients.⁴⁷

ACE inhibitors and ARBs are the preferred treatments for proteinuria in patients with CKD.^48–50 Combination therapy with an ACE inhibitor and an ARB has been used,^51–53 with a better response in proteinuria reduction. However, combination therapy with these drugs cannot currently be recommended, as the only prospective study of this regimen to date suggested worse renal and overall outcomes in patients at high cardiovascular risk.⁵⁴ These drugs may also have renoprotective effects independent of their effects on blood pressure and proteinuria.³⁸ Dietary salt restriction and diuretic therapy can further increase the efficacy of proteinuria reduction by ACE inhibitors or ARBs.^55,56

On the other hand, stopping ACE inhibitors or ARBs may be beneficial as the patient nears end-stage renal disease. Ahmed et al⁵⁷ demonstrated that stopping ACE inhibitors or ARBs in advanced stage 4 CKD (mean estimated GFR 16 mL/min/1.73 m²) was associated with improved GFR and delayed onset of renal replacement therapy. This improvement may be due to regaining the slight decrease in GFR that occurred when these medications were started.

Nondihydropyridine calcium channel blockers such as diltiazem (Cardizem) and verapamil (Calan) have also been shown to be useful for reducing proteinuria,⁵⁸ whereas dihydropyridine calcium channel blockers such as amlodipine (Norvasc) and nifedipine (Procardia), when used without ACE inhibitors or ARBs, can worsen proteinuria.^58,59

Correct metabolic acidosis

The kidneys play an important role in maintaining acid-base balance, keeping the blood from becoming too acidic both by reabsorbing bicarbonate filtered into the urine by the glomerulus and by excreting the daily acid load. Metabolic acidosis can develop when these functions break down at more advanced stages of CKD, most often when the estimated GFR declines to less than 20 mL/min/1.73 m².

Bicarbonate levels of 22 mmol/L or less have been associated with a higher risk of worsening renal function.⁶⁰ When such patients were treated with sodium bicarbonate to achieve a serum bicarbonate of at least 23 mmol/L, they had an 80% lower rate of progression to end-stage renal disease without any increase in edema, admission for congestive heart failure, or change in blood pressure.⁶¹

Susantitaphong et al⁶² reviewed six randomized trials of bicarbonate supplementation in CKD and found that it was associated with improved kidney function and a 79% lower rate of progression to end-stage renal disease.

The proposed mechanism behind this benefit lies in the increase in ammonia production that each surviving nephron must undertake to handle the daily acid load. The increased ammonia is thought to play a role in activating the alternative complement pathway,⁶³ causing renal inflammation and injury.

Recommendation. Bicarbonate therapy should be used to maintain serum bicarbonate levels above 22 mmol/L in CKD.⁶⁴

OTHER ASPECTS OF CKD CARE

Bone mineral disorders

Patients with CKD develop secondary hyperparathyroidism, hyperphosphatemia, and (in advanced CKD) hypocalcemia, all leading to disorders of bone mineral metabolism.

Traditionally, it has been thought that decreased production of 1,25-dihydroxyvitamin D by dysfunctional kidneys leads to decreased suppression of the parathyroid gland and to secondary hyperparathyroidism. The major long-term adverse effect of this is a weakened bone matrix resulting from increased calcium and phosphorus efflux from bones (renal osteodystrophy).

The discovery of fibroblast growth factor 23 (FGF-23) has improved our understanding of the physiology behind disordered bone mineral metabolism in CKD. FGF-23, produced by osteoblasts and osteocytes, acts directly on the kidney to increase renal phosphate excretion. It also suppresses 1,25-dihydroxyvitamin D levels by inhibiting 1-alpha-hydroxylase,⁶⁵ and it stimulates parathyroid hormone secretion. FGF-23 levels rise much earlier in CKD than do parathyroid hormone levels, suggesting that abnormalities in phosphorus balance and FGF-23 may be the earliest pathophysiologic changes.⁶⁶

The initial treatment of bone mineral disorders is to some extent guided by laboratory values. Phosphate levels higher than 3.5 or 4 mg/dL and elevated FGF-23 levels have been associated with increased mortality rates in CKD patients.^{18,19,67–69} All patients should also have their 1,25-dihydroxyvitamin D level checked and supplemented if deficient. In many patients with early stage 3 CKD, this may correct secondary hyperparathyroidism.⁷⁰

Serum phosphorus levels should be kept in the normal range in stage 3 and 4 CKD,⁷¹ either by restricting dietary phosphorus intake (< 800 or < 1,000 mg/day) or by using a phosphate binder, which is taken with meals to prevent phosphorus absorption from the gastrointestinal tract. Current US recommendations are to allow graded increases in parathyroid hormone based on the stage of CKD (Table 2).⁷¹ However, these targets are still an area of uncertainty, with some guidelines suggesting that wider variations in parathyroid hormone can be allowed, so there may be wider variation in clinical practice in this area.⁷² If the serum phosphorus level is in the goal range but parathyroid hormone levels are still high, an activated vitamin D analogue such as calcitriol is recommended, although with the emerging role of FGF-23, some experts also call for early use of a phosphate binder in this group.

The treatment of bone mineral disorders in CKD is fairly complex, and we recommend that it be done by or with the close direction of a nephrologist.

Recommendations on bone disorders

• Check levels of calcium, phosphorus, 25-hydroxyvitamin D, and parathyroid hormone in all patients whose estimated GFR is less than 60 mL/min/1.73 m², with frequency of measurements based on the stage of CKD.⁷¹
• Replace vitamin D if deficient.
• Treat elevated phosphorus levels with a protein-restricted diet (nutrition referral) and a phosphate binder.
• Treat elevated hyperparathyroid hormone levels with a vitamin D analogue once phosphorus levels have been controlled.
• Refer patients with an elevated phosphorus or parathyroid hormone level to a nephrology service for consultation before initiating medical therapy.

Anemia is common, treatment controversial

The treatment of anemia attributed to CKD has been a topic of controversy over the past decade, and we recommend that it be done with the guidance of a nephrologist.

Anemia is common in CKD, and declining kidney function is an independent predictor of anemia.⁷³ Anemia is a risk factor for left ventricular hypertrophy, cardiovascular disease,⁷⁴ and death in CKD.⁷⁵

The anemia of CKD is attributed to relative erythropoietin deficiency and bone marrow resistance to erythropoietin, but this is a diagnosis of exclusion, and other causes of anemia must be ruled out. Iron deficiency is a common cause of anemia in CKD, and treatment of iron deficiency may correct anemia in more than one-third of these patients.^76,77

Erythropoiesis-stimulating agents such as epoetin alfa (Procrit) and darbepoetin (Aranesp) are used to treat renal anemia. However, the target hemoglobin level has been a subject of debate. Three prospective trials^78–80 found no benefit in raising the hemoglobin level to normal ranges using these agents, and several found an association with higher rates of stroke and venous thrombosis. The US Food and Drug Administration suggests that the only role for these agents in CKD is to avoid the need for transfusions. They should not be used to normalize the hemoglobin level. The target, although not explicitly specified, is suggested to be around 10 g/dL.⁸¹

PREPARE FOR END-STAGE RENAL DISEASE

Discuss the options

Because the risk of developing end-stage renal disease rises dramatically once CKD reaches stage 4, all such patients should have a discussion about renal replacement therapy. They should be educated about their options for treatment (hemodialysis, peritoneal dialysis, and transplantation, as well as not proceeding with renal replacement therapy), often in a formal class. They should then be actively engaged in the decision about how to proceed. Survival and quality of life should be discussed, particularly with patients who are over age 80, who are severely ill, or who are living in a nursing facility, as these groups get limited survival benefit from starting dialysis, and quality of life may actually decrease with dialysis.^82,83

The Renal Physicians Association has created clinical practice guidelines for shared decision-making, consisting of 10 practice recommendations that outline a systematic approach to patients needing renal replacement therapy.⁸⁴

Consider preemptive kidney transplantation

Any patient thought to be a suitable candidate for renal transplantation should be referred to a transplantation center for evaluation. Studies have shown that kidney transplantation offers a survival advantage compared with chronic dialysis and should preferably be done preemptively, ie, before dialysis is required.^85–90 Therefore, patients with estimated GFRs in the low 20s should be referred for a transplantation evaluation.

If a living donor is available, the transplantation team usually waits to perform the procedure until the patient is closer to needing dialysis, often when the estimated GFR is around 15 to 16 mL/min/1.73 m². If no living donor is available, the patient can earn time on the deceased-donor waiting list once his or her estimated GFR falls to below 20 mL/min/1.7 m².

Plan for dialysis access

Patients starting hemodialysis first need to undergo a procedure to provide access to the blood. The three options are an arteriovenous fistula, an arteriovenous graft, and a central venous catheter (Figure 1).

An arteriovenous fistula is the best option, being the most durable, followed by a graft and then a catheter.⁹¹ Arteriovenous fistulas also have the lowest rates of infection,⁹² thrombosis,⁹³ and intervention to maintain patency.⁹³

The fistula is created by ligating a vein draining an extremity, most often the nondominant arm, and anastomosing the vein to an artery. The higher arterial pressure causes the vein to dilate and thicken (“arterialize”), thus making it able to withstand repeated cannulation necessary for hemodialysis.

An arteriovenous fistula typically takes 1 to 3 months to “mature” to the point where it can be used,^94,95 and, depending on the patient and experience of the vascular surgeon, a significant number may never mature. Thus, it is important to discuss hemodialysis access before the patient reaches end-stage renal disease so that he or she can be referred to a vascular surgeon early, when the estimated GFR is about 20 mL/min/1.73 m².

An arteriovenous graft. Not all patients have suitable vessels for creation of an arteriovenous fistula. In such patients, an arteriovenous graft, typically made of polytetrafluoroethylene, is the next best option. The graft is typically ready to use in 2 weeks and thus does not require as much advance planning. Grafts tend to narrow more often than fistulas and require more procedures to keep them patent.

A central venous catheter is most often inserted into the internal jugular vein and tunneled under the skin to exit in an area covered by the patient’s shirt.

Tunneled dialysis catheters are associated with higher rates of infection, thrombosis, and overall mortality and are therefore the least preferred choice. They are reserved for patients who have not had advance planning for end-stage renal disease, who do not have acceptable vessels for an arteriovenous fistula or graft, or who have refused surgical access.

Protect the fistula arm. It is recommended that venipuncture, intravenous lines, and blood pressure measurements be avoided in the nondominant upper arm of patients with stage 4 and 5 CKD to protect those veins for the potential creation of an arteriovenous fistula.⁹⁶ For the same reason, peripherally inserted central catheter lines and subclavian catheters should be avoided in these patients. If an arteriovenous fistula has already been placed, this arm must be protected from such procedures at all times.

Studies have shown that late referral to a nephrologist is associated with a lower incidence of starting dialysis with a permanent vascular access.^97,98

If the patient wishes to start peritoneal dialysis, the peritoneal dialysis catheter can usually be used 2 weeks after being inserted.

Starting dialysis

The appropriate time for starting dialysis remains controversial, especially in elderly patients with multiple comorbid conditions.

The IDEAL study⁹⁹ found no benefit in starting dialysis at a GFR of 10 to 14 mL/min compared with 5 to 7 mL/min. Thus, there is no single estimated GFR at which dialysis should be started. Rather, the development of early uremic symptoms and the patient’s quality of life should guide this decision.^{82,83,99–101}

Hemodialysis involves three sessions per week, each taking about 4 hours. Evidence suggests that longer sessions or more sessions per week may offer benefits, especially in terms of blood pressure, volume, and dietary management. This has led to an increase in the popularity of home and in-center nocturnal hemodialysis programs across the United States.

Peritoneal dialysis?

Peritoneal dialysis is an excellent choice for patients who are motivated, can care for themselves at home, and have a support system available to assist them if needed. It allows for daily dialysis, less fluid restriction, and less dietary restriction, and it gives the patient an opportunity to stay independent. It also spares the veins in the arms, which may be needed for vascular access later in life if hemodialysis is needed.

Recommendation. We recommend that peritoneal dialysis be offered to any suitable patient who is approaching end-stage renal disease.

A COMPREHENSIVE, COLLABORATIVE APPROACH

Chronic kidney disease is a multisystem disorder, and its management requires a comprehensive approach (Table 3). Early detection and interventions are key to reducing cardiovascular events and progression to kidney failure.

Early referral to a nephrologist and team collaboration between the primary care provider, the nephrologist, and other health care providers are essential. Early in the course of CKD, it may be appropriate for a nephrologist to evaluate the patient and recommend a set of treatment goals. Follow-up may be infrequent or unnecessary.

As CKD progresses, especially as the patient reaches an estimated GFR of 30 mL/min/1.73 m², the nephrologist will take a more active role in the patient’s care and medical decision-making. In some circumstances, it may even be appropriate for the nephrologist to be the patient’s source of primary care, with the primary care provider as a consultant.

Caring for patients with CKD includes not only strategies to preserve renal function and prolong survival, but also making critical decisions about starting dialysis and about the need for transplantation. Early involvement of a nephrologist and early preparation for end-stage renal disease with preemptive transplantation and arteriovenous fistula placement are associated with better patient outcomes. Key to this is collaboration between the primary care provider and the nephrologist, with levels of responsibility for patient care that adapt to the patient’s degree of renal dysfunction and other comorbidities. Such strategies to select patients for timely nephrology referral may help improve outcomes in this vulnerable population.

Accountable-care organizations are becoming more prominent in the United States, and therefore health care systems in the near future will be reimbursed on the basis of their ability to care for patient populations rather than individual patients. As a result, primary care physicians will need to be well versed in the care of patients with common chronic diseases such as chronic kidney disease (CKD). By one estimate, patients with CKD constitute 14% of the US population age 20 and older, or more than 31 million people.¹

An earlier article in this journal reviewed how to identify patients with CKD and how to interpret the estimated glomerular filtration rate (GFR).² This article examines the care of patients with advanced CKD, how to manage their health risks, and how to optimize their care by coordinating with nephrologists.

GOALS OF CKD CARE

CKD is defined either as renal damage (which is most commonly manifested by proteinuria, but which may include pathologic changes on biopsy or other markers of damage on serum, urine, or imaging studies), or as a GFR less than 60 mL/min/1.73 m² for at least 3 months.³ It is divided into five stages (Table 1).

Since most patients with CKD never reach end-stage renal disease, much of their care is aimed at slowing the progression of renal dysfunction and addressing medical issues that arise as a result of CKD. To these ends, it is important to detect CKD early and refer these patients to a nephrology team in a timely manner. Their care can be separated into several important tasks:

• Identify the cause of CKD, if possible; address potentially reversible causes such as obstruction or medication-related causes. If a primarily glomerular process (marked by heavy proteinuria and dysmorphic red blood cells and red blood cell casts in the urine sediment) or interstitial nephritis (manifested by white blood cells in the urine) is suspected, refer to a nephrologist early.
• Provide treatment to correct the specific cause (if one is present) or slow the deterioration of renal function.
• Address cardiovascular risk factors.
• Address metabolic abnormalities related to CKD.
• If the CKD is advanced, educate the patient about end-stage renal disease and its treatment options, and guide the patient through the transition to end-stage renal disease.

WHEN SHOULD A NEPHROLOGIST BE CONSULTED?

The ideal timing of referral to a nephrologist is not well defined and depends on the comfort level of the primary care provider.

Treatments to slow the progression of CKD and decrease cardiovascular risk should begin early in CKD (ie, in stage 3) and can be managed by the primary care provider with guidance from a nephrologist. Patients referred to a nephrologist while in stage 3 have been shown to go longer without CKD progression than those referred in later stages.⁴ Early referral to a nephrologist has also been associated with a decreased mortality rate.⁵ The studies that found these trends, however, were limited by the fact that patients with stage 3 CKD are less likely to progress to end-stage renal disease or to die of cardiovascular disease than patients with stage 4 or 5 CKD.

Once stage 4 CKD develops, the nephrologist should take a more active role in the care plan. In this stage, cardiovascular risk rises, and the risk of developing end-stage renal disease rises dramatically.⁶ With comprehensive care in a CKD clinic, even patients with advanced CKD are more likely to have a stabilization of renal function.⁷ Kinchen et al⁸ found that patients referred to a nephrologist within 4 months of starting dialysis had a lower survival rate than those referred earlier. Therefore, if a nephrologist was not involved in the patient’s care prior to stage 4, then a referral must be made.

Recommendation. Patients with stage 3 CKD can be referred for an initial evaluation and development of a treatment plan, but most of the responsibility for their care can remain with the primary care provider. Once stage 4 CKD develops, the nephrologist should assume an increasing role. However, if glomerular disease is suspected, we recommend referral to a nephrologist regardless of the estimated GFR.

ELEVATED CARDIOVASCULAR RISK

Patients with stage 3 CKD are 20 times more likely to die of a cardiovascular event than to reach end-stage renal disease.⁶ This increased risk does not quite reach the status of a cardiovascular disease risk equivalent, as does diabetes,^9,10 but cardiovascular risk reduction should be a primary focus of care for the CKD patient.

The cardiovascular risk in part is attributed to a high prevalence of traditional cardiovascular risk factors, including diabetes mellitus, hypertension, and hyperlipidemia.^11,12 About two-thirds of CKD patients have metabolic syndrome, which is a risk factor for cardiovascular disease and is associated with more rapid progression of CKD.¹³ In addition, renal dysfunction, proteinuria, and hyperphosphatemia are also risk factors for cardiovascular disease.^14–19

The risk of death from a cardiovascular event increases as kidney function declines, with reported 5-year death rates of 19.5% in stage 2, 24.3% in stage 3, and 45.7% in stage 4 CKD. However, imbalance between mortality risk and progression to end-stage renal disease may be age-dependent.²⁰ Younger patients (age 45 and younger) are more likely to progress to end-stage renal disease, whereas in older patients (over age 65), the relative risk of dying of cardiovascular disease is higher.

Aggressive lipid management

Hyperlipidemia is a common risk factor for cardiovascular morbidity and mortality in CKD.²¹ However, until recently, all studies of outcomes of patients treated for hyperlipidemia excluded patients with CKD. Post hoc analyses of these studies ^22–27 showed statins to be beneficial in primary and secondary cardiovascular prevention in patents with “normal” serum creatinine values but estimated GFR levels of 50 to 59 mL/min/1.73 m².

The SHARP trial²⁸ was the first prospective trial to study lipid-lowering therapy in patients with CKD. In this trial, patients with various stages of CKD, including advanced CKD, had fewer major vascular events if they received the combination of low-dose simvastatin (Zocor) and ezetimibe (Zetia). However, the evidence does not suggest that statin therapy slows the progression of CKD.^28–31

Recommendation. Manage hyperlipidemia aggressively using statin therapy with or without ezetimibe, with a target low-density lipoprotein cholesterol level below 100 mg/dL.³²

Manage other cardiovascular risk factors

Because hypertension and proteinuria are risk factors not only for cardiovascular disease but also for progression of CKD, they are discussed in the section below.

ATTEMPT TO PREVENT WORSENING OF RENAL FUNCTION

Medications to avoid

It is important to review a CKD patient’s medication list—prescription and over-the-counter drugs—to identify any that may contribute to a worsening of renal function. CKD patients need to be informed about avoiding medications such as nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and herbal supplements because they can cause further renal injury. In addition, other medications (eg, metformin) are contraindicated in CKD because of side effects that may occur in CKD.

Patients should be encouraged to discuss any changes in their medications, including over-the-counter products, with their primary care physicians.

Manage hypertension aggressively

Many patients with CKD also have hypertension,^33,34 possibly because they have a higher frequency of underlying essential hypertension or because CKD often worsens preexisting hypertension. Moreover, uncontrolled hypertension is associated with a further decline in renal function.^35,36

The ACCORD trial³⁷ found no benefit in lowering systolic blood pressure to less than 120 mm Hg compared with less than 140 mm Hg in patients with diabetes mellitus. (The patients in this study did not necessarily have CKD.)

A meta-analysis³⁸ of trials of antihypertensive treatment in patients with CKD found that the optimal target systolic blood pressure for decreasing the progression of CKD was 110 to 129 mm Hg. The relative risk of progression of renal dysfunction was:

• 1.83 (95% confidence interval [CI] 0.97–3.44) at 130 mm to 139 mm Hg, vs
• 3.14 (95% CI 1.64–5.99) at 160 mm Hg or higher.

There is also evidence that blood pressure control can be relaxed as patients age. While the exact age differs among published guidelines, the evidence supports a goal blood pressure of less than 150/90 mm Hg once a patient reaches the age of 70, regardless of CKD or proteinuria.

Recommendation. Current evidence suggests the following blood pressure goals in CKD patients:

• With diabetes mellitus or proteinuria: < 130/80 mm Hg
• Without proteinuria: < 140/90 mm Hg
• Age 70 and older: <150/90 mm Hg.³⁹

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are the preferred antihypertensive drugs in patients with diabetes or proteinuria (see below).

Manage proteinuria

Proteinuria is also associated with progression of CKD. AASK,⁴⁰ a study that included nondiabetic African American patients whose estimated GFRs were between 20 and 60 mL/min/1.73 m², showed that higher levels of proteinuria were associated with a higher risk of decline in GFR and a higher risk of end-stage renal disease. Findings were similar to those in studies of other CKD populations.^41–43 Proteinuria is also an independent risk factor for cardiovascular disease and death. Multiple large studies^16,17,44,45 have found associations between higher levels of albumin excretion and risk of major cardiovascular events, cardiovascular death, and death from any cause in people with and without diabetes.

Reducing proteinuria has been shown to both slow progression of renal dysfunction and reduce the cardiovascular risk.^44,45 In a substudy of the IDNT⁴⁶ in patients with diabetic nephropathy, each 50% reduction in urinary protein excretion was associated with a 56% reduction in risk of progression of CKD. Similar effects have been shown in nondiabetic CKD patients.⁴⁷

ACE inhibitors and ARBs are the preferred treatments for proteinuria in patients with CKD.^48–50 Combination therapy with an ACE inhibitor and an ARB has been used,^51–53 with a better response in proteinuria reduction. However, combination therapy with these drugs cannot currently be recommended, as the only prospective study of this regimen to date suggested worse renal and overall outcomes in patients at high cardiovascular risk.⁵⁴ These drugs may also have renoprotective effects independent of their effects on blood pressure and proteinuria.³⁸ Dietary salt restriction and diuretic therapy can further increase the efficacy of proteinuria reduction by ACE inhibitors or ARBs.^55,56

On the other hand, stopping ACE inhibitors or ARBs may be beneficial as the patient nears end-stage renal disease. Ahmed et al⁵⁷ demonstrated that stopping ACE inhibitors or ARBs in advanced stage 4 CKD (mean estimated GFR 16 mL/min/1.73 m²) was associated with improved GFR and delayed onset of renal replacement therapy. This improvement may be due to regaining the slight decrease in GFR that occurred when these medications were started.

Nondihydropyridine calcium channel blockers such as diltiazem (Cardizem) and verapamil (Calan) have also been shown to be useful for reducing proteinuria,⁵⁸ whereas dihydropyridine calcium channel blockers such as amlodipine (Norvasc) and nifedipine (Procardia), when used without ACE inhibitors or ARBs, can worsen proteinuria.^58,59

Correct metabolic acidosis

The kidneys play an important role in maintaining acid-base balance, keeping the blood from becoming too acidic both by reabsorbing bicarbonate filtered into the urine by the glomerulus and by excreting the daily acid load. Metabolic acidosis can develop when these functions break down at more advanced stages of CKD, most often when the estimated GFR declines to less than 20 mL/min/1.73 m².

Bicarbonate levels of 22 mmol/L or less have been associated with a higher risk of worsening renal function.⁶⁰ When such patients were treated with sodium bicarbonate to achieve a serum bicarbonate of at least 23 mmol/L, they had an 80% lower rate of progression to end-stage renal disease without any increase in edema, admission for congestive heart failure, or change in blood pressure.⁶¹

Susantitaphong et al⁶² reviewed six randomized trials of bicarbonate supplementation in CKD and found that it was associated with improved kidney function and a 79% lower rate of progression to end-stage renal disease.

The proposed mechanism behind this benefit lies in the increase in ammonia production that each surviving nephron must undertake to handle the daily acid load. The increased ammonia is thought to play a role in activating the alternative complement pathway,⁶³ causing renal inflammation and injury.

Recommendation. Bicarbonate therapy should be used to maintain serum bicarbonate levels above 22 mmol/L in CKD.⁶⁴

OTHER ASPECTS OF CKD CARE

Bone mineral disorders

Patients with CKD develop secondary hyperparathyroidism, hyperphosphatemia, and (in advanced CKD) hypocalcemia, all leading to disorders of bone mineral metabolism.

Traditionally, it has been thought that decreased production of 1,25-dihydroxyvitamin D by dysfunctional kidneys leads to decreased suppression of the parathyroid gland and to secondary hyperparathyroidism. The major long-term adverse effect of this is a weakened bone matrix resulting from increased calcium and phosphorus efflux from bones (renal osteodystrophy).

The discovery of fibroblast growth factor 23 (FGF-23) has improved our understanding of the physiology behind disordered bone mineral metabolism in CKD. FGF-23, produced by osteoblasts and osteocytes, acts directly on the kidney to increase renal phosphate excretion. It also suppresses 1,25-dihydroxyvitamin D levels by inhibiting 1-alpha-hydroxylase,⁶⁵ and it stimulates parathyroid hormone secretion. FGF-23 levels rise much earlier in CKD than do parathyroid hormone levels, suggesting that abnormalities in phosphorus balance and FGF-23 may be the earliest pathophysiologic changes.⁶⁶

The initial treatment of bone mineral disorders is to some extent guided by laboratory values. Phosphate levels higher than 3.5 or 4 mg/dL and elevated FGF-23 levels have been associated with increased mortality rates in CKD patients.^{18,19,67–69} All patients should also have their 1,25-dihydroxyvitamin D level checked and supplemented if deficient. In many patients with early stage 3 CKD, this may correct secondary hyperparathyroidism.⁷⁰

Serum phosphorus levels should be kept in the normal range in stage 3 and 4 CKD,⁷¹ either by restricting dietary phosphorus intake (< 800 or < 1,000 mg/day) or by using a phosphate binder, which is taken with meals to prevent phosphorus absorption from the gastrointestinal tract. Current US recommendations are to allow graded increases in parathyroid hormone based on the stage of CKD (Table 2).⁷¹ However, these targets are still an area of uncertainty, with some guidelines suggesting that wider variations in parathyroid hormone can be allowed, so there may be wider variation in clinical practice in this area.⁷² If the serum phosphorus level is in the goal range but parathyroid hormone levels are still high, an activated vitamin D analogue such as calcitriol is recommended, although with the emerging role of FGF-23, some experts also call for early use of a phosphate binder in this group.

The treatment of bone mineral disorders in CKD is fairly complex, and we recommend that it be done by or with the close direction of a nephrologist.

Recommendations on bone disorders

• Check levels of calcium, phosphorus, 25-hydroxyvitamin D, and parathyroid hormone in all patients whose estimated GFR is less than 60 mL/min/1.73 m², with frequency of measurements based on the stage of CKD.⁷¹
• Replace vitamin D if deficient.
• Treat elevated phosphorus levels with a protein-restricted diet (nutrition referral) and a phosphate binder.
• Treat elevated hyperparathyroid hormone levels with a vitamin D analogue once phosphorus levels have been controlled.
• Refer patients with an elevated phosphorus or parathyroid hormone level to a nephrology service for consultation before initiating medical therapy.

Anemia is common, treatment controversial

The treatment of anemia attributed to CKD has been a topic of controversy over the past decade, and we recommend that it be done with the guidance of a nephrologist.

Anemia is common in CKD, and declining kidney function is an independent predictor of anemia.⁷³ Anemia is a risk factor for left ventricular hypertrophy, cardiovascular disease,⁷⁴ and death in CKD.⁷⁵

The anemia of CKD is attributed to relative erythropoietin deficiency and bone marrow resistance to erythropoietin, but this is a diagnosis of exclusion, and other causes of anemia must be ruled out. Iron deficiency is a common cause of anemia in CKD, and treatment of iron deficiency may correct anemia in more than one-third of these patients.^76,77

Erythropoiesis-stimulating agents such as epoetin alfa (Procrit) and darbepoetin (Aranesp) are used to treat renal anemia. However, the target hemoglobin level has been a subject of debate. Three prospective trials^78–80 found no benefit in raising the hemoglobin level to normal ranges using these agents, and several found an association with higher rates of stroke and venous thrombosis. The US Food and Drug Administration suggests that the only role for these agents in CKD is to avoid the need for transfusions. They should not be used to normalize the hemoglobin level. The target, although not explicitly specified, is suggested to be around 10 g/dL.⁸¹

PREPARE FOR END-STAGE RENAL DISEASE

Discuss the options

Because the risk of developing end-stage renal disease rises dramatically once CKD reaches stage 4, all such patients should have a discussion about renal replacement therapy. They should be educated about their options for treatment (hemodialysis, peritoneal dialysis, and transplantation, as well as not proceeding with renal replacement therapy), often in a formal class. They should then be actively engaged in the decision about how to proceed. Survival and quality of life should be discussed, particularly with patients who are over age 80, who are severely ill, or who are living in a nursing facility, as these groups get limited survival benefit from starting dialysis, and quality of life may actually decrease with dialysis.^82,83

The Renal Physicians Association has created clinical practice guidelines for shared decision-making, consisting of 10 practice recommendations that outline a systematic approach to patients needing renal replacement therapy.⁸⁴

Consider preemptive kidney transplantation

Any patient thought to be a suitable candidate for renal transplantation should be referred to a transplantation center for evaluation. Studies have shown that kidney transplantation offers a survival advantage compared with chronic dialysis and should preferably be done preemptively, ie, before dialysis is required.^85–90 Therefore, patients with estimated GFRs in the low 20s should be referred for a transplantation evaluation.

If a living donor is available, the transplantation team usually waits to perform the procedure until the patient is closer to needing dialysis, often when the estimated GFR is around 15 to 16 mL/min/1.73 m². If no living donor is available, the patient can earn time on the deceased-donor waiting list once his or her estimated GFR falls to below 20 mL/min/1.7 m².

Plan for dialysis access

Patients starting hemodialysis first need to undergo a procedure to provide access to the blood. The three options are an arteriovenous fistula, an arteriovenous graft, and a central venous catheter (Figure 1).

An arteriovenous fistula is the best option, being the most durable, followed by a graft and then a catheter.⁹¹ Arteriovenous fistulas also have the lowest rates of infection,⁹² thrombosis,⁹³ and intervention to maintain patency.⁹³

The fistula is created by ligating a vein draining an extremity, most often the nondominant arm, and anastomosing the vein to an artery. The higher arterial pressure causes the vein to dilate and thicken (“arterialize”), thus making it able to withstand repeated cannulation necessary for hemodialysis.

An arteriovenous fistula typically takes 1 to 3 months to “mature” to the point where it can be used,^94,95 and, depending on the patient and experience of the vascular surgeon, a significant number may never mature. Thus, it is important to discuss hemodialysis access before the patient reaches end-stage renal disease so that he or she can be referred to a vascular surgeon early, when the estimated GFR is about 20 mL/min/1.73 m².

An arteriovenous graft. Not all patients have suitable vessels for creation of an arteriovenous fistula. In such patients, an arteriovenous graft, typically made of polytetrafluoroethylene, is the next best option. The graft is typically ready to use in 2 weeks and thus does not require as much advance planning. Grafts tend to narrow more often than fistulas and require more procedures to keep them patent.

A central venous catheter is most often inserted into the internal jugular vein and tunneled under the skin to exit in an area covered by the patient’s shirt.

Tunneled dialysis catheters are associated with higher rates of infection, thrombosis, and overall mortality and are therefore the least preferred choice. They are reserved for patients who have not had advance planning for end-stage renal disease, who do not have acceptable vessels for an arteriovenous fistula or graft, or who have refused surgical access.

Protect the fistula arm. It is recommended that venipuncture, intravenous lines, and blood pressure measurements be avoided in the nondominant upper arm of patients with stage 4 and 5 CKD to protect those veins for the potential creation of an arteriovenous fistula.⁹⁶ For the same reason, peripherally inserted central catheter lines and subclavian catheters should be avoided in these patients. If an arteriovenous fistula has already been placed, this arm must be protected from such procedures at all times.

Studies have shown that late referral to a nephrologist is associated with a lower incidence of starting dialysis with a permanent vascular access.^97,98

If the patient wishes to start peritoneal dialysis, the peritoneal dialysis catheter can usually be used 2 weeks after being inserted.

Starting dialysis

The appropriate time for starting dialysis remains controversial, especially in elderly patients with multiple comorbid conditions.

The IDEAL study⁹⁹ found no benefit in starting dialysis at a GFR of 10 to 14 mL/min compared with 5 to 7 mL/min. Thus, there is no single estimated GFR at which dialysis should be started. Rather, the development of early uremic symptoms and the patient’s quality of life should guide this decision.^{82,83,99–101}

Hemodialysis involves three sessions per week, each taking about 4 hours. Evidence suggests that longer sessions or more sessions per week may offer benefits, especially in terms of blood pressure, volume, and dietary management. This has led to an increase in the popularity of home and in-center nocturnal hemodialysis programs across the United States.

Peritoneal dialysis?

Peritoneal dialysis is an excellent choice for patients who are motivated, can care for themselves at home, and have a support system available to assist them if needed. It allows for daily dialysis, less fluid restriction, and less dietary restriction, and it gives the patient an opportunity to stay independent. It also spares the veins in the arms, which may be needed for vascular access later in life if hemodialysis is needed.

Recommendation. We recommend that peritoneal dialysis be offered to any suitable patient who is approaching end-stage renal disease.

A COMPREHENSIVE, COLLABORATIVE APPROACH

Chronic kidney disease is a multisystem disorder, and its management requires a comprehensive approach (Table 3). Early detection and interventions are key to reducing cardiovascular events and progression to kidney failure.

Early referral to a nephrologist and team collaboration between the primary care provider, the nephrologist, and other health care providers are essential. Early in the course of CKD, it may be appropriate for a nephrologist to evaluate the patient and recommend a set of treatment goals. Follow-up may be infrequent or unnecessary.

As CKD progresses, especially as the patient reaches an estimated GFR of 30 mL/min/1.73 m², the nephrologist will take a more active role in the patient’s care and medical decision-making. In some circumstances, it may even be appropriate for the nephrologist to be the patient’s source of primary care, with the primary care provider as a consultant.

Caring for patients with CKD includes not only strategies to preserve renal function and prolong survival, but also making critical decisions about starting dialysis and about the need for transplantation. Early involvement of a nephrologist and early preparation for end-stage renal disease with preemptive transplantation and arteriovenous fistula placement are associated with better patient outcomes. Key to this is collaboration between the primary care provider and the nephrologist, with levels of responsibility for patient care that adapt to the patient’s degree of renal dysfunction and other comorbidities. Such strategies to select patients for timely nephrology referral may help improve outcomes in this vulnerable population.

Accountable-care organizations are becoming more prominent in the United States, and therefore health care systems in the near future will be reimbursed on the basis of their ability to care for patient populations rather than individual patients. As a result, primary care physicians will need to be well versed in the care of patients with common chronic diseases such as chronic kidney disease (CKD). By one estimate, patients with CKD constitute 14% of the US population age 20 and older, or more than 31 million people.¹

An earlier article in this journal reviewed how to identify patients with CKD and how to interpret the estimated glomerular filtration rate (GFR).² This article examines the care of patients with advanced CKD, how to manage their health risks, and how to optimize their care by coordinating with nephrologists.

GOALS OF CKD CARE

CKD is defined either as renal damage (which is most commonly manifested by proteinuria, but which may include pathologic changes on biopsy or other markers of damage on serum, urine, or imaging studies), or as a GFR less than 60 mL/min/1.73 m² for at least 3 months.³ It is divided into five stages (Table 1).

Since most patients with CKD never reach end-stage renal disease, much of their care is aimed at slowing the progression of renal dysfunction and addressing medical issues that arise as a result of CKD. To these ends, it is important to detect CKD early and refer these patients to a nephrology team in a timely manner. Their care can be separated into several important tasks:

• Identify the cause of CKD, if possible; address potentially reversible causes such as obstruction or medication-related causes. If a primarily glomerular process (marked by heavy proteinuria and dysmorphic red blood cells and red blood cell casts in the urine sediment) or interstitial nephritis (manifested by white blood cells in the urine) is suspected, refer to a nephrologist early.
• Provide treatment to correct the specific cause (if one is present) or slow the deterioration of renal function.
• Address cardiovascular risk factors.
• Address metabolic abnormalities related to CKD.
• If the CKD is advanced, educate the patient about end-stage renal disease and its treatment options, and guide the patient through the transition to end-stage renal disease.

WHEN SHOULD A NEPHROLOGIST BE CONSULTED?

The ideal timing of referral to a nephrologist is not well defined and depends on the comfort level of the primary care provider.

Treatments to slow the progression of CKD and decrease cardiovascular risk should begin early in CKD (ie, in stage 3) and can be managed by the primary care provider with guidance from a nephrologist. Patients referred to a nephrologist while in stage 3 have been shown to go longer without CKD progression than those referred in later stages.⁴ Early referral to a nephrologist has also been associated with a decreased mortality rate.⁵ The studies that found these trends, however, were limited by the fact that patients with stage 3 CKD are less likely to progress to end-stage renal disease or to die of cardiovascular disease than patients with stage 4 or 5 CKD.

Once stage 4 CKD develops, the nephrologist should take a more active role in the care plan. In this stage, cardiovascular risk rises, and the risk of developing end-stage renal disease rises dramatically.⁶ With comprehensive care in a CKD clinic, even patients with advanced CKD are more likely to have a stabilization of renal function.⁷ Kinchen et al⁸ found that patients referred to a nephrologist within 4 months of starting dialysis had a lower survival rate than those referred earlier. Therefore, if a nephrologist was not involved in the patient’s care prior to stage 4, then a referral must be made.

Recommendation. Patients with stage 3 CKD can be referred for an initial evaluation and development of a treatment plan, but most of the responsibility for their care can remain with the primary care provider. Once stage 4 CKD develops, the nephrologist should assume an increasing role. However, if glomerular disease is suspected, we recommend referral to a nephrologist regardless of the estimated GFR.

ELEVATED CARDIOVASCULAR RISK

Patients with stage 3 CKD are 20 times more likely to die of a cardiovascular event than to reach end-stage renal disease.⁶ This increased risk does not quite reach the status of a cardiovascular disease risk equivalent, as does diabetes,^9,10 but cardiovascular risk reduction should be a primary focus of care for the CKD patient.

The cardiovascular risk in part is attributed to a high prevalence of traditional cardiovascular risk factors, including diabetes mellitus, hypertension, and hyperlipidemia.^11,12 About two-thirds of CKD patients have metabolic syndrome, which is a risk factor for cardiovascular disease and is associated with more rapid progression of CKD.¹³ In addition, renal dysfunction, proteinuria, and hyperphosphatemia are also risk factors for cardiovascular disease.^14–19

The risk of death from a cardiovascular event increases as kidney function declines, with reported 5-year death rates of 19.5% in stage 2, 24.3% in stage 3, and 45.7% in stage 4 CKD. However, imbalance between mortality risk and progression to end-stage renal disease may be age-dependent.²⁰ Younger patients (age 45 and younger) are more likely to progress to end-stage renal disease, whereas in older patients (over age 65), the relative risk of dying of cardiovascular disease is higher.

Aggressive lipid management

Hyperlipidemia is a common risk factor for cardiovascular morbidity and mortality in CKD.²¹ However, until recently, all studies of outcomes of patients treated for hyperlipidemia excluded patients with CKD. Post hoc analyses of these studies ^22–27 showed statins to be beneficial in primary and secondary cardiovascular prevention in patents with “normal” serum creatinine values but estimated GFR levels of 50 to 59 mL/min/1.73 m².

The SHARP trial²⁸ was the first prospective trial to study lipid-lowering therapy in patients with CKD. In this trial, patients with various stages of CKD, including advanced CKD, had fewer major vascular events if they received the combination of low-dose simvastatin (Zocor) and ezetimibe (Zetia). However, the evidence does not suggest that statin therapy slows the progression of CKD.^28–31

Recommendation. Manage hyperlipidemia aggressively using statin therapy with or without ezetimibe, with a target low-density lipoprotein cholesterol level below 100 mg/dL.³²

Manage other cardiovascular risk factors

Because hypertension and proteinuria are risk factors not only for cardiovascular disease but also for progression of CKD, they are discussed in the section below.

ATTEMPT TO PREVENT WORSENING OF RENAL FUNCTION

Medications to avoid

It is important to review a CKD patient’s medication list—prescription and over-the-counter drugs—to identify any that may contribute to a worsening of renal function. CKD patients need to be informed about avoiding medications such as nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and herbal supplements because they can cause further renal injury. In addition, other medications (eg, metformin) are contraindicated in CKD because of side effects that may occur in CKD.

Patients should be encouraged to discuss any changes in their medications, including over-the-counter products, with their primary care physicians.

Manage hypertension aggressively

Many patients with CKD also have hypertension,^33,34 possibly because they have a higher frequency of underlying essential hypertension or because CKD often worsens preexisting hypertension. Moreover, uncontrolled hypertension is associated with a further decline in renal function.^35,36

The ACCORD trial³⁷ found no benefit in lowering systolic blood pressure to less than 120 mm Hg compared with less than 140 mm Hg in patients with diabetes mellitus. (The patients in this study did not necessarily have CKD.)

A meta-analysis³⁸ of trials of antihypertensive treatment in patients with CKD found that the optimal target systolic blood pressure for decreasing the progression of CKD was 110 to 129 mm Hg. The relative risk of progression of renal dysfunction was:

• 1.83 (95% confidence interval [CI] 0.97–3.44) at 130 mm to 139 mm Hg, vs
• 3.14 (95% CI 1.64–5.99) at 160 mm Hg or higher.

There is also evidence that blood pressure control can be relaxed as patients age. While the exact age differs among published guidelines, the evidence supports a goal blood pressure of less than 150/90 mm Hg once a patient reaches the age of 70, regardless of CKD or proteinuria.

Recommendation. Current evidence suggests the following blood pressure goals in CKD patients:

• With diabetes mellitus or proteinuria: < 130/80 mm Hg
• Without proteinuria: < 140/90 mm Hg
• Age 70 and older: <150/90 mm Hg.³⁹

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are the preferred antihypertensive drugs in patients with diabetes or proteinuria (see below).

Manage proteinuria

Proteinuria is also associated with progression of CKD. AASK,⁴⁰ a study that included nondiabetic African American patients whose estimated GFRs were between 20 and 60 mL/min/1.73 m², showed that higher levels of proteinuria were associated with a higher risk of decline in GFR and a higher risk of end-stage renal disease. Findings were similar to those in studies of other CKD populations.^41–43 Proteinuria is also an independent risk factor for cardiovascular disease and death. Multiple large studies^16,17,44,45 have found associations between higher levels of albumin excretion and risk of major cardiovascular events, cardiovascular death, and death from any cause in people with and without diabetes.

Reducing proteinuria has been shown to both slow progression of renal dysfunction and reduce the cardiovascular risk.^44,45 In a substudy of the IDNT⁴⁶ in patients with diabetic nephropathy, each 50% reduction in urinary protein excretion was associated with a 56% reduction in risk of progression of CKD. Similar effects have been shown in nondiabetic CKD patients.⁴⁷

ACE inhibitors and ARBs are the preferred treatments for proteinuria in patients with CKD.^48–50 Combination therapy with an ACE inhibitor and an ARB has been used,^51–53 with a better response in proteinuria reduction. However, combination therapy with these drugs cannot currently be recommended, as the only prospective study of this regimen to date suggested worse renal and overall outcomes in patients at high cardiovascular risk.⁵⁴ These drugs may also have renoprotective effects independent of their effects on blood pressure and proteinuria.³⁸ Dietary salt restriction and diuretic therapy can further increase the efficacy of proteinuria reduction by ACE inhibitors or ARBs.^55,56

On the other hand, stopping ACE inhibitors or ARBs may be beneficial as the patient nears end-stage renal disease. Ahmed et al⁵⁷ demonstrated that stopping ACE inhibitors or ARBs in advanced stage 4 CKD (mean estimated GFR 16 mL/min/1.73 m²) was associated with improved GFR and delayed onset of renal replacement therapy. This improvement may be due to regaining the slight decrease in GFR that occurred when these medications were started.

Nondihydropyridine calcium channel blockers such as diltiazem (Cardizem) and verapamil (Calan) have also been shown to be useful for reducing proteinuria,⁵⁸ whereas dihydropyridine calcium channel blockers such as amlodipine (Norvasc) and nifedipine (Procardia), when used without ACE inhibitors or ARBs, can worsen proteinuria.^58,59

Correct metabolic acidosis

The kidneys play an important role in maintaining acid-base balance, keeping the blood from becoming too acidic both by reabsorbing bicarbonate filtered into the urine by the glomerulus and by excreting the daily acid load. Metabolic acidosis can develop when these functions break down at more advanced stages of CKD, most often when the estimated GFR declines to less than 20 mL/min/1.73 m².

Bicarbonate levels of 22 mmol/L or less have been associated with a higher risk of worsening renal function.⁶⁰ When such patients were treated with sodium bicarbonate to achieve a serum bicarbonate of at least 23 mmol/L, they had an 80% lower rate of progression to end-stage renal disease without any increase in edema, admission for congestive heart failure, or change in blood pressure.⁶¹

Susantitaphong et al⁶² reviewed six randomized trials of bicarbonate supplementation in CKD and found that it was associated with improved kidney function and a 79% lower rate of progression to end-stage renal disease.

The proposed mechanism behind this benefit lies in the increase in ammonia production that each surviving nephron must undertake to handle the daily acid load. The increased ammonia is thought to play a role in activating the alternative complement pathway,⁶³ causing renal inflammation and injury.

Recommendation. Bicarbonate therapy should be used to maintain serum bicarbonate levels above 22 mmol/L in CKD.⁶⁴

OTHER ASPECTS OF CKD CARE

Bone mineral disorders

Patients with CKD develop secondary hyperparathyroidism, hyperphosphatemia, and (in advanced CKD) hypocalcemia, all leading to disorders of bone mineral metabolism.

Traditionally, it has been thought that decreased production of 1,25-dihydroxyvitamin D by dysfunctional kidneys leads to decreased suppression of the parathyroid gland and to secondary hyperparathyroidism. The major long-term adverse effect of this is a weakened bone matrix resulting from increased calcium and phosphorus efflux from bones (renal osteodystrophy).

The discovery of fibroblast growth factor 23 (FGF-23) has improved our understanding of the physiology behind disordered bone mineral metabolism in CKD. FGF-23, produced by osteoblasts and osteocytes, acts directly on the kidney to increase renal phosphate excretion. It also suppresses 1,25-dihydroxyvitamin D levels by inhibiting 1-alpha-hydroxylase,⁶⁵ and it stimulates parathyroid hormone secretion. FGF-23 levels rise much earlier in CKD than do parathyroid hormone levels, suggesting that abnormalities in phosphorus balance and FGF-23 may be the earliest pathophysiologic changes.⁶⁶

The initial treatment of bone mineral disorders is to some extent guided by laboratory values. Phosphate levels higher than 3.5 or 4 mg/dL and elevated FGF-23 levels have been associated with increased mortality rates in CKD patients.^{18,19,67–69} All patients should also have their 1,25-dihydroxyvitamin D level checked and supplemented if deficient. In many patients with early stage 3 CKD, this may correct secondary hyperparathyroidism.⁷⁰

Serum phosphorus levels should be kept in the normal range in stage 3 and 4 CKD,⁷¹ either by restricting dietary phosphorus intake (< 800 or < 1,000 mg/day) or by using a phosphate binder, which is taken with meals to prevent phosphorus absorption from the gastrointestinal tract. Current US recommendations are to allow graded increases in parathyroid hormone based on the stage of CKD (Table 2).⁷¹ However, these targets are still an area of uncertainty, with some guidelines suggesting that wider variations in parathyroid hormone can be allowed, so there may be wider variation in clinical practice in this area.⁷² If the serum phosphorus level is in the goal range but parathyroid hormone levels are still high, an activated vitamin D analogue such as calcitriol is recommended, although with the emerging role of FGF-23, some experts also call for early use of a phosphate binder in this group.

The treatment of bone mineral disorders in CKD is fairly complex, and we recommend that it be done by or with the close direction of a nephrologist.

Recommendations on bone disorders

• Check levels of calcium, phosphorus, 25-hydroxyvitamin D, and parathyroid hormone in all patients whose estimated GFR is less than 60 mL/min/1.73 m², with frequency of measurements based on the stage of CKD.⁷¹
• Replace vitamin D if deficient.
• Treat elevated phosphorus levels with a protein-restricted diet (nutrition referral) and a phosphate binder.
• Treat elevated hyperparathyroid hormone levels with a vitamin D analogue once phosphorus levels have been controlled.
• Refer patients with an elevated phosphorus or parathyroid hormone level to a nephrology service for consultation before initiating medical therapy.

Anemia is common, treatment controversial

The treatment of anemia attributed to CKD has been a topic of controversy over the past decade, and we recommend that it be done with the guidance of a nephrologist.

Anemia is common in CKD, and declining kidney function is an independent predictor of anemia.⁷³ Anemia is a risk factor for left ventricular hypertrophy, cardiovascular disease,⁷⁴ and death in CKD.⁷⁵

The anemia of CKD is attributed to relative erythropoietin deficiency and bone marrow resistance to erythropoietin, but this is a diagnosis of exclusion, and other causes of anemia must be ruled out. Iron deficiency is a common cause of anemia in CKD, and treatment of iron deficiency may correct anemia in more than one-third of these patients.^76,77

Erythropoiesis-stimulating agents such as epoetin alfa (Procrit) and darbepoetin (Aranesp) are used to treat renal anemia. However, the target hemoglobin level has been a subject of debate. Three prospective trials^78–80 found no benefit in raising the hemoglobin level to normal ranges using these agents, and several found an association with higher rates of stroke and venous thrombosis. The US Food and Drug Administration suggests that the only role for these agents in CKD is to avoid the need for transfusions. They should not be used to normalize the hemoglobin level. The target, although not explicitly specified, is suggested to be around 10 g/dL.⁸¹

PREPARE FOR END-STAGE RENAL DISEASE

Discuss the options

Because the risk of developing end-stage renal disease rises dramatically once CKD reaches stage 4, all such patients should have a discussion about renal replacement therapy. They should be educated about their options for treatment (hemodialysis, peritoneal dialysis, and transplantation, as well as not proceeding with renal replacement therapy), often in a formal class. They should then be actively engaged in the decision about how to proceed. Survival and quality of life should be discussed, particularly with patients who are over age 80, who are severely ill, or who are living in a nursing facility, as these groups get limited survival benefit from starting dialysis, and quality of life may actually decrease with dialysis.^82,83

The Renal Physicians Association has created clinical practice guidelines for shared decision-making, consisting of 10 practice recommendations that outline a systematic approach to patients needing renal replacement therapy.⁸⁴

Consider preemptive kidney transplantation

Any patient thought to be a suitable candidate for renal transplantation should be referred to a transplantation center for evaluation. Studies have shown that kidney transplantation offers a survival advantage compared with chronic dialysis and should preferably be done preemptively, ie, before dialysis is required.^85–90 Therefore, patients with estimated GFRs in the low 20s should be referred for a transplantation evaluation.

If a living donor is available, the transplantation team usually waits to perform the procedure until the patient is closer to needing dialysis, often when the estimated GFR is around 15 to 16 mL/min/1.73 m². If no living donor is available, the patient can earn time on the deceased-donor waiting list once his or her estimated GFR falls to below 20 mL/min/1.7 m².

Plan for dialysis access

Patients starting hemodialysis first need to undergo a procedure to provide access to the blood. The three options are an arteriovenous fistula, an arteriovenous graft, and a central venous catheter (Figure 1).

An arteriovenous fistula is the best option, being the most durable, followed by a graft and then a catheter.⁹¹ Arteriovenous fistulas also have the lowest rates of infection,⁹² thrombosis,⁹³ and intervention to maintain patency.⁹³

The fistula is created by ligating a vein draining an extremity, most often the nondominant arm, and anastomosing the vein to an artery. The higher arterial pressure causes the vein to dilate and thicken (“arterialize”), thus making it able to withstand repeated cannulation necessary for hemodialysis.

An arteriovenous fistula typically takes 1 to 3 months to “mature” to the point where it can be used,^94,95 and, depending on the patient and experience of the vascular surgeon, a significant number may never mature. Thus, it is important to discuss hemodialysis access before the patient reaches end-stage renal disease so that he or she can be referred to a vascular surgeon early, when the estimated GFR is about 20 mL/min/1.73 m².

An arteriovenous graft. Not all patients have suitable vessels for creation of an arteriovenous fistula. In such patients, an arteriovenous graft, typically made of polytetrafluoroethylene, is the next best option. The graft is typically ready to use in 2 weeks and thus does not require as much advance planning. Grafts tend to narrow more often than fistulas and require more procedures to keep them patent.

A central venous catheter is most often inserted into the internal jugular vein and tunneled under the skin to exit in an area covered by the patient’s shirt.

Tunneled dialysis catheters are associated with higher rates of infection, thrombosis, and overall mortality and are therefore the least preferred choice. They are reserved for patients who have not had advance planning for end-stage renal disease, who do not have acceptable vessels for an arteriovenous fistula or graft, or who have refused surgical access.

Protect the fistula arm. It is recommended that venipuncture, intravenous lines, and blood pressure measurements be avoided in the nondominant upper arm of patients with stage 4 and 5 CKD to protect those veins for the potential creation of an arteriovenous fistula.⁹⁶ For the same reason, peripherally inserted central catheter lines and subclavian catheters should be avoided in these patients. If an arteriovenous fistula has already been placed, this arm must be protected from such procedures at all times.

Studies have shown that late referral to a nephrologist is associated with a lower incidence of starting dialysis with a permanent vascular access.^97,98

If the patient wishes to start peritoneal dialysis, the peritoneal dialysis catheter can usually be used 2 weeks after being inserted.

Starting dialysis

The appropriate time for starting dialysis remains controversial, especially in elderly patients with multiple comorbid conditions.

The IDEAL study⁹⁹ found no benefit in starting dialysis at a GFR of 10 to 14 mL/min compared with 5 to 7 mL/min. Thus, there is no single estimated GFR at which dialysis should be started. Rather, the development of early uremic symptoms and the patient’s quality of life should guide this decision.^{82,83,99–101}

Hemodialysis involves three sessions per week, each taking about 4 hours. Evidence suggests that longer sessions or more sessions per week may offer benefits, especially in terms of blood pressure, volume, and dietary management. This has led to an increase in the popularity of home and in-center nocturnal hemodialysis programs across the United States.

Peritoneal dialysis?

Peritoneal dialysis is an excellent choice for patients who are motivated, can care for themselves at home, and have a support system available to assist them if needed. It allows for daily dialysis, less fluid restriction, and less dietary restriction, and it gives the patient an opportunity to stay independent. It also spares the veins in the arms, which may be needed for vascular access later in life if hemodialysis is needed.

Recommendation. We recommend that peritoneal dialysis be offered to any suitable patient who is approaching end-stage renal disease.

A COMPREHENSIVE, COLLABORATIVE APPROACH

Chronic kidney disease is a multisystem disorder, and its management requires a comprehensive approach (Table 3). Early detection and interventions are key to reducing cardiovascular events and progression to kidney failure.

Early referral to a nephrologist and team collaboration between the primary care provider, the nephrologist, and other health care providers are essential. Early in the course of CKD, it may be appropriate for a nephrologist to evaluate the patient and recommend a set of treatment goals. Follow-up may be infrequent or unnecessary.

As CKD progresses, especially as the patient reaches an estimated GFR of 30 mL/min/1.73 m², the nephrologist will take a more active role in the patient’s care and medical decision-making. In some circumstances, it may even be appropriate for the nephrologist to be the patient’s source of primary care, with the primary care provider as a consultant.

Caring for patients with CKD includes not only strategies to preserve renal function and prolong survival, but also making critical decisions about starting dialysis and about the need for transplantation. Early involvement of a nephrologist and early preparation for end-stage renal disease with preemptive transplantation and arteriovenous fistula placement are associated with better patient outcomes. Key to this is collaboration between the primary care provider and the nephrologist, with levels of responsibility for patient care that adapt to the patient’s degree of renal dysfunction and other comorbidities. Such strategies to select patients for timely nephrology referral may help improve outcomes in this vulnerable population.

New research has found that hospital-onset Clostridium difficile infections increase length of stay (LOS), risk of in-hospital mortality, and hospital costs for inpatients with sepsis.

Authors of a new study titled, "The Impact of Hospital-onset Clostridium difficile Infection on Outcomes of Hospitalized Patients with Sepsis," report that after multivariate adjustment, in-hospital mortality rate was 24% for patients with sepsis who develop C. diff infections, versus 15% of inpatient controls, according to the paper that was published online in the Journal of Hospital Medicine earlier this month. Adjusted LOS among cases with C. diff was 5.1 days longer than controls (95% confidence interval: 4.4–5.8), and the median-adjusted cost increase was $4,916 (P<0.001).

"Big numbers, but I'm actually not surprised," says lead author Tara Lagu, MD, MPH, a hospitalist at the Center for Quality of Care Research at Baystate Medical Center in Springfield, Mass. "I know that it happens, because I see it all the time."

Dr. Lagu says that when a patient is on day four of five of a stay for sepsis and develops diarrhea, precautions and treatment will last a minimum of three days, which drives up LOS and cost of care.

In the report, Dr. Lagu did not compare the cost-effectiveness of C. diff prevention programs aimed at sepsis patients, but she's hopeful that is how physicians will use the data.

"I'm just suggesting that if, as a hospital, you're trying to figure out if your program is worth it, think about these numbers in terms of prevention,” she says. "If it looks like the cost is worth it, then you should keep doing what you're doing. If not, then maybe you should do something different if you're not preventing enough cases."

Visit our website for more information on preventing, managing C. diff infections.

New research has found that hospital-onset Clostridium difficile infections increase length of stay (LOS), risk of in-hospital mortality, and hospital costs for inpatients with sepsis.

Authors of a new study titled, "The Impact of Hospital-onset Clostridium difficile Infection on Outcomes of Hospitalized Patients with Sepsis," report that after multivariate adjustment, in-hospital mortality rate was 24% for patients with sepsis who develop C. diff infections, versus 15% of inpatient controls, according to the paper that was published online in the Journal of Hospital Medicine earlier this month. Adjusted LOS among cases with C. diff was 5.1 days longer than controls (95% confidence interval: 4.4–5.8), and the median-adjusted cost increase was $4,916 (P<0.001).

"Big numbers, but I'm actually not surprised," says lead author Tara Lagu, MD, MPH, a hospitalist at the Center for Quality of Care Research at Baystate Medical Center in Springfield, Mass. "I know that it happens, because I see it all the time."

Dr. Lagu says that when a patient is on day four of five of a stay for sepsis and develops diarrhea, precautions and treatment will last a minimum of three days, which drives up LOS and cost of care.

In the report, Dr. Lagu did not compare the cost-effectiveness of C. diff prevention programs aimed at sepsis patients, but she's hopeful that is how physicians will use the data.

"I'm just suggesting that if, as a hospital, you're trying to figure out if your program is worth it, think about these numbers in terms of prevention,” she says. "If it looks like the cost is worth it, then you should keep doing what you're doing. If not, then maybe you should do something different if you're not preventing enough cases."

Visit our website for more information on preventing, managing C. diff infections.

New research has found that hospital-onset Clostridium difficile infections increase length of stay (LOS), risk of in-hospital mortality, and hospital costs for inpatients with sepsis.

Authors of a new study titled, "The Impact of Hospital-onset Clostridium difficile Infection on Outcomes of Hospitalized Patients with Sepsis," report that after multivariate adjustment, in-hospital mortality rate was 24% for patients with sepsis who develop C. diff infections, versus 15% of inpatient controls, according to the paper that was published online in the Journal of Hospital Medicine earlier this month. Adjusted LOS among cases with C. diff was 5.1 days longer than controls (95% confidence interval: 4.4–5.8), and the median-adjusted cost increase was $4,916 (P<0.001).

"Big numbers, but I'm actually not surprised," says lead author Tara Lagu, MD, MPH, a hospitalist at the Center for Quality of Care Research at Baystate Medical Center in Springfield, Mass. "I know that it happens, because I see it all the time."

Dr. Lagu says that when a patient is on day four of five of a stay for sepsis and develops diarrhea, precautions and treatment will last a minimum of three days, which drives up LOS and cost of care.

In the report, Dr. Lagu did not compare the cost-effectiveness of C. diff prevention programs aimed at sepsis patients, but she's hopeful that is how physicians will use the data.

"I'm just suggesting that if, as a hospital, you're trying to figure out if your program is worth it, think about these numbers in terms of prevention,” she says. "If it looks like the cost is worth it, then you should keep doing what you're doing. If not, then maybe you should do something different if you're not preventing enough cases."

Visit our website for more information on preventing, managing C. diff infections.

Clinical question: In patients with ischemic heart disease (IHD) undergoing non-cardiac surgery, do pre-operative beta blockers reduce post-operative major cardiovascular events (MACE) or mortality at 30 days?

Background: Pre-operative beta blocker use has become more restricted, as evidence about which patients derive benefit has become clearer. Opinions and practice vary regarding whether all patients with IHD, or only certain populations within this group, benefit from pre-operative beta blockers.

Study design: Retrospective, national registry-based cohort study.

Setting: Denmark, 2004-2009.

Synopsis: No benefit was found for the overall cohort of 28,263 patients. Patients with IHD and heart failure (n=7990) had lower risk of MACE (HR=0.75, 95% CI, 0.70-0.87) and mortality (HR=0.80, 95% CI, 0.70-0.92). Patients with IHD and myocardial infarction within two years (n=1664) had lower risk of MACE (HR=0.54, 95% CI, 0.37-0.78) but not mortality. Beta blocker dose and compliance were unknown. Whether patients had symptoms or inducible ischemia was not clear. This study supports the concept that higher-risk patients benefit more from pre-operative beta blockers, but it is not high-grade evidence.

Bottom line: Not all patients with IHD benefit from pre-operative beta blockers; those with concomitant heart failure or recent MI have a lower risk of MACE and/or mortality at 30 days with beta blockers.

Citation: Andersson C, Merie C, Jorgensen M, et al. Association of ß-blocker therapy with risks of adverse cardiovascular events and deaths in patients with ischemic heart disease undergoing non-cardiac surgery: A Danish nationwide cohort study JAMA Intern Med. 2014;174(3):336-344.

Clinical question: In patients with ischemic heart disease (IHD) undergoing non-cardiac surgery, do pre-operative beta blockers reduce post-operative major cardiovascular events (MACE) or mortality at 30 days?

Background: Pre-operative beta blocker use has become more restricted, as evidence about which patients derive benefit has become clearer. Opinions and practice vary regarding whether all patients with IHD, or only certain populations within this group, benefit from pre-operative beta blockers.

Study design: Retrospective, national registry-based cohort study.

Setting: Denmark, 2004-2009.

Synopsis: No benefit was found for the overall cohort of 28,263 patients. Patients with IHD and heart failure (n=7990) had lower risk of MACE (HR=0.75, 95% CI, 0.70-0.87) and mortality (HR=0.80, 95% CI, 0.70-0.92). Patients with IHD and myocardial infarction within two years (n=1664) had lower risk of MACE (HR=0.54, 95% CI, 0.37-0.78) but not mortality. Beta blocker dose and compliance were unknown. Whether patients had symptoms or inducible ischemia was not clear. This study supports the concept that higher-risk patients benefit more from pre-operative beta blockers, but it is not high-grade evidence.

Bottom line: Not all patients with IHD benefit from pre-operative beta blockers; those with concomitant heart failure or recent MI have a lower risk of MACE and/or mortality at 30 days with beta blockers.

Citation: Andersson C, Merie C, Jorgensen M, et al. Association of ß-blocker therapy with risks of adverse cardiovascular events and deaths in patients with ischemic heart disease undergoing non-cardiac surgery: A Danish nationwide cohort study JAMA Intern Med. 2014;174(3):336-344.

Clinical question: In patients with ischemic heart disease (IHD) undergoing non-cardiac surgery, do pre-operative beta blockers reduce post-operative major cardiovascular events (MACE) or mortality at 30 days?

Background: Pre-operative beta blocker use has become more restricted, as evidence about which patients derive benefit has become clearer. Opinions and practice vary regarding whether all patients with IHD, or only certain populations within this group, benefit from pre-operative beta blockers.

Study design: Retrospective, national registry-based cohort study.

Setting: Denmark, 2004-2009.

Synopsis: No benefit was found for the overall cohort of 28,263 patients. Patients with IHD and heart failure (n=7990) had lower risk of MACE (HR=0.75, 95% CI, 0.70-0.87) and mortality (HR=0.80, 95% CI, 0.70-0.92). Patients with IHD and myocardial infarction within two years (n=1664) had lower risk of MACE (HR=0.54, 95% CI, 0.37-0.78) but not mortality. Beta blocker dose and compliance were unknown. Whether patients had symptoms or inducible ischemia was not clear. This study supports the concept that higher-risk patients benefit more from pre-operative beta blockers, but it is not high-grade evidence.

Bottom line: Not all patients with IHD benefit from pre-operative beta blockers; those with concomitant heart failure or recent MI have a lower risk of MACE and/or mortality at 30 days with beta blockers.

Citation: Andersson C, Merie C, Jorgensen M, et al. Association of ß-blocker therapy with risks of adverse cardiovascular events and deaths in patients with ischemic heart disease undergoing non-cardiac surgery: A Danish nationwide cohort study JAMA Intern Med. 2014;174(3):336-344.

PHILADELPHIA – Eteplirsen safely maintained its beneficial effect on walking speeds for certain patients with Duchenne muscular dystrophy for more than 2 years and was the first drug to show stabilized diaphragm function over the same period.

The investigational gene therapy drug had a stabilizing effect on patients’ walking speed over the course of 120 weeks regardless of whether they started it earlier or later in the open-label extension of the initial 24-week, randomized trial, but those who started treatment earlier maintained a higher walking speed, Dr. Jerry R. Mendell said at the annual meeting of the American Academy of Neurology.

Coinvestigator Dr. Edward M. Kaye of Sarepta Therapeutics, the study sponsor, presented in-depth safety and pharmacokinetics data that showed no significant treatment-related adverse events with eteplirsen in the small study. No patients have discontinued or disrupted treatment, and no laboratory evidence of toxicity has been seen to date.

The initial 24-week, double-blind, randomized, placebo-controlled study involved four patients who were given the equivalent of 30 mg/kg eteplirsen weekly, four given 50 mg/kg eteplirsen weekly, and four given placebo. At the start of the open-label extension study, two of the placebo-treated patients were transitioned to 30 mg/kg weekly and two to 50 mg/kg weekly.

All patients underwent muscle biopsy at baseline, followed by biopsies at 12 weeks in two of the high-dose patients and in two of the placebo-treated patients, and at 24 weeks in the four patients taking 30 mg/kg weekly and in two placebo-treated patients.

"This design permitted a comparison between high dose over a shorter time interval and low dose over a longer time interval," said Dr. Mendell of the Center for Gene Therapy at Nationwide Children’s Hospital, Columbus, Ohio.

All patients underwent a biopsy at 1 year (48 weeks) in the open-label extension (Ann. Neurol. 2013;74:637-47).

By 48 weeks, the mean percentage of dystrophin-positive muscle fibers was 34% in the placebo/30 mg/kg delayed-treatment group, 43% in the placebo/50 mg/kg delayed-treatment group, 42% in the 50-mg/kg group, and 52% in the 30-mg/kg group.

Distance traveled on the 6-minute walk test began to diverge between active and placebo-treated patients at 12 weeks and stabilized at 24 weeks among those who received active treatment, but continued to decline until 36 weeks for placebo-treated patients who started treatment at 24 weeks.

At 120 weeks, the patients who had received continuous treatment with eteplirsen declined by a mean of 14 m on the 6-minute walk test since baseline, compared with a decline of 79 m in those who underwent delayed treatment with eteplirsen. In comparison, studies of the natural history of Duchenne muscular dystrophy (DMD) have shown steady declines on the 6-minute walk test, ranging from 30 to 115 m at 1 year and 97 to 125 m at 2 years.

There was "remarkable stability" in diaphragm function over the course of treatment with eteplirsen, "which is quite different from the natural history of untreated patients," Dr. Mendell said. In all 12 patients, maximal expiratory pressure remained stable, going from a mean of 90% of predicted at baseline to 95% at 120 weeks. The same was true for maximal inspiratory pressure, moving from 79% of expected at baseline to 80% at 120 weeks. In contrast, the natural history of untreated DMD shows that pulmonary function declines substantially over time: by 3.9%/year for maximal inspiratory pressure after starting at 90% of predicted at 9 years of age, and by 3.6%/year after starting at 45% of predicted at 9 years of age (Pediatr. Pulmonol. 2014;49:473-81).

Eteplirsen was created to help patients with a deletion of exon 51 in dystrophin, which causes a nonfunctional dystrophin protein. The drug is a charge-neutral phosphorodiamidate morpholino oligomer (PMO) that targets the 13% of DMD patients with this mutation by directing alternative splicing of the dystrophin gene through its ability to bind to exon 51 of dystrophin pre-mRNA. This restores transcription and translation of a truncated, yet functional, dystrophin protein, such as those found in Becker muscular dystrophy.

The neutral charge of eteplirsen helps it to avoid binding to serum proteins, which is one of the problems that have occurred with phosphorothioate antisense oligonucleotide-based drugs. Phosphorothioate antisense drugs have also been linked to immune activation, hepatotoxicity, thrombocytopenia, coagulopathy, renal toxicity, and proteinuria. But Dr. Kaye reported that eteplirsen is mainly excreted by the kidneys, has a half-life of about 3 hours, and showed no evidence of those problems. Only 13 of 453 urine protein assessments tested positive, but all were low, transient, and resolved spontaneously.

"The reason that this is important is there has actually been very little human data until recently, despite the fact that [PMOs have] been around for over 30 years. Most of the work has been done in animals and in research laboratories, and it’s only until recently that people have been exposed to the drug," Dr. Kaye said.

The study was funded by Sarepta Therapeutics. Dr. Kaye and two coauthors are employees of the company. Dr. Mendell had no relevant disclosures.

[email protected]

PHILADELPHIA – Eteplirsen safely maintained its beneficial effect on walking speeds for certain patients with Duchenne muscular dystrophy for more than 2 years and was the first drug to show stabilized diaphragm function over the same period.

The investigational gene therapy drug had a stabilizing effect on patients’ walking speed over the course of 120 weeks regardless of whether they started it earlier or later in the open-label extension of the initial 24-week, randomized trial, but those who started treatment earlier maintained a higher walking speed, Dr. Jerry R. Mendell said at the annual meeting of the American Academy of Neurology.

Coinvestigator Dr. Edward M. Kaye of Sarepta Therapeutics, the study sponsor, presented in-depth safety and pharmacokinetics data that showed no significant treatment-related adverse events with eteplirsen in the small study. No patients have discontinued or disrupted treatment, and no laboratory evidence of toxicity has been seen to date.

The initial 24-week, double-blind, randomized, placebo-controlled study involved four patients who were given the equivalent of 30 mg/kg eteplirsen weekly, four given 50 mg/kg eteplirsen weekly, and four given placebo. At the start of the open-label extension study, two of the placebo-treated patients were transitioned to 30 mg/kg weekly and two to 50 mg/kg weekly.

All patients underwent muscle biopsy at baseline, followed by biopsies at 12 weeks in two of the high-dose patients and in two of the placebo-treated patients, and at 24 weeks in the four patients taking 30 mg/kg weekly and in two placebo-treated patients.

"This design permitted a comparison between high dose over a shorter time interval and low dose over a longer time interval," said Dr. Mendell of the Center for Gene Therapy at Nationwide Children’s Hospital, Columbus, Ohio.

All patients underwent a biopsy at 1 year (48 weeks) in the open-label extension (Ann. Neurol. 2013;74:637-47).

By 48 weeks, the mean percentage of dystrophin-positive muscle fibers was 34% in the placebo/30 mg/kg delayed-treatment group, 43% in the placebo/50 mg/kg delayed-treatment group, 42% in the 50-mg/kg group, and 52% in the 30-mg/kg group.

Distance traveled on the 6-minute walk test began to diverge between active and placebo-treated patients at 12 weeks and stabilized at 24 weeks among those who received active treatment, but continued to decline until 36 weeks for placebo-treated patients who started treatment at 24 weeks.

At 120 weeks, the patients who had received continuous treatment with eteplirsen declined by a mean of 14 m on the 6-minute walk test since baseline, compared with a decline of 79 m in those who underwent delayed treatment with eteplirsen. In comparison, studies of the natural history of Duchenne muscular dystrophy (DMD) have shown steady declines on the 6-minute walk test, ranging from 30 to 115 m at 1 year and 97 to 125 m at 2 years.

There was "remarkable stability" in diaphragm function over the course of treatment with eteplirsen, "which is quite different from the natural history of untreated patients," Dr. Mendell said. In all 12 patients, maximal expiratory pressure remained stable, going from a mean of 90% of predicted at baseline to 95% at 120 weeks. The same was true for maximal inspiratory pressure, moving from 79% of expected at baseline to 80% at 120 weeks. In contrast, the natural history of untreated DMD shows that pulmonary function declines substantially over time: by 3.9%/year for maximal inspiratory pressure after starting at 90% of predicted at 9 years of age, and by 3.6%/year after starting at 45% of predicted at 9 years of age (Pediatr. Pulmonol. 2014;49:473-81).

Eteplirsen was created to help patients with a deletion of exon 51 in dystrophin, which causes a nonfunctional dystrophin protein. The drug is a charge-neutral phosphorodiamidate morpholino oligomer (PMO) that targets the 13% of DMD patients with this mutation by directing alternative splicing of the dystrophin gene through its ability to bind to exon 51 of dystrophin pre-mRNA. This restores transcription and translation of a truncated, yet functional, dystrophin protein, such as those found in Becker muscular dystrophy.

The neutral charge of eteplirsen helps it to avoid binding to serum proteins, which is one of the problems that have occurred with phosphorothioate antisense oligonucleotide-based drugs. Phosphorothioate antisense drugs have also been linked to immune activation, hepatotoxicity, thrombocytopenia, coagulopathy, renal toxicity, and proteinuria. But Dr. Kaye reported that eteplirsen is mainly excreted by the kidneys, has a half-life of about 3 hours, and showed no evidence of those problems. Only 13 of 453 urine protein assessments tested positive, but all were low, transient, and resolved spontaneously.

"The reason that this is important is there has actually been very little human data until recently, despite the fact that [PMOs have] been around for over 30 years. Most of the work has been done in animals and in research laboratories, and it’s only until recently that people have been exposed to the drug," Dr. Kaye said.

The study was funded by Sarepta Therapeutics. Dr. Kaye and two coauthors are employees of the company. Dr. Mendell had no relevant disclosures.

[email protected]

PHILADELPHIA – Eteplirsen safely maintained its beneficial effect on walking speeds for certain patients with Duchenne muscular dystrophy for more than 2 years and was the first drug to show stabilized diaphragm function over the same period.

The investigational gene therapy drug had a stabilizing effect on patients’ walking speed over the course of 120 weeks regardless of whether they started it earlier or later in the open-label extension of the initial 24-week, randomized trial, but those who started treatment earlier maintained a higher walking speed, Dr. Jerry R. Mendell said at the annual meeting of the American Academy of Neurology.

Coinvestigator Dr. Edward M. Kaye of Sarepta Therapeutics, the study sponsor, presented in-depth safety and pharmacokinetics data that showed no significant treatment-related adverse events with eteplirsen in the small study. No patients have discontinued or disrupted treatment, and no laboratory evidence of toxicity has been seen to date.

The initial 24-week, double-blind, randomized, placebo-controlled study involved four patients who were given the equivalent of 30 mg/kg eteplirsen weekly, four given 50 mg/kg eteplirsen weekly, and four given placebo. At the start of the open-label extension study, two of the placebo-treated patients were transitioned to 30 mg/kg weekly and two to 50 mg/kg weekly.

All patients underwent muscle biopsy at baseline, followed by biopsies at 12 weeks in two of the high-dose patients and in two of the placebo-treated patients, and at 24 weeks in the four patients taking 30 mg/kg weekly and in two placebo-treated patients.

"This design permitted a comparison between high dose over a shorter time interval and low dose over a longer time interval," said Dr. Mendell of the Center for Gene Therapy at Nationwide Children’s Hospital, Columbus, Ohio.

All patients underwent a biopsy at 1 year (48 weeks) in the open-label extension (Ann. Neurol. 2013;74:637-47).

By 48 weeks, the mean percentage of dystrophin-positive muscle fibers was 34% in the placebo/30 mg/kg delayed-treatment group, 43% in the placebo/50 mg/kg delayed-treatment group, 42% in the 50-mg/kg group, and 52% in the 30-mg/kg group.

Distance traveled on the 6-minute walk test began to diverge between active and placebo-treated patients at 12 weeks and stabilized at 24 weeks among those who received active treatment, but continued to decline until 36 weeks for placebo-treated patients who started treatment at 24 weeks.

At 120 weeks, the patients who had received continuous treatment with eteplirsen declined by a mean of 14 m on the 6-minute walk test since baseline, compared with a decline of 79 m in those who underwent delayed treatment with eteplirsen. In comparison, studies of the natural history of Duchenne muscular dystrophy (DMD) have shown steady declines on the 6-minute walk test, ranging from 30 to 115 m at 1 year and 97 to 125 m at 2 years.

There was "remarkable stability" in diaphragm function over the course of treatment with eteplirsen, "which is quite different from the natural history of untreated patients," Dr. Mendell said. In all 12 patients, maximal expiratory pressure remained stable, going from a mean of 90% of predicted at baseline to 95% at 120 weeks. The same was true for maximal inspiratory pressure, moving from 79% of expected at baseline to 80% at 120 weeks. In contrast, the natural history of untreated DMD shows that pulmonary function declines substantially over time: by 3.9%/year for maximal inspiratory pressure after starting at 90% of predicted at 9 years of age, and by 3.6%/year after starting at 45% of predicted at 9 years of age (Pediatr. Pulmonol. 2014;49:473-81).

Eteplirsen was created to help patients with a deletion of exon 51 in dystrophin, which causes a nonfunctional dystrophin protein. The drug is a charge-neutral phosphorodiamidate morpholino oligomer (PMO) that targets the 13% of DMD patients with this mutation by directing alternative splicing of the dystrophin gene through its ability to bind to exon 51 of dystrophin pre-mRNA. This restores transcription and translation of a truncated, yet functional, dystrophin protein, such as those found in Becker muscular dystrophy.

The neutral charge of eteplirsen helps it to avoid binding to serum proteins, which is one of the problems that have occurred with phosphorothioate antisense oligonucleotide-based drugs. Phosphorothioate antisense drugs have also been linked to immune activation, hepatotoxicity, thrombocytopenia, coagulopathy, renal toxicity, and proteinuria. But Dr. Kaye reported that eteplirsen is mainly excreted by the kidneys, has a half-life of about 3 hours, and showed no evidence of those problems. Only 13 of 453 urine protein assessments tested positive, but all were low, transient, and resolved spontaneously.

"The reason that this is important is there has actually been very little human data until recently, despite the fact that [PMOs have] been around for over 30 years. Most of the work has been done in animals and in research laboratories, and it’s only until recently that people have been exposed to the drug," Dr. Kaye said.

The study was funded by Sarepta Therapeutics. Dr. Kaye and two coauthors are employees of the company. Dr. Mendell had no relevant disclosures.

[email protected]

ANSWER

The radiograph demonstrates no acute osseous injury, such as fracture or dislocation. Of interest and note is increased sclerosis within both femoral heads, more so on the left versus the right side. Given the patient’s young age, such findings could be related to early avascular necrosis. His clinical symptoms certainly correlate. MRI or bone scan, as well as orthopedic evaluation, is warranted in such a case. 

Fortunately, subsequent MRI of both hips did not show any avascular necrosis but rather osteoarthritic changes. The MRI of his spinal column was negative as well.

ANSWER

The radiograph demonstrates no acute osseous injury, such as fracture or dislocation. Of interest and note is increased sclerosis within both femoral heads, more so on the left versus the right side. Given the patient’s young age, such findings could be related to early avascular necrosis. His clinical symptoms certainly correlate. MRI or bone scan, as well as orthopedic evaluation, is warranted in such a case. 

Fortunately, subsequent MRI of both hips did not show any avascular necrosis but rather osteoarthritic changes. The MRI of his spinal column was negative as well.

ANSWER

The radiograph demonstrates no acute osseous injury, such as fracture or dislocation. Of interest and note is increased sclerosis within both femoral heads, more so on the left versus the right side. Given the patient’s young age, such findings could be related to early avascular necrosis. His clinical symptoms certainly correlate. MRI or bone scan, as well as orthopedic evaluation, is warranted in such a case. 

Fortunately, subsequent MRI of both hips did not show any avascular necrosis but rather osteoarthritic changes. The MRI of his spinal column was negative as well.

ANSWER

The correct interpretation of this ECG includes sinus bradycardia with marked sinus arrhythmia and junctional escape beats with sinus arrest. An intraventricular conduction defect is also present. 

Sinus bradycardia is indicated by the normal PQRST complexes at a rate of less than 60 beats/min. A marked sinus arrhythmia is ­evidenced by more than one pause (between third and fourth beats and seventh and eighth beats on the lead I rhythm strip) on the ECG. 

Sinus arrest occurs when the sinus node fails to conduct (absence of P wave during the interval of the pause). A normal QRS complex without a preceding P wave indicates a junctional escape beat. Finally, an intraventricular conduction defect is documented by a QRS duration ≥ 110 ms in the absence of a right or left bundle branch block.

ANSWER

The correct interpretation of this ECG includes sinus bradycardia with marked sinus arrhythmia and junctional escape beats with sinus arrest. An intraventricular conduction defect is also present. 

Sinus bradycardia is indicated by the normal PQRST complexes at a rate of less than 60 beats/min. A marked sinus arrhythmia is ­evidenced by more than one pause (between third and fourth beats and seventh and eighth beats on the lead I rhythm strip) on the ECG. 

Sinus arrest occurs when the sinus node fails to conduct (absence of P wave during the interval of the pause). A normal QRS complex without a preceding P wave indicates a junctional escape beat. Finally, an intraventricular conduction defect is documented by a QRS duration ≥ 110 ms in the absence of a right or left bundle branch block.

ANSWER

The correct interpretation of this ECG includes sinus bradycardia with marked sinus arrhythmia and junctional escape beats with sinus arrest. An intraventricular conduction defect is also present. 

Sinus bradycardia is indicated by the normal PQRST complexes at a rate of less than 60 beats/min. A marked sinus arrhythmia is ­evidenced by more than one pause (between third and fourth beats and seventh and eighth beats on the lead I rhythm strip) on the ECG. 

Sinus arrest occurs when the sinus node fails to conduct (absence of P wave during the interval of the pause). A normal QRS complex without a preceding P wave indicates a junctional escape beat. Finally, an intraventricular conduction defect is documented by a QRS duration ≥ 110 ms in the absence of a right or left bundle branch block.