Drug Therapy

Constipation is both a symptom and, when chronic, a multisymptom disorder, and it can overlap with other gastrointestinal tract disorders such as dyspepsia and gastroesophageal reflux disease. Furthermore, one should keep in mind the possibility of cancer and be alert for its warning signs.

Since constipation has a variety of causes and forms, one treatment does not fit all patients. Conservative measures such as recommending that the patient increase his or her intake of dietary fiber and water and engage in more physical activity are still the cornerstone of treatment, but they do not help all patients. On the other hand, polyethylene glycol and stimulant laxatives, which are traditionally given only for a short time, can be safe and effective when given long-term if other agents fail. New agents have become available or are in development.

In this article we outline our approach to constipation, as a guide for internists.

CONSTIPATION IS COMMON, BUT HOW SHOULD WE DEFINE IT?

Constipation affects 2% to 27% (average 14.8%) of the North American adult population—approximately 63 million people.¹ It is more common than many other chronic diseases, including hypertension (48 million people), migraine (33 million), obesity (50 million), and diabetes mellitus (15 million).^1–3

Constipation affects more women than men (2.1:1 ratio) and more nonwhites than whites (1.68:1).¹ It occurs in all age groups but is more common in those older than 65 years and younger than 4 years.^4,5

Constipation accounts for more than 2.5 million office visits and more than $500 million spent on laxatives per year.^6,7 Also, people with constipation may report decreased productivity and increased absenteeism.⁸

The broad range in the prevalence of constipation cited above reflects differences in how it is defined and, in particular, a lack of agreement between how patients and physicians perceive it.^1,9 Physicians mainly define constipation on the basis of stool frequency, considering fewer than three bowel movements per week to be abnormal.¹ In contrast, patients typically define it on the basis of bothersome symptoms such as straining, passage of hard stool, unproductive urges, inability to defecate at will, and sensations of incomplete evacuation or abdominal bloating.^1,9,10

The Rome III diagnostic criteria were developed to provide a consistent diagnostic approach for use in clinical practice and clinical trials.¹¹ The Rome III criteria define functional chronic constipation as a chronic bowel disorder characterized by two or more of the following:

• Straining
• Lumpy or hard stools
• Sensations of incomplete evacuation
• Sensations of anorectal obstruction or blockage
• Use of manual maneuvers to facilitate defecation (eg, digital evacuation, support of the pelvic floor) during at least 25% of defecations
• Fewer than three bowel movements per week.

In addition, loose stools should rarely occur without the use of laxatives, and there should be insufficient criteria for irritable bowel syndrome.¹¹ Chronicity is established by symptom onset within the previous 6 months and symptom duration of at least 3 months.

In contrast, patients with irritable bowel syndrome, also a functional bowel disorder, experience recurrent abdominal pain and discomfort associated with two or more of the following: symptom improvement with defecation, symptom onset associated with a change in the frequency of bowel movements, and a change in the form or appearance of the stool.

THREE TYPES OF IDIOPATHIC CONSTIPATION

There are three types of primary or idiopathic constipation^5,9,12,13:

• Functional
• Slow-transit
• Outlet dysfunction.

Functional constipation includes functional chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. It presents with a sense of difficult or delayed evacuation, hard stools, or abdominal bloating or discomfort.^6,9,13 The predominant symptom of constipation-predominant irritable bowel syndrome is severe discomfort or pain; in chronic idiopathic constipation, pain and discomfort may be present but are not the primary symptom.

Slow-transit constipation (or delayed-transit constipation) is associated with a prolonged time between bowel movements. Its symptoms include low stool frequency, lack of urge to defecate, abdominal distention, bloating, and abdominal discomfort.¹⁴

Outlet dysfunction. Disorders of defecation can be due to mechanical causes such as Hirschsprung disease, anal stricture, cancer, prolapse, and large rectoceles, or from pelvic floor dysfunction. Pelvic floor dysfunction may be due to inadequate or excessive perineal descent or to inadequate propulsive forces, as may occur in neurologic or neuromuscular conditions and dyssynergia.

Pelvic floor dyssynergia, also called anorectal dyssynergia, dyssynergic defecation, and anismus, results from a functional defect in coordinated evacuation. The characteristic symptom is a feeling of being unable to adequately empty the rectum.¹⁴ Other symptoms such as excessive straining and manual disimpaction indicate but are not unique to pelvic floor dyssynergia.^14,15

Combined forms. Patients may have more than one type of primary constipation and presentation, and pelvic floor dyssynergia has been shown to prolong intestinal transit, which may improve with treatment.

Secondary constipation can be due to causes such as diet, lifestyle, certain medications (calcium channel blockers, beta-blockers, opioids, diuretics, antidepressants, anticonvulsants, antacids, anticholinergics, and antispasmodics),^5,16 underlying medical conditions (diabetes, hypothyroidism, multiple sclerosis, parkinsonism),^16,17 pregnancy, and advanced age.¹⁸

NEUROTRANSMITTERS MAY PLAY A ROLE

Among the mechanisms thought to cause chronic constipation are impaired gastrointestinal motility,^19–22 reduced intestinal secretions,^21–23 and inadequate reflex relaxation of the pelvic floor muscles.^22,24

Neurotransmitters such as serotonin, somatostatin, peptide YY, and vasoactive intestinal peptide affect intestinal secretion and motility.^25,26 Hyperactivity of these neurotransmitters associated with increased secretion and motility results in diarrhea, whereas hypoactivity leads to decreased secretion, delayed transit, and constipation.²³

Serotonin has a role in regulating visceral pain perception and intestinal motility, as well as secretion.^26–28 Clinical trials have shown that activation of serotonin receptors in the gut enhances gastrointestinal motility, inhibits visceral sensitivity, and stimulates intestinal secretion.^26,27,29

A hypothesis has recently been proposed that degeneration of enteric neurons may also play a role in the development of severe idiopathic constipation.³⁰

DIAGNOSIS IS MOSTLY CLINICAL

The history and physical examination remain the cornerstones in the diagnosis and subsequent treatment of chronic constipation.

History

Risk factors for primary and secondary constipation to note during the interview include age (< 4 years, > 65 years); low-fiber diet; female sex; lack of physical activity; history of childhood constipation, endocrine and neuromuscular disorders, abuse, depression, or anxiety; family history of cancer; and personal history of pelvic surgery.

Since drugs can also cause chronic constipation, especially in elderly or immobile patients, medication lists should be reviewed and adjustments should be made if necessary (or possible) before recommending laxatives or invasive testing, if no alarm signs are present.

Alarm signs such as weight loss, hematochezia, melena, change in bowel habits, and symptoms refractory to therapy may represent colon cancer and indicate the need for early diagnostic testing.

Physical examination

Physical examination should always include inspection of the perianal area for evidence of hemorrhoids or fissures. Digital rectal examination may reveal a contracted sphincter or a puborectalis muscle that contracts with the Valsalva maneuver, suggesting dysfunction.

Laboratory testing

If the history and physical examination suggest that the constipation may be secondary, or if the patient is 50 years of age or older, then laboratory studies such as a complete blood cell count, serum electrolyte levels, blood sugar level, and thyroid function studies may help rule out a metabolic, endocrine, or organic cause.

Colonoscopy, other tests

At present, little evidence suggests that routine testing is warranted in patients without evidence of secondary constipation and without alarm signs. However, diagnostic studies are indicated in patients 50 years of age and older, as well as in those with alarm symptoms such as hematochezia, anemia, a positive fecal occult blood test, unintentional loss of more than 10 pounds, family history of colon cancer or inflammatory bowel disease, fever, nausea, vomiting, acute onset (especially in the elderly), and lack of improvement with conventional therapies regardless of age.²

The full length of the colon should be inspected by colonoscopy or by flexible sigmoidoscopy paired with a barium enema study to rule out structural disease. Of note, all patients 50 years of age or older should be screened for colon cancer.

If the patient does not respond to therapy, further tests such as colonic transit studies, anorectal manometry with balloon expulsion, and, possibly, defecating proctography or dynamic pelvic magnetic resonance imaging may be considered. These patients would likely also benefit from referral to a gastroenterologist for further management

DIET AND LIFESTYLE AS TREATMENT

For many years, health care providers have provided reassurance and recommended diet and lifestyle modifications as treatment for constipation. Increased water intake, increased activity, and a scheduled attempt at defecation when motor activity in the colon is highest, ie, in the morning or after eating, have all been recommended.

Data on the efficacy of these recommendations are scarce and often contradictory. Studies have shown that increasing water intake or daily exercise is not always helpful.^32–34 Nevertheless, many patients who comply with dietary and exercise recommendations have improvement in symptoms. Eating fewer meals per day (and hence taking in fewer calories) has been shown to be associated with constipation in the elderly. However, no relationships between fiber or fluid intake and constipation were noted.³⁵

In a study in which chronically constipated patients were fed a standardized diet that contained 25 g of fiber a day, stool frequency increased significantly and laxative use decreased.³⁶ While on a high-fiber diet, the patients were divided into two groups, one that drank 1.1 L of fluid per day and one that drank 2.1 L of mineral water per day. Both groups experienced further improvements in stool frequency and decreases in laxative use, with the mineral-water group benefiting the most.³⁶

Recently, Murakami and others³⁷ found, in a cross-sectional study in young Japanese women with low daily fiber intake (6.4 g/day), that low water intake from foods and low magnesium intake were associated with an increasing prevalence of functional constipation as defined by the Rome III criteria. Constipation was also found to be significantly associated with low intake of fruits and vegetables in a study from Singapore.³⁸

Moderate physical activity and high fiber intake may be associated with a lower prevalence of constipation in women. In the Nurses’ Health Study, more than 62,000 women between the ages of 36 and 61 were surveyed, and those who said they engaged in daily physical activity had a lower prevalence of constipation (prevalence ratio [PR] = 0.56, 95% confidence interval [CI] 0.44–0.70), as did those with a median fiber intake of 20 g/day (PR = 0.64, 95% CI 0.57–0.73).³⁹

BULK LAXATIVES (FIBER SUPPLEMENTS): THE FIRST-LINE TREATMENT

Fiber remains the first-line treatment for constipation. It may relieve or improve symptoms in functional constipation. However, fewer than 30% of patients with either slow-transit constipation or pelvic floor dysfunction have improvement in symptoms with fiber, and in these types of constipation it can even worsen symptoms.⁴⁰

There is much confusion about what types of fiber should be recommended and how the various types of fiber perform in resolving constipation.

Insoluble fiber

Insoluble fiber resists bacterial degradation in the colon and can retain more water than soluble fiber can.

Bran 20 g/day increased the frequency of bowel movements by 55%, increased fecal weight by 157%, and decreased intestinal transit time by 50% in women who had three or fewer bowel movements per week.⁴¹

Muller-Lissner⁴² and others performed a meta-analysis and found that bran (25 g/day) increased stool weight and decreased transit time in both healthy controls and patients with chronic constipation. Yet constipated patients taking bran still had lower stool weights and slower transit times than did healthy subjects.

When bran 20 g/day was compared with placebo in chronically constipated patients, bowel frequency and stool weight increased with both treatments,⁴³ suggesting that factors other than intake may affect bowel function and transit time. However, bran was more effective than placebo in decreasing oroanal transit time.

Elderly constipated patients who received bran 10 g twice a day had significantly shorter transit times (89 hours vs 126 hours) than did those who received psyllium (a soluble fiber) 6 g twice daily. They also needed less additional laxative.⁴⁴

Soluble fiber

Soluble fiber also affects the bowel habits of both healthy and constipated patients.

Methylcellulose, given to healthy volunteers at a dose of 4 g/day, resulted in statistically significant increases in stool weight, fecal water weight, and fecal solids.⁴⁵ In constipated patients, methylcellulose 1 g/day was as effective as psyllium 3.4 g/day at increasing stool frequency, fecal water weight, and fecal solids.⁴⁵

Konjac glucomannan was also shown to significantly increase stool frequency, water weight, and fecal solids.⁴⁶

Psyllium. In a study that randomly assigned 22 patients with chronic constipation to receive either psyllium 5 g twice daily or placebo for 8 weeks, followed by a 4-week washout phase in which placebo was given,⁴⁷ those who received psyllium reported significant improvements in stool consistency and pain with defecation, as well as significant increases in both stool frequency (3.8 vs 2.9 per week, P < .05) and stool weight (665 g vs 405 g, P < .05). However, colonic transit times and anorectal manometric measurements did not differ significantly between those who received psyllium vs placebo.⁴⁷

Fiber may not help everyone

Others have also shown that while fiber may improve stool characteristics, it may not significantly alter the sensorimotor functions of the colon and pelvic floor.

Cheskin et al⁴⁸ performed a crossover study in 10 constipated men and women in the community. Patients received either 24 g of psyllium fiber daily or a placebo fiber for 1 month and then crossed over to the other treatment for the next month. The most common cause of constipation in this study was pelvic floor dysfunction. Total gut transit time was significantly increased by psyllium fiber, and there was a trend toward increased stool frequency, demonstrating that psyllium clinically improved constipation. However, pelvic floor dysfunction, as measured by rectal manometry, was not improved.

It may be that only people with normal-transit constipation, not those with underlying slow-transit constipation or pelvic floor dysfunction, are helped by additional dietary fiber. Voderholzer and others⁴⁰ studied 149 consecutive patients with chronic constipation and evaluated their response to at least 6 weeks of psyllium (Plantago ovata seeds 15 to 30 g/day) by serial symptom measurements, oroanal transit times, and functional rectoanal evaluation with defecography, manometry, and sigmoidoscopy. Of the patients with no evidence of pelvic floor dysfunction or slow-transit constipation, 85% improved. However, 80% of those with slow-transit constipation and 63% of those with pelvic floor dysfunction did not improve with the use of fiber. The authors concluded that it is reasonable to try dietary fiber in patients with constipation and, if no improvement is noted, to then consider further investigation for other subtypes of constipation (ie, slow-transit or pelvic-floor dysfunction).

Adverse effects may limit the use of fiber and may differ depending on the type of fiber used. Soluble fiber may be better tolerated, especially in patients with constipation-predominant irritable bowel syndrome.⁴⁹ Side effects include the sensation of bloating and distention, excessive gas production, and abdominal cramping.

Our recommendations on fiber

We recommend the following regarding fiber in constipated patients:

• Increase fiber intake from natural foods up to 20 g/day. This increase should be completed over 2 to 3 weeks to minimize adverse effects.
• Consider adding a fiber supplement, such as psyllium, if increasing the intake of natural fiber does not relieve constipation-related symptoms.
• If symptoms persist despite the use of fiber supplements and diet and lifestyle modification, then further structural and functional investigation of the colon (anorectal manometry, colonoscopy, defecography, colon manometry) should be considered.

OSMOTIC LAXATIVES

Osmotic laxatives are molecules that are either not absorbed or poorly absorbed and that draw water into the intestinal lumen to maintain isotonicity between the intestinal contents and the serum. Examples are polyethylene glycol, sodium phosphate (Fleet phosphosoda), magnesium hydroxide, magnesium citrate, the sugars lactulose and sorbitol, and glycerin.

Certain formulations of this class of laxative can cause bloating, diarrhea, electrolyte disturbances, volume overload, or dehydration. These effects limit their use, and these medications should be used with caution in patients prone to renal insufficiency or cardiac abnormalities.

Polyethylene glycol

Polyethylene glycol is an exception. It is not absorbed and lacks electrolytes, making it an attractive option in patients with underlying renal or cardiac dysfunction. In several placebo-controlled trials,^50–52 various formulations significantly increased stool frequency while significantly decreasing straining, use of other laxatives, and colonic transit. No increase in adverse effects was noted compared with placebo.

Compared with lactulose, polyethylene glycol at about 21 g/day significantly increased bowel movement frequency while significantly decreasing the sense of straining with bowel movements and flatus due to laxative use.⁵¹ Both polyethylene glycol and lactulose accelerate colonic transit, although polyethylene glycol does so to a greater extent.⁵³

Polyethylene glycol has been safe and effective when used for up to 6 months.⁵⁴

Lactulose and sorbitol

Carbohydrate or sugar-based laxatives, if taken in sufficient doses, have a cathartic effect through two mechanisms: a primary osmotic effect of the sugar itself and a secondary osmotic effect as a substrate for colonic bacteria to cleave to acid metabolites, which exert an osmotic effect in the colon. This secondary effect will be discussed in a later section.

Lactulose and sorbitol are sugars that are poorly absorbed by the intestine. Lactulose has been shown to be more effective than placebo in increasing stool frequency, volume, weight, and consistency in chronically constipated patients.⁵⁵ In a head-to-head comparison between sugar laxatives, 70% sorbitol was as effective as lactulose in increasing the frequency of bowel movements, and it was similar in its adverse effects⁵⁶; 70% sorbitol is a cost-effective alternative to lactulose in the elderly nursing home population.⁵⁷

Compared with fiber alone, lactulose use leads to a significantly higher number of bowel movements and better stool consistency.⁵⁸ However, when lactulose was compared with a combination of fiber and a stimulant laxative, it was less effective than the combination therapy.^59,60

Sugar laxatives, while effective, may have dose-limiting or use-limiting adverse effects such as abdominal bloating and flatulence.

Phosphate, magnesium

Sodium phosphate, like polyethylene glycol, is often used as a bowel preparation before colonoscopy, for which it is about as good or slightly better than polyethylene glycol.^61,62

Although magnesium and sodium phosphate preparations are effective, there are multiple reports of clinically significant electrolyte abnormalities, renal failure, and congestive heart failure occurring with these preparations. Therefore, they must be used with discretion and caution in appropriate patients with frequent monitoring.

STIMULANT (IRRITANT) LAXATIVES

Stimulant laxatives are usually reserved for use when bulking agents and osmotic laxatives fail. Their mechanism of action involves the alteration of intestinal motility and intestinal fluid secretion.

Anthraquinones (cascara, aloe, and senna), castor oil, and diphenylmethanes (bisacodyl) are the most commonly used stimulant laxatives. They work relatively quickly, often eliciting a bowel movement 2 to 8 hours after they are taken.

This class of laxatives has historically been underused or given for only short periods of time, owing to concern about impairing colonic function, damaging the enteric nervous system, causing laxative dependency, causing cathartic colon, and even causing colon cancer. However, there is very little evidence to support these concerns. Stimulant laxatives can be used on a more regular basis when bulking or osmotic agents fail.⁶³

Possibly of greatest concern is the potential for the overuse and abuse of stimulant laxatives. Excessive use can cause electrolyte disturbances brought about by high-volume watery diarrhea. Risk factors for overuse and abuse include underlying psychiatric disturbances and eating disorders. Prescribing other types of laxatives or cathartic agents may reduce risk, but the potential for abuse exists with all categories of laxatives.

TEGASEROD: GONE BUT STILL AVAILABLE, ON A CONTROLLED BASIS

Tegaserod (Zelnorm), a serotonin (5-HT4) agonist, was used predominantly in women with constipation-predominant irritable bowel syndrome and in men and women with chronic constipation. However, it was suspended from the market in the United States in March 2007 owing to concern about a high risk of adverse cardiovascular effects compared with placebo.

In a double-blind, randomized controlled trial, men with chronic constipation who received tegaserod 6 mg twice a day for 12 weeks had more spontaneous bowel movements than those receiving placebo (P = .04).⁶⁴

Lin et al⁶⁵ evaluated the use of tegaserod 6 mg twice daily for 4 weeks in both men and women with chronic constipation. Those receiving tegaserod had significantly more spontaneous bowel movements per week, less straining, and better stool consistency than those receiving placebo.

Tegaserod can still be obtained for appropriate patients via a treatment investigational new drug application. Safety data are under further review by the US Food and Drug Administration. Studies of other serotonin agonists are under way.

LUBIPROSTONE

Lubiprostone (Amitiza) is an agonist of the chloride channel subtype 2, found on the apical membrane of intestinal epithelial cells. It causes increased chloride secretion into the intestinal lumen, enhancing intestinal fluid secretion. It has been shown to be effective in chronic constipation by improving stool consistency and increasing the motility of the small intestine and colon.⁶⁶ It is approved for treating chronic constipation in adults.

In randomized, double-blind trials, patients receiving lubiprostone 24 fig twice daily for 4 weeks had significantly more bowel movements per week, reported significantly better stool consistency and less abdominal bloating and straining, and rated their constipation as less severe than did patients receiving placebo.^67–69

More recently, in an open-label study, lubiprostone improved constipation symptoms when taken for up to 48 weeks.⁷⁰

The drug is well tolerated, but its adverse effects include nausea (which appears to be dose-dependent and may diminish over time or if the drug is taken with food), diarrhea, and headache.⁶⁸ Of note, the drug appears to be well tolerated by older people (65 years of age and older), in whom adverse effects occur less often than in younger users.⁷¹ However, adverse events may cause up to 20% of patients to stop taking the drug.⁶⁹ When lubiprostone is discontinued, patients may once again revert to their baseline bowel habit.⁷²

Lubiprostone has not been compared with conventional laxatives, and cost may prohibit it from becoming a first-line drug for chronic constipation.⁷³

OTHER PROMOTILITY AGENTS

Several promotility agents have been studied for treating chronic idiopathic constipation.

Cisapride (Propulsid), a 5-HT3 receptor antagonist and 5-HT4 receptor agonist, and prucalopride, a 5-HT4 agonist, were effective in relieving symptoms associated with chronic constipation.^74–76 However, safety issues (cardiac arrhythmias) necessitated withdrawal of cisapride from the US market in 2000. Prucalopride is undergoing clinical trials.⁷⁷

Renzapride, a mixed 5-HT4 receptor agonist and 5-HT3 receptor antagonist, has been shown to improve stool consistency and to increase colonic transit in patients with constipation-predominant irritable bowel syndrome.⁷⁸ Renzapride has been studied in patients with this condition,^78–81 but not in patients with chronic constipation. Renzapride is in phase III clinical development in the United States for treating constipation-predominant irritable bowel syndrome.

EMERGING TREATMENTS

New drugs with novel mechanisms of action are being investigated for the treatment of chronic idiopathic constipation.

Neurotrophin-3, a neurotrophic factor, modulates the development of the nervous system by regulating the survival and differentiation of nerves.⁸² In patients with functional constipation, subcutaneous doses of neurotrophin-3 improved stool frequency, the number of complete spontaneous bowel movements, and stool consistency.⁸³

Alvimopan is a selective antagonist of the muopioid receptor that is being studied for opiate-related constipation and postoperative ileus.^84,85 Little of this drug is systemically absorbed and it does not cross the blood-brain barrier; thus, it relieves the opiate-related side effects, ie, bloating, abdominal discomfort, and reduced stool frequency, without interfering with the central analgesic effects.

Linaclotide (MD 1100), a poorly absorbed guanylate cyclase agonist, is also being investigated as a treatment for chronic constipation.⁸⁶ Linaclotide increases intestinal fluid secretion and transit via stimulation of cyclic guanosine monophosphate production and activation of the cystic fibrosis transmembrane conductance regulator.^86,87 In preliminary studies, linaclotide increased stool frequency and the Bristol Stool Form Scale consistency score (Table 1) by increasing intestinal fluid secretion and transit.⁸⁶

Chenodeoxycholic acid is a bile acid that is synthesized from cholesterol.⁸⁸ Treatment of constipation with chenodeoxycholic acid has been proposed, given its laxative effect. A study by Bazzoli et al⁸⁹ showed increased stool frequency and a decrease in stool consistency in chronic constipation patients given chenodeoxycholic acid 10 mg/kg/day. The main side effect was diarrhea. Chenodeoxycholic acid may be worthwhile in the management of constipation, but more studies are needed.

PROBIOTICS AND PREBIOTICS

The bacteria of the colon influence peristalsis of the colon.⁹⁰ Probiotics (live bacterial preparations) and prebiotics (nondigestible preparations that stimulate the growth or activity of beneficial colonic bacteria) have been gaining interest as potential therapies for constipation.^91,92

Probiotic bacterial preparations are generally composed of strains of Bifodobacterium,^93,94Lactobacillus,⁹⁵ and combinations thereof, and are available as mixed preparations of multiple bacterial strains of Lactobacillus, Bifodobacterium, and Streptococcus species, such as VSL#3.⁹⁶

Probiotics may help relieve constipation, but their effect may depend on the strain of bacteria used and the population being studied.⁹⁷ In a double-blind parallel study in 70 healthy adults, ingestion of 375 g/day of milk fermented with B animalis strain DN-173 010 for 11 days reduced colon transit time by 20% from baseline. The effect was more pronounced in women, particularly in those with longer baseline transit.⁹⁸

Lactic acid-producing bacteria are considered commensal organisms with essentially no pathogenic potential.⁹⁹ A review of the safety of bifodobacteria and lactobacilli concluded there was no health risk to consumers.¹⁰⁰

Prebiotics are short-chain carbohydrates such as lactulose that stimulate the activity of beneficial colonic bacteria.⁹¹ They are thought to have a small laxative effect that is likely both osmotic and due to beneficial actions of bacteria for which they are a substrate. Both konjac glucomannan and lactulose, sugar-based laxatives and prebiotics, have been shown to significantly increase the fecal concentrations of lactobacilli and total bacteria, possibly through increases in stool bulk.⁴⁶ Prebiotics that have been the focus of research include inulin, fructo-oligosaccharides, and galacto-oligosaccharides.⁹¹ Evidence on the efficacy of probiotics and prebiotics at relieving symptoms of constipation, however, is inconclusive because few well-controlled clinical studies have been done.^91,92

STRATEGIES FOR MANAGING CHRONIC CONSTIPATION

In the absence of secondary causes, treatment of chronic constipation is focused on relieving symptoms.

If symptoms are refractory to these traditional treatments, agents such as lactulose and polyethylene glycol may provide relief.^11,21 Although they do not address the underlying cause of constipation, these agents increase the fluid content of the intestine, contributing to improved stool consistency, and consequently increase the frequency of bowel movements.

Lubiprostone similarly increases the fluid content of the colon, contributing to improved stool consistency, reduced fecal transit time, and increased frequency of bowel movements.^66,70,102 Unlike lactulose and polyethylene glycol, which are indicated only for short-term use, lubiprostone has been found to be safe and effective when used for up to 48 weeks.^70,71

Biofeedback is the preferred treatment for pelvic floor dyssynergia, in which it has a success rate of 70% to 81% and in which it is superior to standard treatment (laxatives, fiber, and education).^103–105 In an instrument-based training program, patients receive auditory or visual feedback or both to help train the pelvic floor and relax the anal sphincter while simulating defecation. It also improves rectal sensation to assist in proper evacuation. The best outcomes are achieved when committed patients receive instruction from empathetic, properly trained physical therapists or other technicians. Studies show that the benefits of biofeedback are long-lasting.¹⁰⁴ It does not improve slow-transit constipation, though pelvic floor dyssynergia and slow-transit constipation can overlap.

Constipation is both a symptom and, when chronic, a multisymptom disorder, and it can overlap with other gastrointestinal tract disorders such as dyspepsia and gastroesophageal reflux disease. Furthermore, one should keep in mind the possibility of cancer and be alert for its warning signs.

Since constipation has a variety of causes and forms, one treatment does not fit all patients. Conservative measures such as recommending that the patient increase his or her intake of dietary fiber and water and engage in more physical activity are still the cornerstone of treatment, but they do not help all patients. On the other hand, polyethylene glycol and stimulant laxatives, which are traditionally given only for a short time, can be safe and effective when given long-term if other agents fail. New agents have become available or are in development.

In this article we outline our approach to constipation, as a guide for internists.

CONSTIPATION IS COMMON, BUT HOW SHOULD WE DEFINE IT?

Constipation affects 2% to 27% (average 14.8%) of the North American adult population—approximately 63 million people.¹ It is more common than many other chronic diseases, including hypertension (48 million people), migraine (33 million), obesity (50 million), and diabetes mellitus (15 million).^1–3

Constipation affects more women than men (2.1:1 ratio) and more nonwhites than whites (1.68:1).¹ It occurs in all age groups but is more common in those older than 65 years and younger than 4 years.^4,5

Constipation accounts for more than 2.5 million office visits and more than $500 million spent on laxatives per year.^6,7 Also, people with constipation may report decreased productivity and increased absenteeism.⁸

The broad range in the prevalence of constipation cited above reflects differences in how it is defined and, in particular, a lack of agreement between how patients and physicians perceive it.^1,9 Physicians mainly define constipation on the basis of stool frequency, considering fewer than three bowel movements per week to be abnormal.¹ In contrast, patients typically define it on the basis of bothersome symptoms such as straining, passage of hard stool, unproductive urges, inability to defecate at will, and sensations of incomplete evacuation or abdominal bloating.^1,9,10

The Rome III diagnostic criteria were developed to provide a consistent diagnostic approach for use in clinical practice and clinical trials.¹¹ The Rome III criteria define functional chronic constipation as a chronic bowel disorder characterized by two or more of the following:

• Straining
• Lumpy or hard stools
• Sensations of incomplete evacuation
• Sensations of anorectal obstruction or blockage
• Use of manual maneuvers to facilitate defecation (eg, digital evacuation, support of the pelvic floor) during at least 25% of defecations
• Fewer than three bowel movements per week.

In addition, loose stools should rarely occur without the use of laxatives, and there should be insufficient criteria for irritable bowel syndrome.¹¹ Chronicity is established by symptom onset within the previous 6 months and symptom duration of at least 3 months.

In contrast, patients with irritable bowel syndrome, also a functional bowel disorder, experience recurrent abdominal pain and discomfort associated with two or more of the following: symptom improvement with defecation, symptom onset associated with a change in the frequency of bowel movements, and a change in the form or appearance of the stool.

THREE TYPES OF IDIOPATHIC CONSTIPATION

There are three types of primary or idiopathic constipation^5,9,12,13:

• Functional
• Slow-transit
• Outlet dysfunction.

Functional constipation includes functional chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. It presents with a sense of difficult or delayed evacuation, hard stools, or abdominal bloating or discomfort.^6,9,13 The predominant symptom of constipation-predominant irritable bowel syndrome is severe discomfort or pain; in chronic idiopathic constipation, pain and discomfort may be present but are not the primary symptom.

Slow-transit constipation (or delayed-transit constipation) is associated with a prolonged time between bowel movements. Its symptoms include low stool frequency, lack of urge to defecate, abdominal distention, bloating, and abdominal discomfort.¹⁴

Outlet dysfunction. Disorders of defecation can be due to mechanical causes such as Hirschsprung disease, anal stricture, cancer, prolapse, and large rectoceles, or from pelvic floor dysfunction. Pelvic floor dysfunction may be due to inadequate or excessive perineal descent or to inadequate propulsive forces, as may occur in neurologic or neuromuscular conditions and dyssynergia.

Pelvic floor dyssynergia, also called anorectal dyssynergia, dyssynergic defecation, and anismus, results from a functional defect in coordinated evacuation. The characteristic symptom is a feeling of being unable to adequately empty the rectum.¹⁴ Other symptoms such as excessive straining and manual disimpaction indicate but are not unique to pelvic floor dyssynergia.^14,15

Combined forms. Patients may have more than one type of primary constipation and presentation, and pelvic floor dyssynergia has been shown to prolong intestinal transit, which may improve with treatment.

Secondary constipation can be due to causes such as diet, lifestyle, certain medications (calcium channel blockers, beta-blockers, opioids, diuretics, antidepressants, anticonvulsants, antacids, anticholinergics, and antispasmodics),^5,16 underlying medical conditions (diabetes, hypothyroidism, multiple sclerosis, parkinsonism),^16,17 pregnancy, and advanced age.¹⁸

NEUROTRANSMITTERS MAY PLAY A ROLE

Among the mechanisms thought to cause chronic constipation are impaired gastrointestinal motility,^19–22 reduced intestinal secretions,^21–23 and inadequate reflex relaxation of the pelvic floor muscles.^22,24

Neurotransmitters such as serotonin, somatostatin, peptide YY, and vasoactive intestinal peptide affect intestinal secretion and motility.^25,26 Hyperactivity of these neurotransmitters associated with increased secretion and motility results in diarrhea, whereas hypoactivity leads to decreased secretion, delayed transit, and constipation.²³

Serotonin has a role in regulating visceral pain perception and intestinal motility, as well as secretion.^26–28 Clinical trials have shown that activation of serotonin receptors in the gut enhances gastrointestinal motility, inhibits visceral sensitivity, and stimulates intestinal secretion.^26,27,29

A hypothesis has recently been proposed that degeneration of enteric neurons may also play a role in the development of severe idiopathic constipation.³⁰

DIAGNOSIS IS MOSTLY CLINICAL

The history and physical examination remain the cornerstones in the diagnosis and subsequent treatment of chronic constipation.

History

Risk factors for primary and secondary constipation to note during the interview include age (< 4 years, > 65 years); low-fiber diet; female sex; lack of physical activity; history of childhood constipation, endocrine and neuromuscular disorders, abuse, depression, or anxiety; family history of cancer; and personal history of pelvic surgery.

Since drugs can also cause chronic constipation, especially in elderly or immobile patients, medication lists should be reviewed and adjustments should be made if necessary (or possible) before recommending laxatives or invasive testing, if no alarm signs are present.

Alarm signs such as weight loss, hematochezia, melena, change in bowel habits, and symptoms refractory to therapy may represent colon cancer and indicate the need for early diagnostic testing.

Physical examination

Physical examination should always include inspection of the perianal area for evidence of hemorrhoids or fissures. Digital rectal examination may reveal a contracted sphincter or a puborectalis muscle that contracts with the Valsalva maneuver, suggesting dysfunction.

Laboratory testing

If the history and physical examination suggest that the constipation may be secondary, or if the patient is 50 years of age or older, then laboratory studies such as a complete blood cell count, serum electrolyte levels, blood sugar level, and thyroid function studies may help rule out a metabolic, endocrine, or organic cause.

Colonoscopy, other tests

At present, little evidence suggests that routine testing is warranted in patients without evidence of secondary constipation and without alarm signs. However, diagnostic studies are indicated in patients 50 years of age and older, as well as in those with alarm symptoms such as hematochezia, anemia, a positive fecal occult blood test, unintentional loss of more than 10 pounds, family history of colon cancer or inflammatory bowel disease, fever, nausea, vomiting, acute onset (especially in the elderly), and lack of improvement with conventional therapies regardless of age.²

The full length of the colon should be inspected by colonoscopy or by flexible sigmoidoscopy paired with a barium enema study to rule out structural disease. Of note, all patients 50 years of age or older should be screened for colon cancer.

If the patient does not respond to therapy, further tests such as colonic transit studies, anorectal manometry with balloon expulsion, and, possibly, defecating proctography or dynamic pelvic magnetic resonance imaging may be considered. These patients would likely also benefit from referral to a gastroenterologist for further management

DIET AND LIFESTYLE AS TREATMENT

For many years, health care providers have provided reassurance and recommended diet and lifestyle modifications as treatment for constipation. Increased water intake, increased activity, and a scheduled attempt at defecation when motor activity in the colon is highest, ie, in the morning or after eating, have all been recommended.

Data on the efficacy of these recommendations are scarce and often contradictory. Studies have shown that increasing water intake or daily exercise is not always helpful.^32–34 Nevertheless, many patients who comply with dietary and exercise recommendations have improvement in symptoms. Eating fewer meals per day (and hence taking in fewer calories) has been shown to be associated with constipation in the elderly. However, no relationships between fiber or fluid intake and constipation were noted.³⁵

In a study in which chronically constipated patients were fed a standardized diet that contained 25 g of fiber a day, stool frequency increased significantly and laxative use decreased.³⁶ While on a high-fiber diet, the patients were divided into two groups, one that drank 1.1 L of fluid per day and one that drank 2.1 L of mineral water per day. Both groups experienced further improvements in stool frequency and decreases in laxative use, with the mineral-water group benefiting the most.³⁶

Recently, Murakami and others³⁷ found, in a cross-sectional study in young Japanese women with low daily fiber intake (6.4 g/day), that low water intake from foods and low magnesium intake were associated with an increasing prevalence of functional constipation as defined by the Rome III criteria. Constipation was also found to be significantly associated with low intake of fruits and vegetables in a study from Singapore.³⁸

Moderate physical activity and high fiber intake may be associated with a lower prevalence of constipation in women. In the Nurses’ Health Study, more than 62,000 women between the ages of 36 and 61 were surveyed, and those who said they engaged in daily physical activity had a lower prevalence of constipation (prevalence ratio [PR] = 0.56, 95% confidence interval [CI] 0.44–0.70), as did those with a median fiber intake of 20 g/day (PR = 0.64, 95% CI 0.57–0.73).³⁹

BULK LAXATIVES (FIBER SUPPLEMENTS): THE FIRST-LINE TREATMENT

Fiber remains the first-line treatment for constipation. It may relieve or improve symptoms in functional constipation. However, fewer than 30% of patients with either slow-transit constipation or pelvic floor dysfunction have improvement in symptoms with fiber, and in these types of constipation it can even worsen symptoms.⁴⁰

There is much confusion about what types of fiber should be recommended and how the various types of fiber perform in resolving constipation.

Insoluble fiber

Insoluble fiber resists bacterial degradation in the colon and can retain more water than soluble fiber can.

Bran 20 g/day increased the frequency of bowel movements by 55%, increased fecal weight by 157%, and decreased intestinal transit time by 50% in women who had three or fewer bowel movements per week.⁴¹

Muller-Lissner⁴² and others performed a meta-analysis and found that bran (25 g/day) increased stool weight and decreased transit time in both healthy controls and patients with chronic constipation. Yet constipated patients taking bran still had lower stool weights and slower transit times than did healthy subjects.

When bran 20 g/day was compared with placebo in chronically constipated patients, bowel frequency and stool weight increased with both treatments,⁴³ suggesting that factors other than intake may affect bowel function and transit time. However, bran was more effective than placebo in decreasing oroanal transit time.

Elderly constipated patients who received bran 10 g twice a day had significantly shorter transit times (89 hours vs 126 hours) than did those who received psyllium (a soluble fiber) 6 g twice daily. They also needed less additional laxative.⁴⁴

Soluble fiber

Soluble fiber also affects the bowel habits of both healthy and constipated patients.

Methylcellulose, given to healthy volunteers at a dose of 4 g/day, resulted in statistically significant increases in stool weight, fecal water weight, and fecal solids.⁴⁵ In constipated patients, methylcellulose 1 g/day was as effective as psyllium 3.4 g/day at increasing stool frequency, fecal water weight, and fecal solids.⁴⁵

Konjac glucomannan was also shown to significantly increase stool frequency, water weight, and fecal solids.⁴⁶

Psyllium. In a study that randomly assigned 22 patients with chronic constipation to receive either psyllium 5 g twice daily or placebo for 8 weeks, followed by a 4-week washout phase in which placebo was given,⁴⁷ those who received psyllium reported significant improvements in stool consistency and pain with defecation, as well as significant increases in both stool frequency (3.8 vs 2.9 per week, P < .05) and stool weight (665 g vs 405 g, P < .05). However, colonic transit times and anorectal manometric measurements did not differ significantly between those who received psyllium vs placebo.⁴⁷

Fiber may not help everyone

Others have also shown that while fiber may improve stool characteristics, it may not significantly alter the sensorimotor functions of the colon and pelvic floor.

Cheskin et al⁴⁸ performed a crossover study in 10 constipated men and women in the community. Patients received either 24 g of psyllium fiber daily or a placebo fiber for 1 month and then crossed over to the other treatment for the next month. The most common cause of constipation in this study was pelvic floor dysfunction. Total gut transit time was significantly increased by psyllium fiber, and there was a trend toward increased stool frequency, demonstrating that psyllium clinically improved constipation. However, pelvic floor dysfunction, as measured by rectal manometry, was not improved.

It may be that only people with normal-transit constipation, not those with underlying slow-transit constipation or pelvic floor dysfunction, are helped by additional dietary fiber. Voderholzer and others⁴⁰ studied 149 consecutive patients with chronic constipation and evaluated their response to at least 6 weeks of psyllium (Plantago ovata seeds 15 to 30 g/day) by serial symptom measurements, oroanal transit times, and functional rectoanal evaluation with defecography, manometry, and sigmoidoscopy. Of the patients with no evidence of pelvic floor dysfunction or slow-transit constipation, 85% improved. However, 80% of those with slow-transit constipation and 63% of those with pelvic floor dysfunction did not improve with the use of fiber. The authors concluded that it is reasonable to try dietary fiber in patients with constipation and, if no improvement is noted, to then consider further investigation for other subtypes of constipation (ie, slow-transit or pelvic-floor dysfunction).

Adverse effects may limit the use of fiber and may differ depending on the type of fiber used. Soluble fiber may be better tolerated, especially in patients with constipation-predominant irritable bowel syndrome.⁴⁹ Side effects include the sensation of bloating and distention, excessive gas production, and abdominal cramping.

Our recommendations on fiber

We recommend the following regarding fiber in constipated patients:

• Increase fiber intake from natural foods up to 20 g/day. This increase should be completed over 2 to 3 weeks to minimize adverse effects.
• Consider adding a fiber supplement, such as psyllium, if increasing the intake of natural fiber does not relieve constipation-related symptoms.
• If symptoms persist despite the use of fiber supplements and diet and lifestyle modification, then further structural and functional investigation of the colon (anorectal manometry, colonoscopy, defecography, colon manometry) should be considered.

OSMOTIC LAXATIVES

Osmotic laxatives are molecules that are either not absorbed or poorly absorbed and that draw water into the intestinal lumen to maintain isotonicity between the intestinal contents and the serum. Examples are polyethylene glycol, sodium phosphate (Fleet phosphosoda), magnesium hydroxide, magnesium citrate, the sugars lactulose and sorbitol, and glycerin.

Certain formulations of this class of laxative can cause bloating, diarrhea, electrolyte disturbances, volume overload, or dehydration. These effects limit their use, and these medications should be used with caution in patients prone to renal insufficiency or cardiac abnormalities.

Polyethylene glycol

Polyethylene glycol is an exception. It is not absorbed and lacks electrolytes, making it an attractive option in patients with underlying renal or cardiac dysfunction. In several placebo-controlled trials,^50–52 various formulations significantly increased stool frequency while significantly decreasing straining, use of other laxatives, and colonic transit. No increase in adverse effects was noted compared with placebo.

Compared with lactulose, polyethylene glycol at about 21 g/day significantly increased bowel movement frequency while significantly decreasing the sense of straining with bowel movements and flatus due to laxative use.⁵¹ Both polyethylene glycol and lactulose accelerate colonic transit, although polyethylene glycol does so to a greater extent.⁵³

Polyethylene glycol has been safe and effective when used for up to 6 months.⁵⁴

Lactulose and sorbitol

Carbohydrate or sugar-based laxatives, if taken in sufficient doses, have a cathartic effect through two mechanisms: a primary osmotic effect of the sugar itself and a secondary osmotic effect as a substrate for colonic bacteria to cleave to acid metabolites, which exert an osmotic effect in the colon. This secondary effect will be discussed in a later section.

Lactulose and sorbitol are sugars that are poorly absorbed by the intestine. Lactulose has been shown to be more effective than placebo in increasing stool frequency, volume, weight, and consistency in chronically constipated patients.⁵⁵ In a head-to-head comparison between sugar laxatives, 70% sorbitol was as effective as lactulose in increasing the frequency of bowel movements, and it was similar in its adverse effects⁵⁶; 70% sorbitol is a cost-effective alternative to lactulose in the elderly nursing home population.⁵⁷

Compared with fiber alone, lactulose use leads to a significantly higher number of bowel movements and better stool consistency.⁵⁸ However, when lactulose was compared with a combination of fiber and a stimulant laxative, it was less effective than the combination therapy.^59,60

Sugar laxatives, while effective, may have dose-limiting or use-limiting adverse effects such as abdominal bloating and flatulence.

Phosphate, magnesium

Sodium phosphate, like polyethylene glycol, is often used as a bowel preparation before colonoscopy, for which it is about as good or slightly better than polyethylene glycol.^61,62

Although magnesium and sodium phosphate preparations are effective, there are multiple reports of clinically significant electrolyte abnormalities, renal failure, and congestive heart failure occurring with these preparations. Therefore, they must be used with discretion and caution in appropriate patients with frequent monitoring.

STIMULANT (IRRITANT) LAXATIVES

Stimulant laxatives are usually reserved for use when bulking agents and osmotic laxatives fail. Their mechanism of action involves the alteration of intestinal motility and intestinal fluid secretion.

Anthraquinones (cascara, aloe, and senna), castor oil, and diphenylmethanes (bisacodyl) are the most commonly used stimulant laxatives. They work relatively quickly, often eliciting a bowel movement 2 to 8 hours after they are taken.

This class of laxatives has historically been underused or given for only short periods of time, owing to concern about impairing colonic function, damaging the enteric nervous system, causing laxative dependency, causing cathartic colon, and even causing colon cancer. However, there is very little evidence to support these concerns. Stimulant laxatives can be used on a more regular basis when bulking or osmotic agents fail.⁶³

Possibly of greatest concern is the potential for the overuse and abuse of stimulant laxatives. Excessive use can cause electrolyte disturbances brought about by high-volume watery diarrhea. Risk factors for overuse and abuse include underlying psychiatric disturbances and eating disorders. Prescribing other types of laxatives or cathartic agents may reduce risk, but the potential for abuse exists with all categories of laxatives.

TEGASEROD: GONE BUT STILL AVAILABLE, ON A CONTROLLED BASIS

Tegaserod (Zelnorm), a serotonin (5-HT4) agonist, was used predominantly in women with constipation-predominant irritable bowel syndrome and in men and women with chronic constipation. However, it was suspended from the market in the United States in March 2007 owing to concern about a high risk of adverse cardiovascular effects compared with placebo.

In a double-blind, randomized controlled trial, men with chronic constipation who received tegaserod 6 mg twice a day for 12 weeks had more spontaneous bowel movements than those receiving placebo (P = .04).⁶⁴

Lin et al⁶⁵ evaluated the use of tegaserod 6 mg twice daily for 4 weeks in both men and women with chronic constipation. Those receiving tegaserod had significantly more spontaneous bowel movements per week, less straining, and better stool consistency than those receiving placebo.

Tegaserod can still be obtained for appropriate patients via a treatment investigational new drug application. Safety data are under further review by the US Food and Drug Administration. Studies of other serotonin agonists are under way.

LUBIPROSTONE

Lubiprostone (Amitiza) is an agonist of the chloride channel subtype 2, found on the apical membrane of intestinal epithelial cells. It causes increased chloride secretion into the intestinal lumen, enhancing intestinal fluid secretion. It has been shown to be effective in chronic constipation by improving stool consistency and increasing the motility of the small intestine and colon.⁶⁶ It is approved for treating chronic constipation in adults.

In randomized, double-blind trials, patients receiving lubiprostone 24 fig twice daily for 4 weeks had significantly more bowel movements per week, reported significantly better stool consistency and less abdominal bloating and straining, and rated their constipation as less severe than did patients receiving placebo.^67–69

More recently, in an open-label study, lubiprostone improved constipation symptoms when taken for up to 48 weeks.⁷⁰

The drug is well tolerated, but its adverse effects include nausea (which appears to be dose-dependent and may diminish over time or if the drug is taken with food), diarrhea, and headache.⁶⁸ Of note, the drug appears to be well tolerated by older people (65 years of age and older), in whom adverse effects occur less often than in younger users.⁷¹ However, adverse events may cause up to 20% of patients to stop taking the drug.⁶⁹ When lubiprostone is discontinued, patients may once again revert to their baseline bowel habit.⁷²

Lubiprostone has not been compared with conventional laxatives, and cost may prohibit it from becoming a first-line drug for chronic constipation.⁷³

OTHER PROMOTILITY AGENTS

Several promotility agents have been studied for treating chronic idiopathic constipation.

Cisapride (Propulsid), a 5-HT3 receptor antagonist and 5-HT4 receptor agonist, and prucalopride, a 5-HT4 agonist, were effective in relieving symptoms associated with chronic constipation.^74–76 However, safety issues (cardiac arrhythmias) necessitated withdrawal of cisapride from the US market in 2000. Prucalopride is undergoing clinical trials.⁷⁷

Renzapride, a mixed 5-HT4 receptor agonist and 5-HT3 receptor antagonist, has been shown to improve stool consistency and to increase colonic transit in patients with constipation-predominant irritable bowel syndrome.⁷⁸ Renzapride has been studied in patients with this condition,^78–81 but not in patients with chronic constipation. Renzapride is in phase III clinical development in the United States for treating constipation-predominant irritable bowel syndrome.

EMERGING TREATMENTS

New drugs with novel mechanisms of action are being investigated for the treatment of chronic idiopathic constipation.

Neurotrophin-3, a neurotrophic factor, modulates the development of the nervous system by regulating the survival and differentiation of nerves.⁸² In patients with functional constipation, subcutaneous doses of neurotrophin-3 improved stool frequency, the number of complete spontaneous bowel movements, and stool consistency.⁸³

Alvimopan is a selective antagonist of the muopioid receptor that is being studied for opiate-related constipation and postoperative ileus.^84,85 Little of this drug is systemically absorbed and it does not cross the blood-brain barrier; thus, it relieves the opiate-related side effects, ie, bloating, abdominal discomfort, and reduced stool frequency, without interfering with the central analgesic effects.

Linaclotide (MD 1100), a poorly absorbed guanylate cyclase agonist, is also being investigated as a treatment for chronic constipation.⁸⁶ Linaclotide increases intestinal fluid secretion and transit via stimulation of cyclic guanosine monophosphate production and activation of the cystic fibrosis transmembrane conductance regulator.^86,87 In preliminary studies, linaclotide increased stool frequency and the Bristol Stool Form Scale consistency score (Table 1) by increasing intestinal fluid secretion and transit.⁸⁶

Chenodeoxycholic acid is a bile acid that is synthesized from cholesterol.⁸⁸ Treatment of constipation with chenodeoxycholic acid has been proposed, given its laxative effect. A study by Bazzoli et al⁸⁹ showed increased stool frequency and a decrease in stool consistency in chronic constipation patients given chenodeoxycholic acid 10 mg/kg/day. The main side effect was diarrhea. Chenodeoxycholic acid may be worthwhile in the management of constipation, but more studies are needed.

PROBIOTICS AND PREBIOTICS

The bacteria of the colon influence peristalsis of the colon.⁹⁰ Probiotics (live bacterial preparations) and prebiotics (nondigestible preparations that stimulate the growth or activity of beneficial colonic bacteria) have been gaining interest as potential therapies for constipation.^91,92

Probiotic bacterial preparations are generally composed of strains of Bifodobacterium,^93,94Lactobacillus,⁹⁵ and combinations thereof, and are available as mixed preparations of multiple bacterial strains of Lactobacillus, Bifodobacterium, and Streptococcus species, such as VSL#3.⁹⁶

Probiotics may help relieve constipation, but their effect may depend on the strain of bacteria used and the population being studied.⁹⁷ In a double-blind parallel study in 70 healthy adults, ingestion of 375 g/day of milk fermented with B animalis strain DN-173 010 for 11 days reduced colon transit time by 20% from baseline. The effect was more pronounced in women, particularly in those with longer baseline transit.⁹⁸

Lactic acid-producing bacteria are considered commensal organisms with essentially no pathogenic potential.⁹⁹ A review of the safety of bifodobacteria and lactobacilli concluded there was no health risk to consumers.¹⁰⁰

Prebiotics are short-chain carbohydrates such as lactulose that stimulate the activity of beneficial colonic bacteria.⁹¹ They are thought to have a small laxative effect that is likely both osmotic and due to beneficial actions of bacteria for which they are a substrate. Both konjac glucomannan and lactulose, sugar-based laxatives and prebiotics, have been shown to significantly increase the fecal concentrations of lactobacilli and total bacteria, possibly through increases in stool bulk.⁴⁶ Prebiotics that have been the focus of research include inulin, fructo-oligosaccharides, and galacto-oligosaccharides.⁹¹ Evidence on the efficacy of probiotics and prebiotics at relieving symptoms of constipation, however, is inconclusive because few well-controlled clinical studies have been done.^91,92

STRATEGIES FOR MANAGING CHRONIC CONSTIPATION

In the absence of secondary causes, treatment of chronic constipation is focused on relieving symptoms.

If symptoms are refractory to these traditional treatments, agents such as lactulose and polyethylene glycol may provide relief.^11,21 Although they do not address the underlying cause of constipation, these agents increase the fluid content of the intestine, contributing to improved stool consistency, and consequently increase the frequency of bowel movements.

Lubiprostone similarly increases the fluid content of the colon, contributing to improved stool consistency, reduced fecal transit time, and increased frequency of bowel movements.^66,70,102 Unlike lactulose and polyethylene glycol, which are indicated only for short-term use, lubiprostone has been found to be safe and effective when used for up to 48 weeks.^70,71

Biofeedback is the preferred treatment for pelvic floor dyssynergia, in which it has a success rate of 70% to 81% and in which it is superior to standard treatment (laxatives, fiber, and education).^103–105 In an instrument-based training program, patients receive auditory or visual feedback or both to help train the pelvic floor and relax the anal sphincter while simulating defecation. It also improves rectal sensation to assist in proper evacuation. The best outcomes are achieved when committed patients receive instruction from empathetic, properly trained physical therapists or other technicians. Studies show that the benefits of biofeedback are long-lasting.¹⁰⁴ It does not improve slow-transit constipation, though pelvic floor dyssynergia and slow-transit constipation can overlap.

Constipation is both a symptom and, when chronic, a multisymptom disorder, and it can overlap with other gastrointestinal tract disorders such as dyspepsia and gastroesophageal reflux disease. Furthermore, one should keep in mind the possibility of cancer and be alert for its warning signs.

Since constipation has a variety of causes and forms, one treatment does not fit all patients. Conservative measures such as recommending that the patient increase his or her intake of dietary fiber and water and engage in more physical activity are still the cornerstone of treatment, but they do not help all patients. On the other hand, polyethylene glycol and stimulant laxatives, which are traditionally given only for a short time, can be safe and effective when given long-term if other agents fail. New agents have become available or are in development.

In this article we outline our approach to constipation, as a guide for internists.

CONSTIPATION IS COMMON, BUT HOW SHOULD WE DEFINE IT?

Constipation affects 2% to 27% (average 14.8%) of the North American adult population—approximately 63 million people.¹ It is more common than many other chronic diseases, including hypertension (48 million people), migraine (33 million), obesity (50 million), and diabetes mellitus (15 million).^1–3

Constipation affects more women than men (2.1:1 ratio) and more nonwhites than whites (1.68:1).¹ It occurs in all age groups but is more common in those older than 65 years and younger than 4 years.^4,5

Constipation accounts for more than 2.5 million office visits and more than $500 million spent on laxatives per year.^6,7 Also, people with constipation may report decreased productivity and increased absenteeism.⁸

The broad range in the prevalence of constipation cited above reflects differences in how it is defined and, in particular, a lack of agreement between how patients and physicians perceive it.^1,9 Physicians mainly define constipation on the basis of stool frequency, considering fewer than three bowel movements per week to be abnormal.¹ In contrast, patients typically define it on the basis of bothersome symptoms such as straining, passage of hard stool, unproductive urges, inability to defecate at will, and sensations of incomplete evacuation or abdominal bloating.^1,9,10

The Rome III diagnostic criteria were developed to provide a consistent diagnostic approach for use in clinical practice and clinical trials.¹¹ The Rome III criteria define functional chronic constipation as a chronic bowel disorder characterized by two or more of the following:

• Straining
• Lumpy or hard stools
• Sensations of incomplete evacuation
• Sensations of anorectal obstruction or blockage
• Use of manual maneuvers to facilitate defecation (eg, digital evacuation, support of the pelvic floor) during at least 25% of defecations
• Fewer than three bowel movements per week.

In addition, loose stools should rarely occur without the use of laxatives, and there should be insufficient criteria for irritable bowel syndrome.¹¹ Chronicity is established by symptom onset within the previous 6 months and symptom duration of at least 3 months.

In contrast, patients with irritable bowel syndrome, also a functional bowel disorder, experience recurrent abdominal pain and discomfort associated with two or more of the following: symptom improvement with defecation, symptom onset associated with a change in the frequency of bowel movements, and a change in the form or appearance of the stool.

THREE TYPES OF IDIOPATHIC CONSTIPATION

There are three types of primary or idiopathic constipation^5,9,12,13:

• Functional
• Slow-transit
• Outlet dysfunction.

Functional constipation includes functional chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. It presents with a sense of difficult or delayed evacuation, hard stools, or abdominal bloating or discomfort.^6,9,13 The predominant symptom of constipation-predominant irritable bowel syndrome is severe discomfort or pain; in chronic idiopathic constipation, pain and discomfort may be present but are not the primary symptom.

Slow-transit constipation (or delayed-transit constipation) is associated with a prolonged time between bowel movements. Its symptoms include low stool frequency, lack of urge to defecate, abdominal distention, bloating, and abdominal discomfort.¹⁴

Outlet dysfunction. Disorders of defecation can be due to mechanical causes such as Hirschsprung disease, anal stricture, cancer, prolapse, and large rectoceles, or from pelvic floor dysfunction. Pelvic floor dysfunction may be due to inadequate or excessive perineal descent or to inadequate propulsive forces, as may occur in neurologic or neuromuscular conditions and dyssynergia.

Pelvic floor dyssynergia, also called anorectal dyssynergia, dyssynergic defecation, and anismus, results from a functional defect in coordinated evacuation. The characteristic symptom is a feeling of being unable to adequately empty the rectum.¹⁴ Other symptoms such as excessive straining and manual disimpaction indicate but are not unique to pelvic floor dyssynergia.^14,15

Combined forms. Patients may have more than one type of primary constipation and presentation, and pelvic floor dyssynergia has been shown to prolong intestinal transit, which may improve with treatment.

Secondary constipation can be due to causes such as diet, lifestyle, certain medications (calcium channel blockers, beta-blockers, opioids, diuretics, antidepressants, anticonvulsants, antacids, anticholinergics, and antispasmodics),^5,16 underlying medical conditions (diabetes, hypothyroidism, multiple sclerosis, parkinsonism),^16,17 pregnancy, and advanced age.¹⁸

NEUROTRANSMITTERS MAY PLAY A ROLE

Among the mechanisms thought to cause chronic constipation are impaired gastrointestinal motility,^19–22 reduced intestinal secretions,^21–23 and inadequate reflex relaxation of the pelvic floor muscles.^22,24

Neurotransmitters such as serotonin, somatostatin, peptide YY, and vasoactive intestinal peptide affect intestinal secretion and motility.^25,26 Hyperactivity of these neurotransmitters associated with increased secretion and motility results in diarrhea, whereas hypoactivity leads to decreased secretion, delayed transit, and constipation.²³

Serotonin has a role in regulating visceral pain perception and intestinal motility, as well as secretion.^26–28 Clinical trials have shown that activation of serotonin receptors in the gut enhances gastrointestinal motility, inhibits visceral sensitivity, and stimulates intestinal secretion.^26,27,29

A hypothesis has recently been proposed that degeneration of enteric neurons may also play a role in the development of severe idiopathic constipation.³⁰

DIAGNOSIS IS MOSTLY CLINICAL

The history and physical examination remain the cornerstones in the diagnosis and subsequent treatment of chronic constipation.

History

Risk factors for primary and secondary constipation to note during the interview include age (< 4 years, > 65 years); low-fiber diet; female sex; lack of physical activity; history of childhood constipation, endocrine and neuromuscular disorders, abuse, depression, or anxiety; family history of cancer; and personal history of pelvic surgery.

Since drugs can also cause chronic constipation, especially in elderly or immobile patients, medication lists should be reviewed and adjustments should be made if necessary (or possible) before recommending laxatives or invasive testing, if no alarm signs are present.

Alarm signs such as weight loss, hematochezia, melena, change in bowel habits, and symptoms refractory to therapy may represent colon cancer and indicate the need for early diagnostic testing.

Physical examination

Physical examination should always include inspection of the perianal area for evidence of hemorrhoids or fissures. Digital rectal examination may reveal a contracted sphincter or a puborectalis muscle that contracts with the Valsalva maneuver, suggesting dysfunction.

Laboratory testing

If the history and physical examination suggest that the constipation may be secondary, or if the patient is 50 years of age or older, then laboratory studies such as a complete blood cell count, serum electrolyte levels, blood sugar level, and thyroid function studies may help rule out a metabolic, endocrine, or organic cause.

Colonoscopy, other tests

At present, little evidence suggests that routine testing is warranted in patients without evidence of secondary constipation and without alarm signs. However, diagnostic studies are indicated in patients 50 years of age and older, as well as in those with alarm symptoms such as hematochezia, anemia, a positive fecal occult blood test, unintentional loss of more than 10 pounds, family history of colon cancer or inflammatory bowel disease, fever, nausea, vomiting, acute onset (especially in the elderly), and lack of improvement with conventional therapies regardless of age.²

The full length of the colon should be inspected by colonoscopy or by flexible sigmoidoscopy paired with a barium enema study to rule out structural disease. Of note, all patients 50 years of age or older should be screened for colon cancer.

If the patient does not respond to therapy, further tests such as colonic transit studies, anorectal manometry with balloon expulsion, and, possibly, defecating proctography or dynamic pelvic magnetic resonance imaging may be considered. These patients would likely also benefit from referral to a gastroenterologist for further management

DIET AND LIFESTYLE AS TREATMENT

For many years, health care providers have provided reassurance and recommended diet and lifestyle modifications as treatment for constipation. Increased water intake, increased activity, and a scheduled attempt at defecation when motor activity in the colon is highest, ie, in the morning or after eating, have all been recommended.

Data on the efficacy of these recommendations are scarce and often contradictory. Studies have shown that increasing water intake or daily exercise is not always helpful.^32–34 Nevertheless, many patients who comply with dietary and exercise recommendations have improvement in symptoms. Eating fewer meals per day (and hence taking in fewer calories) has been shown to be associated with constipation in the elderly. However, no relationships between fiber or fluid intake and constipation were noted.³⁵

In a study in which chronically constipated patients were fed a standardized diet that contained 25 g of fiber a day, stool frequency increased significantly and laxative use decreased.³⁶ While on a high-fiber diet, the patients were divided into two groups, one that drank 1.1 L of fluid per day and one that drank 2.1 L of mineral water per day. Both groups experienced further improvements in stool frequency and decreases in laxative use, with the mineral-water group benefiting the most.³⁶

Recently, Murakami and others³⁷ found, in a cross-sectional study in young Japanese women with low daily fiber intake (6.4 g/day), that low water intake from foods and low magnesium intake were associated with an increasing prevalence of functional constipation as defined by the Rome III criteria. Constipation was also found to be significantly associated with low intake of fruits and vegetables in a study from Singapore.³⁸

Moderate physical activity and high fiber intake may be associated with a lower prevalence of constipation in women. In the Nurses’ Health Study, more than 62,000 women between the ages of 36 and 61 were surveyed, and those who said they engaged in daily physical activity had a lower prevalence of constipation (prevalence ratio [PR] = 0.56, 95% confidence interval [CI] 0.44–0.70), as did those with a median fiber intake of 20 g/day (PR = 0.64, 95% CI 0.57–0.73).³⁹

BULK LAXATIVES (FIBER SUPPLEMENTS): THE FIRST-LINE TREATMENT

Fiber remains the first-line treatment for constipation. It may relieve or improve symptoms in functional constipation. However, fewer than 30% of patients with either slow-transit constipation or pelvic floor dysfunction have improvement in symptoms with fiber, and in these types of constipation it can even worsen symptoms.⁴⁰

There is much confusion about what types of fiber should be recommended and how the various types of fiber perform in resolving constipation.

Insoluble fiber

Insoluble fiber resists bacterial degradation in the colon and can retain more water than soluble fiber can.

Bran 20 g/day increased the frequency of bowel movements by 55%, increased fecal weight by 157%, and decreased intestinal transit time by 50% in women who had three or fewer bowel movements per week.⁴¹

Muller-Lissner⁴² and others performed a meta-analysis and found that bran (25 g/day) increased stool weight and decreased transit time in both healthy controls and patients with chronic constipation. Yet constipated patients taking bran still had lower stool weights and slower transit times than did healthy subjects.

When bran 20 g/day was compared with placebo in chronically constipated patients, bowel frequency and stool weight increased with both treatments,⁴³ suggesting that factors other than intake may affect bowel function and transit time. However, bran was more effective than placebo in decreasing oroanal transit time.

Elderly constipated patients who received bran 10 g twice a day had significantly shorter transit times (89 hours vs 126 hours) than did those who received psyllium (a soluble fiber) 6 g twice daily. They also needed less additional laxative.⁴⁴

Soluble fiber

Soluble fiber also affects the bowel habits of both healthy and constipated patients.

Methylcellulose, given to healthy volunteers at a dose of 4 g/day, resulted in statistically significant increases in stool weight, fecal water weight, and fecal solids.⁴⁵ In constipated patients, methylcellulose 1 g/day was as effective as psyllium 3.4 g/day at increasing stool frequency, fecal water weight, and fecal solids.⁴⁵

Konjac glucomannan was also shown to significantly increase stool frequency, water weight, and fecal solids.⁴⁶

Psyllium. In a study that randomly assigned 22 patients with chronic constipation to receive either psyllium 5 g twice daily or placebo for 8 weeks, followed by a 4-week washout phase in which placebo was given,⁴⁷ those who received psyllium reported significant improvements in stool consistency and pain with defecation, as well as significant increases in both stool frequency (3.8 vs 2.9 per week, P < .05) and stool weight (665 g vs 405 g, P < .05). However, colonic transit times and anorectal manometric measurements did not differ significantly between those who received psyllium vs placebo.⁴⁷

Fiber may not help everyone

Others have also shown that while fiber may improve stool characteristics, it may not significantly alter the sensorimotor functions of the colon and pelvic floor.

Cheskin et al⁴⁸ performed a crossover study in 10 constipated men and women in the community. Patients received either 24 g of psyllium fiber daily or a placebo fiber for 1 month and then crossed over to the other treatment for the next month. The most common cause of constipation in this study was pelvic floor dysfunction. Total gut transit time was significantly increased by psyllium fiber, and there was a trend toward increased stool frequency, demonstrating that psyllium clinically improved constipation. However, pelvic floor dysfunction, as measured by rectal manometry, was not improved.

It may be that only people with normal-transit constipation, not those with underlying slow-transit constipation or pelvic floor dysfunction, are helped by additional dietary fiber. Voderholzer and others⁴⁰ studied 149 consecutive patients with chronic constipation and evaluated their response to at least 6 weeks of psyllium (Plantago ovata seeds 15 to 30 g/day) by serial symptom measurements, oroanal transit times, and functional rectoanal evaluation with defecography, manometry, and sigmoidoscopy. Of the patients with no evidence of pelvic floor dysfunction or slow-transit constipation, 85% improved. However, 80% of those with slow-transit constipation and 63% of those with pelvic floor dysfunction did not improve with the use of fiber. The authors concluded that it is reasonable to try dietary fiber in patients with constipation and, if no improvement is noted, to then consider further investigation for other subtypes of constipation (ie, slow-transit or pelvic-floor dysfunction).

Adverse effects may limit the use of fiber and may differ depending on the type of fiber used. Soluble fiber may be better tolerated, especially in patients with constipation-predominant irritable bowel syndrome.⁴⁹ Side effects include the sensation of bloating and distention, excessive gas production, and abdominal cramping.

Our recommendations on fiber

We recommend the following regarding fiber in constipated patients:

• Increase fiber intake from natural foods up to 20 g/day. This increase should be completed over 2 to 3 weeks to minimize adverse effects.
• Consider adding a fiber supplement, such as psyllium, if increasing the intake of natural fiber does not relieve constipation-related symptoms.
• If symptoms persist despite the use of fiber supplements and diet and lifestyle modification, then further structural and functional investigation of the colon (anorectal manometry, colonoscopy, defecography, colon manometry) should be considered.

OSMOTIC LAXATIVES

Osmotic laxatives are molecules that are either not absorbed or poorly absorbed and that draw water into the intestinal lumen to maintain isotonicity between the intestinal contents and the serum. Examples are polyethylene glycol, sodium phosphate (Fleet phosphosoda), magnesium hydroxide, magnesium citrate, the sugars lactulose and sorbitol, and glycerin.

Certain formulations of this class of laxative can cause bloating, diarrhea, electrolyte disturbances, volume overload, or dehydration. These effects limit their use, and these medications should be used with caution in patients prone to renal insufficiency or cardiac abnormalities.

Polyethylene glycol

Polyethylene glycol is an exception. It is not absorbed and lacks electrolytes, making it an attractive option in patients with underlying renal or cardiac dysfunction. In several placebo-controlled trials,^50–52 various formulations significantly increased stool frequency while significantly decreasing straining, use of other laxatives, and colonic transit. No increase in adverse effects was noted compared with placebo.

Compared with lactulose, polyethylene glycol at about 21 g/day significantly increased bowel movement frequency while significantly decreasing the sense of straining with bowel movements and flatus due to laxative use.⁵¹ Both polyethylene glycol and lactulose accelerate colonic transit, although polyethylene glycol does so to a greater extent.⁵³

Polyethylene glycol has been safe and effective when used for up to 6 months.⁵⁴

Lactulose and sorbitol

Carbohydrate or sugar-based laxatives, if taken in sufficient doses, have a cathartic effect through two mechanisms: a primary osmotic effect of the sugar itself and a secondary osmotic effect as a substrate for colonic bacteria to cleave to acid metabolites, which exert an osmotic effect in the colon. This secondary effect will be discussed in a later section.

Lactulose and sorbitol are sugars that are poorly absorbed by the intestine. Lactulose has been shown to be more effective than placebo in increasing stool frequency, volume, weight, and consistency in chronically constipated patients.⁵⁵ In a head-to-head comparison between sugar laxatives, 70% sorbitol was as effective as lactulose in increasing the frequency of bowel movements, and it was similar in its adverse effects⁵⁶; 70% sorbitol is a cost-effective alternative to lactulose in the elderly nursing home population.⁵⁷

Compared with fiber alone, lactulose use leads to a significantly higher number of bowel movements and better stool consistency.⁵⁸ However, when lactulose was compared with a combination of fiber and a stimulant laxative, it was less effective than the combination therapy.^59,60

Sugar laxatives, while effective, may have dose-limiting or use-limiting adverse effects such as abdominal bloating and flatulence.

Phosphate, magnesium

Sodium phosphate, like polyethylene glycol, is often used as a bowel preparation before colonoscopy, for which it is about as good or slightly better than polyethylene glycol.^61,62

Although magnesium and sodium phosphate preparations are effective, there are multiple reports of clinically significant electrolyte abnormalities, renal failure, and congestive heart failure occurring with these preparations. Therefore, they must be used with discretion and caution in appropriate patients with frequent monitoring.

STIMULANT (IRRITANT) LAXATIVES

Stimulant laxatives are usually reserved for use when bulking agents and osmotic laxatives fail. Their mechanism of action involves the alteration of intestinal motility and intestinal fluid secretion.

Anthraquinones (cascara, aloe, and senna), castor oil, and diphenylmethanes (bisacodyl) are the most commonly used stimulant laxatives. They work relatively quickly, often eliciting a bowel movement 2 to 8 hours after they are taken.

This class of laxatives has historically been underused or given for only short periods of time, owing to concern about impairing colonic function, damaging the enteric nervous system, causing laxative dependency, causing cathartic colon, and even causing colon cancer. However, there is very little evidence to support these concerns. Stimulant laxatives can be used on a more regular basis when bulking or osmotic agents fail.⁶³

Possibly of greatest concern is the potential for the overuse and abuse of stimulant laxatives. Excessive use can cause electrolyte disturbances brought about by high-volume watery diarrhea. Risk factors for overuse and abuse include underlying psychiatric disturbances and eating disorders. Prescribing other types of laxatives or cathartic agents may reduce risk, but the potential for abuse exists with all categories of laxatives.

TEGASEROD: GONE BUT STILL AVAILABLE, ON A CONTROLLED BASIS

Tegaserod (Zelnorm), a serotonin (5-HT4) agonist, was used predominantly in women with constipation-predominant irritable bowel syndrome and in men and women with chronic constipation. However, it was suspended from the market in the United States in March 2007 owing to concern about a high risk of adverse cardiovascular effects compared with placebo.

In a double-blind, randomized controlled trial, men with chronic constipation who received tegaserod 6 mg twice a day for 12 weeks had more spontaneous bowel movements than those receiving placebo (P = .04).⁶⁴

Lin et al⁶⁵ evaluated the use of tegaserod 6 mg twice daily for 4 weeks in both men and women with chronic constipation. Those receiving tegaserod had significantly more spontaneous bowel movements per week, less straining, and better stool consistency than those receiving placebo.

Tegaserod can still be obtained for appropriate patients via a treatment investigational new drug application. Safety data are under further review by the US Food and Drug Administration. Studies of other serotonin agonists are under way.

LUBIPROSTONE

Lubiprostone (Amitiza) is an agonist of the chloride channel subtype 2, found on the apical membrane of intestinal epithelial cells. It causes increased chloride secretion into the intestinal lumen, enhancing intestinal fluid secretion. It has been shown to be effective in chronic constipation by improving stool consistency and increasing the motility of the small intestine and colon.⁶⁶ It is approved for treating chronic constipation in adults.

In randomized, double-blind trials, patients receiving lubiprostone 24 fig twice daily for 4 weeks had significantly more bowel movements per week, reported significantly better stool consistency and less abdominal bloating and straining, and rated their constipation as less severe than did patients receiving placebo.^67–69

More recently, in an open-label study, lubiprostone improved constipation symptoms when taken for up to 48 weeks.⁷⁰

The drug is well tolerated, but its adverse effects include nausea (which appears to be dose-dependent and may diminish over time or if the drug is taken with food), diarrhea, and headache.⁶⁸ Of note, the drug appears to be well tolerated by older people (65 years of age and older), in whom adverse effects occur less often than in younger users.⁷¹ However, adverse events may cause up to 20% of patients to stop taking the drug.⁶⁹ When lubiprostone is discontinued, patients may once again revert to their baseline bowel habit.⁷²

Lubiprostone has not been compared with conventional laxatives, and cost may prohibit it from becoming a first-line drug for chronic constipation.⁷³

OTHER PROMOTILITY AGENTS

Several promotility agents have been studied for treating chronic idiopathic constipation.

Cisapride (Propulsid), a 5-HT3 receptor antagonist and 5-HT4 receptor agonist, and prucalopride, a 5-HT4 agonist, were effective in relieving symptoms associated with chronic constipation.^74–76 However, safety issues (cardiac arrhythmias) necessitated withdrawal of cisapride from the US market in 2000. Prucalopride is undergoing clinical trials.⁷⁷

Renzapride, a mixed 5-HT4 receptor agonist and 5-HT3 receptor antagonist, has been shown to improve stool consistency and to increase colonic transit in patients with constipation-predominant irritable bowel syndrome.⁷⁸ Renzapride has been studied in patients with this condition,^78–81 but not in patients with chronic constipation. Renzapride is in phase III clinical development in the United States for treating constipation-predominant irritable bowel syndrome.

EMERGING TREATMENTS

New drugs with novel mechanisms of action are being investigated for the treatment of chronic idiopathic constipation.

Neurotrophin-3, a neurotrophic factor, modulates the development of the nervous system by regulating the survival and differentiation of nerves.⁸² In patients with functional constipation, subcutaneous doses of neurotrophin-3 improved stool frequency, the number of complete spontaneous bowel movements, and stool consistency.⁸³

Alvimopan is a selective antagonist of the muopioid receptor that is being studied for opiate-related constipation and postoperative ileus.^84,85 Little of this drug is systemically absorbed and it does not cross the blood-brain barrier; thus, it relieves the opiate-related side effects, ie, bloating, abdominal discomfort, and reduced stool frequency, without interfering with the central analgesic effects.

Linaclotide (MD 1100), a poorly absorbed guanylate cyclase agonist, is also being investigated as a treatment for chronic constipation.⁸⁶ Linaclotide increases intestinal fluid secretion and transit via stimulation of cyclic guanosine monophosphate production and activation of the cystic fibrosis transmembrane conductance regulator.^86,87 In preliminary studies, linaclotide increased stool frequency and the Bristol Stool Form Scale consistency score (Table 1) by increasing intestinal fluid secretion and transit.⁸⁶

Chenodeoxycholic acid is a bile acid that is synthesized from cholesterol.⁸⁸ Treatment of constipation with chenodeoxycholic acid has been proposed, given its laxative effect. A study by Bazzoli et al⁸⁹ showed increased stool frequency and a decrease in stool consistency in chronic constipation patients given chenodeoxycholic acid 10 mg/kg/day. The main side effect was diarrhea. Chenodeoxycholic acid may be worthwhile in the management of constipation, but more studies are needed.

PROBIOTICS AND PREBIOTICS

The bacteria of the colon influence peristalsis of the colon.⁹⁰ Probiotics (live bacterial preparations) and prebiotics (nondigestible preparations that stimulate the growth or activity of beneficial colonic bacteria) have been gaining interest as potential therapies for constipation.^91,92

Probiotic bacterial preparations are generally composed of strains of Bifodobacterium,^93,94Lactobacillus,⁹⁵ and combinations thereof, and are available as mixed preparations of multiple bacterial strains of Lactobacillus, Bifodobacterium, and Streptococcus species, such as VSL#3.⁹⁶

Probiotics may help relieve constipation, but their effect may depend on the strain of bacteria used and the population being studied.⁹⁷ In a double-blind parallel study in 70 healthy adults, ingestion of 375 g/day of milk fermented with B animalis strain DN-173 010 for 11 days reduced colon transit time by 20% from baseline. The effect was more pronounced in women, particularly in those with longer baseline transit.⁹⁸

Lactic acid-producing bacteria are considered commensal organisms with essentially no pathogenic potential.⁹⁹ A review of the safety of bifodobacteria and lactobacilli concluded there was no health risk to consumers.¹⁰⁰

Prebiotics are short-chain carbohydrates such as lactulose that stimulate the activity of beneficial colonic bacteria.⁹¹ They are thought to have a small laxative effect that is likely both osmotic and due to beneficial actions of bacteria for which they are a substrate. Both konjac glucomannan and lactulose, sugar-based laxatives and prebiotics, have been shown to significantly increase the fecal concentrations of lactobacilli and total bacteria, possibly through increases in stool bulk.⁴⁶ Prebiotics that have been the focus of research include inulin, fructo-oligosaccharides, and galacto-oligosaccharides.⁹¹ Evidence on the efficacy of probiotics and prebiotics at relieving symptoms of constipation, however, is inconclusive because few well-controlled clinical studies have been done.^91,92

STRATEGIES FOR MANAGING CHRONIC CONSTIPATION

In the absence of secondary causes, treatment of chronic constipation is focused on relieving symptoms.

If symptoms are refractory to these traditional treatments, agents such as lactulose and polyethylene glycol may provide relief.^11,21 Although they do not address the underlying cause of constipation, these agents increase the fluid content of the intestine, contributing to improved stool consistency, and consequently increase the frequency of bowel movements.

Lubiprostone similarly increases the fluid content of the colon, contributing to improved stool consistency, reduced fecal transit time, and increased frequency of bowel movements.^66,70,102 Unlike lactulose and polyethylene glycol, which are indicated only for short-term use, lubiprostone has been found to be safe and effective when used for up to 48 weeks.^70,71

Biofeedback is the preferred treatment for pelvic floor dyssynergia, in which it has a success rate of 70% to 81% and in which it is superior to standard treatment (laxatives, fiber, and education).^103–105 In an instrument-based training program, patients receive auditory or visual feedback or both to help train the pelvic floor and relax the anal sphincter while simulating defecation. It also improves rectal sensation to assist in proper evacuation. The best outcomes are achieved when committed patients receive instruction from empathetic, properly trained physical therapists or other technicians. Studies show that the benefits of biofeedback are long-lasting.¹⁰⁴ It does not improve slow-transit constipation, though pelvic floor dyssynergia and slow-transit constipation can overlap.

Perhaps the most daunting challenge for any primary care physician, nephrologist, or other internal medicine specialist is how to prevent the progression of chronic kidney disease.

See related article

A MAJOR HEALTH CARE CRISIS

Ten to 20 million people in the United States have chronic kidney disease, with diabetic nephropathy and arterial hypertension accounting for two-thirds of cases. In 2007, the US Renal Data System¹ reported that, at the end of 2005, 341,319 patients were receiving dialysis and another 143,693 had received renal transplants.

The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiatives² has raised the level of awareness of chronic kidney disease among physicians and the general public. We have become more adept at diagnosing chronic kidney disease, in particular by calculating the estimated glomerular filtration rate, and we are starting to learn how to sort out the patients designated as having chronic kidney disease by this calculation but without “true” kidney disease. Nevertheless, the medical profession is still struggling to determine the best way to prevent progression in chronic kidney disease, and no single innovative approach currently exists. Should the emphasis be on the blood pressure target, the level of proteinuria reduction, the classes of medications to be used, or on other factors such as lipid control, vitamin D repletion,³ or glycemic control?

WHY INHIBIT THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM?

Over the last 20 years, investigators have devoted much effort to controlling the adverse effects of the renin-angiotensin-aldosterone system on the renal vasculature and parenchyma. We now understand that this system is a complex cascade and that angiotensin II plays a key role.

Angiotensin II enhances the vascular tone of both the afferent and the efferent glomerular arterioles, helps regulate intraglomerular pressure and glomerular filtration, and stimulates the adrenal cortex to release aldosterone. In addition, it has several nonhemodynamic effects. In particular, it may alter the selective permeability of the glomerular capillary barrier by influencing podocyte morphology and by directing a reorganization of its actin cytostructure.

Podocytes are highly differentiated pericyte-like cells that are essential for normal kidney function, but they have limited regenerative ability. Angiotensin II stimulation can lead to podocyte injury via mechanical stress due to increased intraglomerular pressure or an increase in cytosolic calcium,⁴ formation of bridging between the parietal basement membrane and the glomerular basement membrane,⁵ and extension of the extracapillary disease process to the glomerular-proximal tubular junction.⁶ These alterations can result in progressive atrophy, cell death, subsequent fibrosis, and irreversible loss in functioning renal parenchyma.

EVIDENCE FOR AND AGAINST COMBINATION THERAPY

In theory, by completely inhibiting the renin-angiotensin-aldosterone system in some patients with proteinuric chronic kidney disease (as Dr. Sheldon Hirsch suggests in this issue of the Cleveland Clinic Journal of Medicine⁷), we might be better able to prevent progressive renal injury than with an incomplete blockade of this system.

The rationale for complete blockade stems from evidence that long-term treatment with an angiotensin-converting enzyme (ACE) inhibitor results in the accumulation of angiotensin I, the escape of angiotensin II generation by ACE-independent enzymes (chymases), and the inhibition of angiotensin-(1–7) formation that partially antagonizes the effects of angiotensin II. In addition, aldosterone may injure the kidney by its rapid nongenomic effect on the renal vasculature, resulting in increased renal vascular resistance, with afferent and efferent vasoconstriction. Therefore, treatment with either an ACE inhibitor or an angiotensin receptor blocker (ARB) by itself may delay but not prevent end-stage renal disease for most patients with proteinuric chronic kidney disease.⁸

Combining an ACE inhibitor and an ARB

Regimens in which an ACE inhibitor is combined with an ARB may achieve their therapeutic benefit of lowering proteinuria by modulating the compensatory events in kidney injury that stress “normal” nephrons, inhibiting the podocyte injury responsible for contiguous damage in the tubulointerstitial area, and limiting fibrosis and inflammation. However, few trials actually showed that combining an ACE inhibitor with an ARB leads to greater renal protection in the long term than with either agent alone, despite a greater chance of lowering the protein excretion rate.^9,10

The COOPERATE study. The Combination Treatment of Angiotensin II Receptor Blocker and Angiotensin-Converting-Enzyme Inhibitor in Non-diabetic Renal Disease (COOPERATE) study¹¹ evaluated the renoprotective effects of the combination of trandolapril (Mavik, an ACE inhibitor) and losartan (Cozaar, an ARB). Significantly fewer patients reached one of the end points (doubling of the serum creatinine concentration or end-stage renal disease) with the combined therapy than with either agent alone.

Kunz et al¹² recently performed a meta-analysis, which indicated that the combination of an ACE inhibitor and an ARB reduces proteinuria to a greater extent than either drug alone. However, the total number of patients in each trial was less than 30 on average, the duration of therapy rarely exceeded 1 year, and the effect on changes in the glomerular filtration rate or the need for dialysis was not reported.

ONTARGET. In the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET),¹³ combination therapy had no clear benefit in the group at the highest renal risk (ie, with overt diabetic nephropathy), and it was associated with a trend toward worse results in the low-risk group. Most participants in ONTARGET did not have microalbuminuria or macroalbuminuria, and of interest, these patients without protein excretion were at increased risk for renal events, such as acute renal failure requiring dialysis.

Phillips et al¹⁴ recently reported on the safety profile of patients with symptomatic left ventricular dysfunction treated with the combination of an ACE inhibitor and an ARB. Even in these nonrenal patients there was a significantly higher risk of worsening renal dysfunction (relative risk 4.87, 95% confidence interval 2.39–9.94) and hyperkalemia (relative risk 4.87, 95% confidence interval 2.39–9.94) with combination therapy.

Adding an aldosterone blocker to an ACE inhibitor, ARB, or both

There is little evidence that aldosterone plays a role in the progression of chronic kidney disease. However, several studies found that combining an aldosterone blocker with an ACE inhibitor, ARB, or both had an additional impact on reducing proteinuria and modulating the rate of change in the glomerular filtration rate.^15–17

When aldosterone antagonists were added to an ACE inhibitor, an ARB, or both combined, proteinuria was reduced, but there was little effect on preserving the glomerular filtration rate.¹⁷ However, most of the studies were small, with short observation periods. Hyperkalemia is a risk when using aldosterone antagonists in combination with ACE inhibitors and ARBs, especially in patients with glomerular filtration rates less than 30 mL/minute.¹⁸

Adding a renin inhibitor to an ACE inhibitor or an ARB

Few studies have examined combination therapy with either an ACE inhibitor or ARB plus a renin inhibitor, the newest class of agents that block this system.

Parving et al¹⁹ recently reported the results of combining aliskiren (Tekturna, a renin inhibitor) with losartan in 599 patients with type 2 diabetes and nephropathy. At 6 months, the renin inhibitor showed a renoprotective effect that was independent of its blood-pressure-lowering effect in those who were receiving maximal recommended doses of the ARB.

OTHER FACTORS ALSO INFLUENCE PROGRESSION

Even though there is broad agreement that an approach that neutralizes the effects of the renin-angiotensin-aldosterone system on the kidney would lower blood pressure and protein excretion rates, whether it would change the natural history of chronic kidney disease and prevent progression is less clear. In reality, a number of factors other than the renin-angiotensin-aldosterone system are responsible for the progression of chronic kidney disease. These other factors may help explain why control of this system does not totally prevent deterioration of chronic kidney disease, although the rate may be slowed.

MORE QUESTIONS THAN ANSWERS

A number of provocative questions arise from Dr. Hirsch’s discussion of complete renin-angiotensin-aldosterone system blockade to prevent disease progression:

• Will decreasing proteinuria to a specific target (< 500 mg/day) prevent progression?
• How low should the blood pressure target be set to modulate progression, and should it be the same in all age groups?
• Should complete blockade be applied all at once or in a stepwise fashion depending on the glomerular filtration rate, the level of proteinuria, or both?
• Which patients would benefit most from complete blockade?
• Is direct renin inhibition a critical component of complete blockade?
• What model of chronic disease management is required to avoid unexpected complications if this treatment approach is embraced?

Currently, therefore, there are more questions than answers. This strategy is an intriguing, opinion-based option, but for now it should only be applied to patients with proteinuria and evidence of early progression despite standard therapy who can be closely monitored, and it is not for the faint of heart. In view of the risks of hyperkalemia, hypotension, and perhaps even worsening renal function, more data from carefully designed trials are needed before the general medical community widely applies a complete blockade of the renin-angiotensin-aldosterone pathway to prevent progressive chronic kidney disease.

Perhaps the most daunting challenge for any primary care physician, nephrologist, or other internal medicine specialist is how to prevent the progression of chronic kidney disease.

See related article

A MAJOR HEALTH CARE CRISIS

Ten to 20 million people in the United States have chronic kidney disease, with diabetic nephropathy and arterial hypertension accounting for two-thirds of cases. In 2007, the US Renal Data System¹ reported that, at the end of 2005, 341,319 patients were receiving dialysis and another 143,693 had received renal transplants.

The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiatives² has raised the level of awareness of chronic kidney disease among physicians and the general public. We have become more adept at diagnosing chronic kidney disease, in particular by calculating the estimated glomerular filtration rate, and we are starting to learn how to sort out the patients designated as having chronic kidney disease by this calculation but without “true” kidney disease. Nevertheless, the medical profession is still struggling to determine the best way to prevent progression in chronic kidney disease, and no single innovative approach currently exists. Should the emphasis be on the blood pressure target, the level of proteinuria reduction, the classes of medications to be used, or on other factors such as lipid control, vitamin D repletion,³ or glycemic control?

WHY INHIBIT THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM?

Over the last 20 years, investigators have devoted much effort to controlling the adverse effects of the renin-angiotensin-aldosterone system on the renal vasculature and parenchyma. We now understand that this system is a complex cascade and that angiotensin II plays a key role.

Angiotensin II enhances the vascular tone of both the afferent and the efferent glomerular arterioles, helps regulate intraglomerular pressure and glomerular filtration, and stimulates the adrenal cortex to release aldosterone. In addition, it has several nonhemodynamic effects. In particular, it may alter the selective permeability of the glomerular capillary barrier by influencing podocyte morphology and by directing a reorganization of its actin cytostructure.

Podocytes are highly differentiated pericyte-like cells that are essential for normal kidney function, but they have limited regenerative ability. Angiotensin II stimulation can lead to podocyte injury via mechanical stress due to increased intraglomerular pressure or an increase in cytosolic calcium,⁴ formation of bridging between the parietal basement membrane and the glomerular basement membrane,⁵ and extension of the extracapillary disease process to the glomerular-proximal tubular junction.⁶ These alterations can result in progressive atrophy, cell death, subsequent fibrosis, and irreversible loss in functioning renal parenchyma.

EVIDENCE FOR AND AGAINST COMBINATION THERAPY

In theory, by completely inhibiting the renin-angiotensin-aldosterone system in some patients with proteinuric chronic kidney disease (as Dr. Sheldon Hirsch suggests in this issue of the Cleveland Clinic Journal of Medicine⁷), we might be better able to prevent progressive renal injury than with an incomplete blockade of this system.

The rationale for complete blockade stems from evidence that long-term treatment with an angiotensin-converting enzyme (ACE) inhibitor results in the accumulation of angiotensin I, the escape of angiotensin II generation by ACE-independent enzymes (chymases), and the inhibition of angiotensin-(1–7) formation that partially antagonizes the effects of angiotensin II. In addition, aldosterone may injure the kidney by its rapid nongenomic effect on the renal vasculature, resulting in increased renal vascular resistance, with afferent and efferent vasoconstriction. Therefore, treatment with either an ACE inhibitor or an angiotensin receptor blocker (ARB) by itself may delay but not prevent end-stage renal disease for most patients with proteinuric chronic kidney disease.⁸

Combining an ACE inhibitor and an ARB

Regimens in which an ACE inhibitor is combined with an ARB may achieve their therapeutic benefit of lowering proteinuria by modulating the compensatory events in kidney injury that stress “normal” nephrons, inhibiting the podocyte injury responsible for contiguous damage in the tubulointerstitial area, and limiting fibrosis and inflammation. However, few trials actually showed that combining an ACE inhibitor with an ARB leads to greater renal protection in the long term than with either agent alone, despite a greater chance of lowering the protein excretion rate.^9,10

The COOPERATE study. The Combination Treatment of Angiotensin II Receptor Blocker and Angiotensin-Converting-Enzyme Inhibitor in Non-diabetic Renal Disease (COOPERATE) study¹¹ evaluated the renoprotective effects of the combination of trandolapril (Mavik, an ACE inhibitor) and losartan (Cozaar, an ARB). Significantly fewer patients reached one of the end points (doubling of the serum creatinine concentration or end-stage renal disease) with the combined therapy than with either agent alone.

Kunz et al¹² recently performed a meta-analysis, which indicated that the combination of an ACE inhibitor and an ARB reduces proteinuria to a greater extent than either drug alone. However, the total number of patients in each trial was less than 30 on average, the duration of therapy rarely exceeded 1 year, and the effect on changes in the glomerular filtration rate or the need for dialysis was not reported.

ONTARGET. In the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET),¹³ combination therapy had no clear benefit in the group at the highest renal risk (ie, with overt diabetic nephropathy), and it was associated with a trend toward worse results in the low-risk group. Most participants in ONTARGET did not have microalbuminuria or macroalbuminuria, and of interest, these patients without protein excretion were at increased risk for renal events, such as acute renal failure requiring dialysis.

Phillips et al¹⁴ recently reported on the safety profile of patients with symptomatic left ventricular dysfunction treated with the combination of an ACE inhibitor and an ARB. Even in these nonrenal patients there was a significantly higher risk of worsening renal dysfunction (relative risk 4.87, 95% confidence interval 2.39–9.94) and hyperkalemia (relative risk 4.87, 95% confidence interval 2.39–9.94) with combination therapy.

Adding an aldosterone blocker to an ACE inhibitor, ARB, or both

There is little evidence that aldosterone plays a role in the progression of chronic kidney disease. However, several studies found that combining an aldosterone blocker with an ACE inhibitor, ARB, or both had an additional impact on reducing proteinuria and modulating the rate of change in the glomerular filtration rate.^15–17

When aldosterone antagonists were added to an ACE inhibitor, an ARB, or both combined, proteinuria was reduced, but there was little effect on preserving the glomerular filtration rate.¹⁷ However, most of the studies were small, with short observation periods. Hyperkalemia is a risk when using aldosterone antagonists in combination with ACE inhibitors and ARBs, especially in patients with glomerular filtration rates less than 30 mL/minute.¹⁸

Adding a renin inhibitor to an ACE inhibitor or an ARB

Few studies have examined combination therapy with either an ACE inhibitor or ARB plus a renin inhibitor, the newest class of agents that block this system.

Parving et al¹⁹ recently reported the results of combining aliskiren (Tekturna, a renin inhibitor) with losartan in 599 patients with type 2 diabetes and nephropathy. At 6 months, the renin inhibitor showed a renoprotective effect that was independent of its blood-pressure-lowering effect in those who were receiving maximal recommended doses of the ARB.

OTHER FACTORS ALSO INFLUENCE PROGRESSION

Even though there is broad agreement that an approach that neutralizes the effects of the renin-angiotensin-aldosterone system on the kidney would lower blood pressure and protein excretion rates, whether it would change the natural history of chronic kidney disease and prevent progression is less clear. In reality, a number of factors other than the renin-angiotensin-aldosterone system are responsible for the progression of chronic kidney disease. These other factors may help explain why control of this system does not totally prevent deterioration of chronic kidney disease, although the rate may be slowed.

MORE QUESTIONS THAN ANSWERS

A number of provocative questions arise from Dr. Hirsch’s discussion of complete renin-angiotensin-aldosterone system blockade to prevent disease progression:

• Will decreasing proteinuria to a specific target (< 500 mg/day) prevent progression?
• How low should the blood pressure target be set to modulate progression, and should it be the same in all age groups?
• Should complete blockade be applied all at once or in a stepwise fashion depending on the glomerular filtration rate, the level of proteinuria, or both?
• Which patients would benefit most from complete blockade?
• Is direct renin inhibition a critical component of complete blockade?
• What model of chronic disease management is required to avoid unexpected complications if this treatment approach is embraced?

Currently, therefore, there are more questions than answers. This strategy is an intriguing, opinion-based option, but for now it should only be applied to patients with proteinuria and evidence of early progression despite standard therapy who can be closely monitored, and it is not for the faint of heart. In view of the risks of hyperkalemia, hypotension, and perhaps even worsening renal function, more data from carefully designed trials are needed before the general medical community widely applies a complete blockade of the renin-angiotensin-aldosterone pathway to prevent progressive chronic kidney disease.

Perhaps the most daunting challenge for any primary care physician, nephrologist, or other internal medicine specialist is how to prevent the progression of chronic kidney disease.

See related article

A MAJOR HEALTH CARE CRISIS

Ten to 20 million people in the United States have chronic kidney disease, with diabetic nephropathy and arterial hypertension accounting for two-thirds of cases. In 2007, the US Renal Data System¹ reported that, at the end of 2005, 341,319 patients were receiving dialysis and another 143,693 had received renal transplants.

The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiatives² has raised the level of awareness of chronic kidney disease among physicians and the general public. We have become more adept at diagnosing chronic kidney disease, in particular by calculating the estimated glomerular filtration rate, and we are starting to learn how to sort out the patients designated as having chronic kidney disease by this calculation but without “true” kidney disease. Nevertheless, the medical profession is still struggling to determine the best way to prevent progression in chronic kidney disease, and no single innovative approach currently exists. Should the emphasis be on the blood pressure target, the level of proteinuria reduction, the classes of medications to be used, or on other factors such as lipid control, vitamin D repletion,³ or glycemic control?

WHY INHIBIT THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM?

Over the last 20 years, investigators have devoted much effort to controlling the adverse effects of the renin-angiotensin-aldosterone system on the renal vasculature and parenchyma. We now understand that this system is a complex cascade and that angiotensin II plays a key role.

Angiotensin II enhances the vascular tone of both the afferent and the efferent glomerular arterioles, helps regulate intraglomerular pressure and glomerular filtration, and stimulates the adrenal cortex to release aldosterone. In addition, it has several nonhemodynamic effects. In particular, it may alter the selective permeability of the glomerular capillary barrier by influencing podocyte morphology and by directing a reorganization of its actin cytostructure.

Podocytes are highly differentiated pericyte-like cells that are essential for normal kidney function, but they have limited regenerative ability. Angiotensin II stimulation can lead to podocyte injury via mechanical stress due to increased intraglomerular pressure or an increase in cytosolic calcium,⁴ formation of bridging between the parietal basement membrane and the glomerular basement membrane,⁵ and extension of the extracapillary disease process to the glomerular-proximal tubular junction.⁶ These alterations can result in progressive atrophy, cell death, subsequent fibrosis, and irreversible loss in functioning renal parenchyma.

EVIDENCE FOR AND AGAINST COMBINATION THERAPY

In theory, by completely inhibiting the renin-angiotensin-aldosterone system in some patients with proteinuric chronic kidney disease (as Dr. Sheldon Hirsch suggests in this issue of the Cleveland Clinic Journal of Medicine⁷), we might be better able to prevent progressive renal injury than with an incomplete blockade of this system.

The rationale for complete blockade stems from evidence that long-term treatment with an angiotensin-converting enzyme (ACE) inhibitor results in the accumulation of angiotensin I, the escape of angiotensin II generation by ACE-independent enzymes (chymases), and the inhibition of angiotensin-(1–7) formation that partially antagonizes the effects of angiotensin II. In addition, aldosterone may injure the kidney by its rapid nongenomic effect on the renal vasculature, resulting in increased renal vascular resistance, with afferent and efferent vasoconstriction. Therefore, treatment with either an ACE inhibitor or an angiotensin receptor blocker (ARB) by itself may delay but not prevent end-stage renal disease for most patients with proteinuric chronic kidney disease.⁸

Combining an ACE inhibitor and an ARB

Regimens in which an ACE inhibitor is combined with an ARB may achieve their therapeutic benefit of lowering proteinuria by modulating the compensatory events in kidney injury that stress “normal” nephrons, inhibiting the podocyte injury responsible for contiguous damage in the tubulointerstitial area, and limiting fibrosis and inflammation. However, few trials actually showed that combining an ACE inhibitor with an ARB leads to greater renal protection in the long term than with either agent alone, despite a greater chance of lowering the protein excretion rate.^9,10

The COOPERATE study. The Combination Treatment of Angiotensin II Receptor Blocker and Angiotensin-Converting-Enzyme Inhibitor in Non-diabetic Renal Disease (COOPERATE) study¹¹ evaluated the renoprotective effects of the combination of trandolapril (Mavik, an ACE inhibitor) and losartan (Cozaar, an ARB). Significantly fewer patients reached one of the end points (doubling of the serum creatinine concentration or end-stage renal disease) with the combined therapy than with either agent alone.

Kunz et al¹² recently performed a meta-analysis, which indicated that the combination of an ACE inhibitor and an ARB reduces proteinuria to a greater extent than either drug alone. However, the total number of patients in each trial was less than 30 on average, the duration of therapy rarely exceeded 1 year, and the effect on changes in the glomerular filtration rate or the need for dialysis was not reported.

ONTARGET. In the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET),¹³ combination therapy had no clear benefit in the group at the highest renal risk (ie, with overt diabetic nephropathy), and it was associated with a trend toward worse results in the low-risk group. Most participants in ONTARGET did not have microalbuminuria or macroalbuminuria, and of interest, these patients without protein excretion were at increased risk for renal events, such as acute renal failure requiring dialysis.

Phillips et al¹⁴ recently reported on the safety profile of patients with symptomatic left ventricular dysfunction treated with the combination of an ACE inhibitor and an ARB. Even in these nonrenal patients there was a significantly higher risk of worsening renal dysfunction (relative risk 4.87, 95% confidence interval 2.39–9.94) and hyperkalemia (relative risk 4.87, 95% confidence interval 2.39–9.94) with combination therapy.

Adding an aldosterone blocker to an ACE inhibitor, ARB, or both

There is little evidence that aldosterone plays a role in the progression of chronic kidney disease. However, several studies found that combining an aldosterone blocker with an ACE inhibitor, ARB, or both had an additional impact on reducing proteinuria and modulating the rate of change in the glomerular filtration rate.^15–17

When aldosterone antagonists were added to an ACE inhibitor, an ARB, or both combined, proteinuria was reduced, but there was little effect on preserving the glomerular filtration rate.¹⁷ However, most of the studies were small, with short observation periods. Hyperkalemia is a risk when using aldosterone antagonists in combination with ACE inhibitors and ARBs, especially in patients with glomerular filtration rates less than 30 mL/minute.¹⁸

Adding a renin inhibitor to an ACE inhibitor or an ARB

Few studies have examined combination therapy with either an ACE inhibitor or ARB plus a renin inhibitor, the newest class of agents that block this system.

Parving et al¹⁹ recently reported the results of combining aliskiren (Tekturna, a renin inhibitor) with losartan in 599 patients with type 2 diabetes and nephropathy. At 6 months, the renin inhibitor showed a renoprotective effect that was independent of its blood-pressure-lowering effect in those who were receiving maximal recommended doses of the ARB.

OTHER FACTORS ALSO INFLUENCE PROGRESSION

Even though there is broad agreement that an approach that neutralizes the effects of the renin-angiotensin-aldosterone system on the kidney would lower blood pressure and protein excretion rates, whether it would change the natural history of chronic kidney disease and prevent progression is less clear. In reality, a number of factors other than the renin-angiotensin-aldosterone system are responsible for the progression of chronic kidney disease. These other factors may help explain why control of this system does not totally prevent deterioration of chronic kidney disease, although the rate may be slowed.

MORE QUESTIONS THAN ANSWERS

A number of provocative questions arise from Dr. Hirsch’s discussion of complete renin-angiotensin-aldosterone system blockade to prevent disease progression:

• Will decreasing proteinuria to a specific target (< 500 mg/day) prevent progression?
• How low should the blood pressure target be set to modulate progression, and should it be the same in all age groups?
• Should complete blockade be applied all at once or in a stepwise fashion depending on the glomerular filtration rate, the level of proteinuria, or both?
• Which patients would benefit most from complete blockade?
• Is direct renin inhibition a critical component of complete blockade?
• What model of chronic disease management is required to avoid unexpected complications if this treatment approach is embraced?

Currently, therefore, there are more questions than answers. This strategy is an intriguing, opinion-based option, but for now it should only be applied to patients with proteinuria and evidence of early progression despite standard therapy who can be closely monitored, and it is not for the faint of heart. In view of the risks of hyperkalemia, hypotension, and perhaps even worsening renal function, more data from carefully designed trials are needed before the general medical community widely applies a complete blockade of the renin-angiotensin-aldosterone pathway to prevent progressive chronic kidney disease.

When angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor blockers (ARBs) were introduced, we hoped that these drugs would slow or stop the inexorable progression of chronic kidney disease. This hasn’t come to pass: the incidence of end-stage renal disease continued to increase throughout the 1990s, and although it may have finally reached a plateau, it remains unacceptably high.¹ One reason may be that, used singly, drugs that block the renin-angiotensin-aldosterone system are only moderately successful, as approximately 20% to 40% of patients still reach unfavorable renal end points such as doubling of the serum creatinine level or dialysis.^2–7

See related editorial

In view of these disappointing results, some experts are advocating a new strategy in which they advise that both blood pressure and urinary albumin excretion be lowered to specific goals. To achieve these goals, we will generally have to give higher doses of ACE inhibitors and ARBs alone or use a combination of these and other drugs that block the renin-angiotensin-aldosterone system at various sites.

This article describes how the dual-goal approach, with a focus on renin-angiotensin-aldosterone system inhibition, may be applied in the therapy of proteinuric chronic kidney disease. This appears to be a reasonable approach, based on current evidence, to address the epidemic of renal failure. However, further studies are needed to establish the effectiveness of this approach, and the risk of hyperkalemia following aggressive inhibition of the renin-angiotensin-aldosterone system poses a significant management problem.

ALBUMIN MAY BE TOXIC

While hypertension has long been associated with poor renal outcomes, urinary albumin has more recently been implicated by observational and experimental evidence as a tubular-interstitial toxin that may also accelerate the progression of renal disease.

For example, in both the Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) study⁸ and the Ramipril Efficacy in Nephropathy study,⁴ baseline proteinuria was almost linearly related to worse renal outcomes. In RENAAL, patients who excreted more than about 3 g of albumin per day had an 8.1-fold higher risk of progressing to end-stage renal disease.⁸ Moreover, the more that protein excretion could be reduced, the better the renal outcomes, down to a level of about 500 mg/day.⁸

Of importance, lowering blood pressure did not always decrease protein excretion—nearly 40% of patients had a dissociation between the two.⁹ In fact, prescribing a single ACE inhibitor or ARB while targeting only blood pressure has not predictably reduced protein excretion to 500 mg/day (the proposed goal).^2–7

Although albumin has not been conclusively proven to be a renal toxin, targeting the reduction of proteinuria may also succeed if urinary albumin simply serves as a marker of the success of chronic kidney disease treatment and reflects prognosis.

A DUAL-GOAL APPROACH

In view of the observational and experimental evidence, many experts^10,15–18 are advocating a dual-goal approach that stresses lowering both blood pressure and urinary protein (albumin) excretion. The recommended goal for systolic blood pressure is less than 120 to 125 mm Hg; the goal for proteinuria is less than 300 to 500 mg/24 hours,^16,17,19 aiming to slow the decline in glomerular filtration rate to less than 2 mL/ min/year.^11,20

The strategy of targeting both proteinuria and blood pressure has recently received further support. In a prospective randomized controlled study,²¹ nondiabetic patients with proteinuria received either an ACE inhibitor or an ARB. In one group, the dose was adjusted to lower the blood pressure to less than 130/80 mm/Hg; in the other group, the dose was adjusted to lower the blood pressure to 130/80 and to reduce protein excretion maximally. Only about half as many patients in the group with the dual-goal strategy reached the composite primary end point (doubling of serum creatinine, end-stage renal disease, or death) over a median of 3.7 years of follow-up, as compared with those treated by targeting the blood pressure alone.

In retrospect, the suboptimal success in the earlier landmark studies^2–7 may have derived from the failure of ACE inhibitors and ARBs, used by themselves at moderate doses, to either lower the blood pressure to the recently advised goal (the actual results obtained varied from about 128 to about 145 mm Hg systolic) or, perhaps, to reduce proteinuria to the goal level.

Not all nephrologists currently pursue the stringent proteinuria goal of 500 mg per day—the targeted reduction of proteinuria requires further prospective evidence to support it. However, nephrologists do commonly follow the broad theme that antihypertensive therapy in proteinuric chronic kidney disease should accentuate medicines that protect the kidney beyond their antihypertensive effect (Table 1), and that proteinuria is an important metric that, at the very least, reflects the response to therapy and prognosis.

BLOCKING RENIN-ANGIOTENSIN- ALDOSTERONE MORE COMPLETELY

These issues may be addressed by more complete inhibition of the renin-angiotensin-aldosterone system, now achievable with the addition of aldosterone receptor antagonists and direct renin inhibitors to the ACE inhibitors and ARBs. Although we lack long-term studies of the relative efficacy of these medicines alone or in various combinations, the multistep sequence of the renin-angiotensin-aldosterone system allows for the possibility that more complete suppression via coordinated pharmacologic attention to multiple sites will yield beneficial results.

Combining an ACE inhibitor and an ARB

Even in the absence of ACE, angiotensin II is also produced by other kinases and therefore is not completely suppressed by an ACE inhibitor. For this and other reasons, there are theoretical advantages to adding an ARB to an ACE inhibitor.

In the Combination Treatment of Angiotensin 2 Receptor Blocker and Angiotensin-Converting-Enzyme Inhibitor in Non-Diabetic Renal Disease (COOPERATE) study,²⁰ the combination of an ACE inhibitor and an ARB protected the kidneys better than either medicine alone, not only in terms of less protein in the urine but also in terms of significantly fewer patients progressing to the primary end points of doubling of serum creatinine or end-stage renal disease after 3 years of follow-up (11% of patients on combination therapy vs 23% on single therapy).

Aldosterone receptor antagonists or renin inhibitors plus ACE inhibitors and ARBs

Aldosterone escape is common during long-term therapy with ACE inhibitors and ARBs, and an aldosterone-receptor antagonist reduces proteinuria^11–13 and stabilizes kidney function¹³ in a manner additive to that of ACE inhibitors and ARBs.

Direct renin inhibitors overcome the reactive rises in renin activity and in angiotensin II that complicate therapy with ACE inhibitors and ARBs, and they also reduce urinary aldosterone excretion.¹⁴

When to consider combination therapy

Inhibition of the renin-angiotensin-aldosterone system at multiple sites may be considered in cases of persistent hypertension or proteinuria, or of progression of chronic kidney disease despite single-drug therapy, or more broadly, with increasing evidence that combination therapy may preserve the glomerular filtration rate.^13,20 This article suggests one way to apply the several available renin-angiotensin-aldosterone inhibitors, keeping in mind extensive interindividual variations, uncertain responses, and the absence of a linear evidence-based strategy known to be broadly successful.

INITIAL CONSIDERATION: WHAT IS THE BLOOD PRESSURE GOAL?

Determining the blood pressure goal for a patient may not be as straightforward as usually assumed. Typically, advisories suggest a discrete goal; for example, the Seventh Joint National Committee²² recommended a systolic blood pressure of 130 mm Hg or lower for patients with chronic kidney disease or diabetes. However, if we weigh the risks and benefits, we find that the situation is more nuanced. The blood pressure goal should vary among patients, depending on age, amount of proteinuria, whether the patient can tolerate the lowered blood pressure, and whether lowering the blood pressure to this goal stabilizes kidney function.

Long-term follow-up of the Modification of Diet in Renal Disease (MDRD) study demonstrated a benefit of setting the goal mean arterial pressure to less than 92 mm Hg (about 125 mm Hg systolic) regardless of proteinuria.²³ In addition, a meta-analysis suggested that nondiabetic proteinuric patients benefit from even lower systolic blood pressures (110–119 mm Hg).¹⁹

In older patients

However, in the MDRD study, the goal of approximately 125 mm Hg systolic pertained only to patients no older than 60 years.²³ The goal was increased to about 130 mm Hg for patients 61 to 70 years old. In addition, major clinical studies of chronic kidney disease have excluded patients older than 70 years.^2–7,23

Therapy for chronic kidney disease in this older age group is essentially unstudied, and we should be cautious about extrapolating results of aggressive blood pressure-lowering (and renin-angiotensin-aldosterone inhibition) from younger patients to older patients, who may have extensive vascular disease.^24,25

For patients older than 70 years, guidance is perhaps best provided by the Systolic Hypertension in the Elderly Program (SHEP), which found that lowering systolic blood pressure to an average of 143 mm Hg reduced the incidence of stroke and cardiovascular disease.²⁶ The SHEP study does not establish the optimal blood pressure goal for preventing progressive chronic kidney disease (or even cardiovascular disease) in the older age group. However, this is the lowest systolic pressure yet shown to be generally safe and associated with any improved outcome for these patients.

Additional studies are needed to evaluate whether this blood pressure level provides the best outcomes in patients with chronic kidney disease, or whether even lower blood pressures in the elderly are safe and will further improve either renal or cardiovascular outcomes.

In younger patients

In contrast, younger patients without diabetes or vascular disease may, in theory, be candidates for even lower blood pressure. No major study of chronic kidney disease isolated patients from about 20 to 40 years old for analysis, precluding direct evidence-based guidelines for this cohort at this time.

However, some of these patients may have had premorbid systolic blood pressures of 90 to 110 mm Hg, so systolic pressures of 110 to 120 mm Hg would be “hypertensive” by 10 to 30 mm Hg for them. It is possible that some patients in this cohort will tolerate a systolic pressure lower than 110 mm Hg, and that the lower blood pressure may provide additional long-term renal protection for them. This notion is theoretical, however, and has not been verified by clinical studies.

No one pressure fits all

In summary, an initial target systolic pressure for proteinuric patients, based on available evidence, might be less than 130 mm Hg for patients 61 to 70 years old,²³ less than 125 mm Hg for patients younger than 61 years,²³ and perhaps as low as 110 to 119 mm Hg for non-diabetic patients.¹⁹ Caution is advised against targeting systolic blood pressure less than 140 mm Hg for patients older than 70 years.

These are only initial goals and should be reevaluated as treatment progresses. The achieved blood pressure must be clinically tolerated—symptoms of tissue hypoperfusion indicate that the blood pressure is too low for the patient. In addition, the blood pressure goal (like the proteinuria goal) is only a surrogate end point, and if kidney function declines even though the surrogate end points are attained, then those end points should be reevaluated.

Tailoring blood pressure goals to the individual patient dovetails with the recent suggestion that blood pressure should not be perceived as a rigid dichotomy of “hypertension” vs “normal.”²⁷ There is, in general, a continuous correlation between blood pressure, beginning at low levels, and the risk of cardiorenal disease, and choosing an optimal blood pressure goal for an individual patient requires an ongoing assessment of benefits, risks, and side effects.

STARTING ANTIHYPERTENSIVE THERAPY

The question of which antihypertensive drug to try first is moot in chronic kidney disease because almost all patients need multiple medicines to reach their blood pressure goals.

The Seventh Joint National Committee recommended an ACE inhibitor for initial therapy in hypertensive patients with chronic kidney disease,²² although an ARB is a reasonable first choice for those with type 2 diabetes.^5,6

Diuretics potentiate the effects of ACE inhibitors and ARBs and are generally prescribed concomitantly or as the second choice.

A beta-blocker may be recommended as a third medicine (when needed), to provide a complementary class of antihypertensive, to address the high incidence of concomitant coronary artery disease and systolic dysfunction, and because of evidence that sympathetic excess contributes to the hypertension and progression of chronic kidney disease.^28,29 The National Kidney Foundation³⁰ suggests that the dose of beta-blocker be increased if the heart rate is greater than 84.

INTENSIFYING RENIN-ANGIOTENSIN-ALDOSTERONE INHIBITION: WHICH DRUGS, AND WHEN?

When hypertension and proteinuria persist despite the use of an ACE inhibitor or an ARB, additional inhibition of the renin-angiotensin-aldosterone system is generally recommended to lower both the blood pressure and the protein excretion. Increasing the dose of ACE inhibitor or ARB,^31–34 combining an ACE inhibitor and an ARB,²⁰ or adding an aldosterone receptor antagonist to either an ACE inhibitor or an ARB^11–13 have all been shown to reduce proteinuria (as a surrogate end point), and several studies have, importantly, found that these combinations preserve kidney function over time.^13,20

However, lacking long-term studies that compare these options, we cannot insist upon specific treatment choices or sequences in these situations.

An approach based on serum potassium and volume status

For example, if a patient has obvious signs of volume excess (eg, edema, jugular venous distention, rales) and the serum potassium concentration is less than about 5.0 or 5.5 mEq/L, then an aldosterone receptor antagonist may logically be added or increased in dose.

Aldosterone is more than a kidney hormone

Increasing the diuretic or renin-angiotensin-aldosterone inhibition

For patients who have obvious signs of volume excess and a serum potassium level greater than 5.0 mEq/L, the dosage of kaliuretic (potassium-excreting) diuretic (usually a loop diuretic in chronic kidney disease) can be increased. Although kaliuretic diuretics do not specifically lower proteinuria, they will help control volume and blood pressure and, by lowering the serum potassium level, facilitate the subsequent augmention of renin-angiotensin-aldosterone inhibition.

When a hypertensive patient does not seem to have excess volume or tachycardia and the serum potassium level is less than about 5.5 mEq/L, then additional renin-angiotensin-aldosterone inhibition is indicated.¹⁶ This may be accomplished either by increasing the ACE inhibitor or the ARB to its maximal antihypertensive dose or by starting combination therapy.

Starting a calcium channel blocker

When the serum potassium level is higher than about 5.5 mEq/L, further inhibition of the renin-angiotensin-aldosterone system is contraindicated, and a nondihydropyridine calcium channel blocker can be added for its anti-hypertensive and antiproteinuric effects.^16,36

When nondihydropyridine calcium channel blockers are contraindicated due to their antiinotropic effect, an attractive alternative may be to cautiously increase the dose of kaliuretic diuretics. Given the high prevalence of (often covert) volume excess in chronic kidney disease, empiric diuresis may lower blood pressure, particularly in patients already receiving several vasodilators.³⁷ Moreover, as mentioned, by reducing serum potassium, kaliuretic diuretics help allow for a subsequent increase in renin-angiotensin-aldosterone inhibition.

IF BLOOD PRESSURE IS NORMAL, BUT PROTEINURIA PERSISTS

Because lowering blood pressure does not necessarily reduce protein excretion, some patients achieve their blood pressure goal but still have excessive proteinuria. Proponents of the dual-goal approach suggest that these patients require further treatment modifications to reach the proteinuria goal and their optimal renal prognosis.

A cautious increase in renin-angiotensin-aldosterone inhibition is possible but is likely to be limited by low blood pressure. When applicable, any nonessential antihypertensive drug that does not specifically reduce proteinuria (ie, dihydropyridine calcium channel blockers and central and direct vasodilators) should first be discontinued. This allows additional renin-angiotensin-aldosterone inhibition to reduce proteinuria without causing hypotension.

In addition, “ultra-high” doses of these drugs—two or more times the maximal antihypertensive dose—appear to reduce proteinuria without further reducing blood pressure.^31–34

Various combinations of an ACE inhibitor, an ARB, and an aldosterone receptor antagonist (and possibly a renin inhibitor) may also be prescribed, striving for more complete suppression of the renin-angiotensin-aldosterone system, with dose adjustments to prevent hypotension.

KEEPING SERUM POTASSIUM AT SAFE LEVELS

Intensive inhibition of the renin-angiotensin-aldosterone system, via higher doses or combination therapy, increases the risk of hyperkalemia. This risk must be addressed energetically to prevent a potentially life-threatening complication.

When prescribed by nephrologists in clinical studies, renin-angiotensin-aldosterone inhibition has proven safe, with minimal adverse events (including hyperkalemia), even with high doses,^32–34 in stage 4 chronic kidney disease (ie, with a glomerular filtration rate of 15 to 29 mL/min/1.73m², inclusively)⁷ and with combination therapy.^11–13,20

However, the increased incidence of hyperkalemia reported with spironolactone in patients with congestive heart failure following publication of the Randomized Aldactone Evaluation Study³⁸ suggests that safety in clinical studies should not be extrapolated to mean safety in routine, community use. Patients with chronic kidney disease should not be given high doses or combinations of these drugs unless the treating physician is experienced in the prevention and treatment of hyperkalemia; typically such therapy should be guided by a nephrologist.

When serum potassium levels exceed 5.6 mEq/L, renin-angiotensin-aldosterone inhibitors should be decreased in dose or discontinued.³⁹ Ideally, the drug or drugs should be restarted (to provide the potential benefits of these classes of drugs) when hyperkalemia has resolved, but this requires not only resolution of hyperkalemia but also steps to prevent this serious problem from recurring. The serum potassium level should be checked frequently, particularly after any increase in renin-angiotensin-aldosterone inhibition.

Treating hyperkalemia

Potential treatments for hyperkalemia include dietary restriction, sodium bicarbonate,³⁹ fludrocortisone (Florinef),⁴⁰ kaliuretic diuretics, and sodium polystyrene sulfonate (Kayexalate). Nonsteroidal anti-inflammatory drugs should be avoided.

Dietary restriction should be particularly emphasized: if potassium intake is decreased to the same extent as renin-angiotensin-aldosterone inhibitors reduce its excretion, then the serum potassium level will remain acceptable. All dietary supplements whose contents are not precisely known should be proscribed. A list of high-potassium foods to avoid should be given with the initial prescription for the drug. If briefly reviewed at each visit, with feedback given based on measured serum potassium levels, dietary treatment is typically effective (personal observation).

Fludrocortisone is an option when dietary potassium restriction fails.

An increase in the dose of diuretic is typically required with fludrocortisone to prevent sodium retention. The combination of dietary potassium restriction, fludrocortisone (0.1 mg/day, 3–5 days a week), and furosemide (Lasix) allowed high doses of an ACE inhibitor or a combination of an ACE inhibitor and an ARB to be given in 132 patients with chronic kidney disease.⁴⁰ Over several years, their mean peak potassium level was 4.87 mEq/L, and no instance of acute hyperkalemia requiried stopping the ACE inhibitor or ARB.

However, fludrocortisone is an aldosterone analogue with potentially long-term aldosterone-mediated injurious effects on heart and renal function, even though only low doses were required in the three-pronged approach to hyperkalemia.⁴⁰ The long-term effect of a regimen of an ACE inhibitor plus an ARB plus fludrocortisone on cardiac and renal outcomes is unknown and of concern.

Therefore, fludrocortisone should probably be avoided in patients with systolic heart dysfunction and should be used cautiously in general. Its use might be limited to patients with proteinuric chronic kidney disease that progresses despite therapy, particularly when that progression is in the context of inability to give significant renin-angiotensin-aldosterone inhibition because of hyperkalemia.

MORE STUDY NEEDED

Chronic kidney disease treatment is becoming increasingly complex, with a lengthening list of potentially effective drugs, difficult-to-reach goals, and a less structured approach. This complexity is magnified by issues of potassium homeostasis and interindividual variations in response to renin-angiotensin-aldosterone inhibition.

More prospective studies are needed to confirm the benefits of targeting proteinuria along with blood pressure and the metrics of the goals in tandem, but, based on available information, the dual-goal approach has been recommended for proteinuric patients,^10,15–18 and evidence is accumulating for greater renal protection from larger doses of renin-angiotensin-aldosterone inhibitors and from using these drugs in combination.

When angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor blockers (ARBs) were introduced, we hoped that these drugs would slow or stop the inexorable progression of chronic kidney disease. This hasn’t come to pass: the incidence of end-stage renal disease continued to increase throughout the 1990s, and although it may have finally reached a plateau, it remains unacceptably high.¹ One reason may be that, used singly, drugs that block the renin-angiotensin-aldosterone system are only moderately successful, as approximately 20% to 40% of patients still reach unfavorable renal end points such as doubling of the serum creatinine level or dialysis.^2–7

See related editorial

In view of these disappointing results, some experts are advocating a new strategy in which they advise that both blood pressure and urinary albumin excretion be lowered to specific goals. To achieve these goals, we will generally have to give higher doses of ACE inhibitors and ARBs alone or use a combination of these and other drugs that block the renin-angiotensin-aldosterone system at various sites.

This article describes how the dual-goal approach, with a focus on renin-angiotensin-aldosterone system inhibition, may be applied in the therapy of proteinuric chronic kidney disease. This appears to be a reasonable approach, based on current evidence, to address the epidemic of renal failure. However, further studies are needed to establish the effectiveness of this approach, and the risk of hyperkalemia following aggressive inhibition of the renin-angiotensin-aldosterone system poses a significant management problem.

ALBUMIN MAY BE TOXIC

While hypertension has long been associated with poor renal outcomes, urinary albumin has more recently been implicated by observational and experimental evidence as a tubular-interstitial toxin that may also accelerate the progression of renal disease.

For example, in both the Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) study⁸ and the Ramipril Efficacy in Nephropathy study,⁴ baseline proteinuria was almost linearly related to worse renal outcomes. In RENAAL, patients who excreted more than about 3 g of albumin per day had an 8.1-fold higher risk of progressing to end-stage renal disease.⁸ Moreover, the more that protein excretion could be reduced, the better the renal outcomes, down to a level of about 500 mg/day.⁸

Of importance, lowering blood pressure did not always decrease protein excretion—nearly 40% of patients had a dissociation between the two.⁹ In fact, prescribing a single ACE inhibitor or ARB while targeting only blood pressure has not predictably reduced protein excretion to 500 mg/day (the proposed goal).^2–7

Although albumin has not been conclusively proven to be a renal toxin, targeting the reduction of proteinuria may also succeed if urinary albumin simply serves as a marker of the success of chronic kidney disease treatment and reflects prognosis.

A DUAL-GOAL APPROACH

In view of the observational and experimental evidence, many experts^10,15–18 are advocating a dual-goal approach that stresses lowering both blood pressure and urinary protein (albumin) excretion. The recommended goal for systolic blood pressure is less than 120 to 125 mm Hg; the goal for proteinuria is less than 300 to 500 mg/24 hours,^16,17,19 aiming to slow the decline in glomerular filtration rate to less than 2 mL/ min/year.^11,20

The strategy of targeting both proteinuria and blood pressure has recently received further support. In a prospective randomized controlled study,²¹ nondiabetic patients with proteinuria received either an ACE inhibitor or an ARB. In one group, the dose was adjusted to lower the blood pressure to less than 130/80 mm/Hg; in the other group, the dose was adjusted to lower the blood pressure to 130/80 and to reduce protein excretion maximally. Only about half as many patients in the group with the dual-goal strategy reached the composite primary end point (doubling of serum creatinine, end-stage renal disease, or death) over a median of 3.7 years of follow-up, as compared with those treated by targeting the blood pressure alone.

In retrospect, the suboptimal success in the earlier landmark studies^2–7 may have derived from the failure of ACE inhibitors and ARBs, used by themselves at moderate doses, to either lower the blood pressure to the recently advised goal (the actual results obtained varied from about 128 to about 145 mm Hg systolic) or, perhaps, to reduce proteinuria to the goal level.

Not all nephrologists currently pursue the stringent proteinuria goal of 500 mg per day—the targeted reduction of proteinuria requires further prospective evidence to support it. However, nephrologists do commonly follow the broad theme that antihypertensive therapy in proteinuric chronic kidney disease should accentuate medicines that protect the kidney beyond their antihypertensive effect (Table 1), and that proteinuria is an important metric that, at the very least, reflects the response to therapy and prognosis.

BLOCKING RENIN-ANGIOTENSIN- ALDOSTERONE MORE COMPLETELY

These issues may be addressed by more complete inhibition of the renin-angiotensin-aldosterone system, now achievable with the addition of aldosterone receptor antagonists and direct renin inhibitors to the ACE inhibitors and ARBs. Although we lack long-term studies of the relative efficacy of these medicines alone or in various combinations, the multistep sequence of the renin-angiotensin-aldosterone system allows for the possibility that more complete suppression via coordinated pharmacologic attention to multiple sites will yield beneficial results.

Combining an ACE inhibitor and an ARB

Even in the absence of ACE, angiotensin II is also produced by other kinases and therefore is not completely suppressed by an ACE inhibitor. For this and other reasons, there are theoretical advantages to adding an ARB to an ACE inhibitor.

In the Combination Treatment of Angiotensin 2 Receptor Blocker and Angiotensin-Converting-Enzyme Inhibitor in Non-Diabetic Renal Disease (COOPERATE) study,²⁰ the combination of an ACE inhibitor and an ARB protected the kidneys better than either medicine alone, not only in terms of less protein in the urine but also in terms of significantly fewer patients progressing to the primary end points of doubling of serum creatinine or end-stage renal disease after 3 years of follow-up (11% of patients on combination therapy vs 23% on single therapy).

Aldosterone receptor antagonists or renin inhibitors plus ACE inhibitors and ARBs

Aldosterone escape is common during long-term therapy with ACE inhibitors and ARBs, and an aldosterone-receptor antagonist reduces proteinuria^11–13 and stabilizes kidney function¹³ in a manner additive to that of ACE inhibitors and ARBs.

Direct renin inhibitors overcome the reactive rises in renin activity and in angiotensin II that complicate therapy with ACE inhibitors and ARBs, and they also reduce urinary aldosterone excretion.¹⁴

When to consider combination therapy

Inhibition of the renin-angiotensin-aldosterone system at multiple sites may be considered in cases of persistent hypertension or proteinuria, or of progression of chronic kidney disease despite single-drug therapy, or more broadly, with increasing evidence that combination therapy may preserve the glomerular filtration rate.^13,20 This article suggests one way to apply the several available renin-angiotensin-aldosterone inhibitors, keeping in mind extensive interindividual variations, uncertain responses, and the absence of a linear evidence-based strategy known to be broadly successful.

INITIAL CONSIDERATION: WHAT IS THE BLOOD PRESSURE GOAL?

Determining the blood pressure goal for a patient may not be as straightforward as usually assumed. Typically, advisories suggest a discrete goal; for example, the Seventh Joint National Committee²² recommended a systolic blood pressure of 130 mm Hg or lower for patients with chronic kidney disease or diabetes. However, if we weigh the risks and benefits, we find that the situation is more nuanced. The blood pressure goal should vary among patients, depending on age, amount of proteinuria, whether the patient can tolerate the lowered blood pressure, and whether lowering the blood pressure to this goal stabilizes kidney function.

Long-term follow-up of the Modification of Diet in Renal Disease (MDRD) study demonstrated a benefit of setting the goal mean arterial pressure to less than 92 mm Hg (about 125 mm Hg systolic) regardless of proteinuria.²³ In addition, a meta-analysis suggested that nondiabetic proteinuric patients benefit from even lower systolic blood pressures (110–119 mm Hg).¹⁹

In older patients

However, in the MDRD study, the goal of approximately 125 mm Hg systolic pertained only to patients no older than 60 years.²³ The goal was increased to about 130 mm Hg for patients 61 to 70 years old. In addition, major clinical studies of chronic kidney disease have excluded patients older than 70 years.^2–7,23

Therapy for chronic kidney disease in this older age group is essentially unstudied, and we should be cautious about extrapolating results of aggressive blood pressure-lowering (and renin-angiotensin-aldosterone inhibition) from younger patients to older patients, who may have extensive vascular disease.^24,25

For patients older than 70 years, guidance is perhaps best provided by the Systolic Hypertension in the Elderly Program (SHEP), which found that lowering systolic blood pressure to an average of 143 mm Hg reduced the incidence of stroke and cardiovascular disease.²⁶ The SHEP study does not establish the optimal blood pressure goal for preventing progressive chronic kidney disease (or even cardiovascular disease) in the older age group. However, this is the lowest systolic pressure yet shown to be generally safe and associated with any improved outcome for these patients.

Additional studies are needed to evaluate whether this blood pressure level provides the best outcomes in patients with chronic kidney disease, or whether even lower blood pressures in the elderly are safe and will further improve either renal or cardiovascular outcomes.

In younger patients

In contrast, younger patients without diabetes or vascular disease may, in theory, be candidates for even lower blood pressure. No major study of chronic kidney disease isolated patients from about 20 to 40 years old for analysis, precluding direct evidence-based guidelines for this cohort at this time.

However, some of these patients may have had premorbid systolic blood pressures of 90 to 110 mm Hg, so systolic pressures of 110 to 120 mm Hg would be “hypertensive” by 10 to 30 mm Hg for them. It is possible that some patients in this cohort will tolerate a systolic pressure lower than 110 mm Hg, and that the lower blood pressure may provide additional long-term renal protection for them. This notion is theoretical, however, and has not been verified by clinical studies.

No one pressure fits all

In summary, an initial target systolic pressure for proteinuric patients, based on available evidence, might be less than 130 mm Hg for patients 61 to 70 years old,²³ less than 125 mm Hg for patients younger than 61 years,²³ and perhaps as low as 110 to 119 mm Hg for non-diabetic patients.¹⁹ Caution is advised against targeting systolic blood pressure less than 140 mm Hg for patients older than 70 years.

These are only initial goals and should be reevaluated as treatment progresses. The achieved blood pressure must be clinically tolerated—symptoms of tissue hypoperfusion indicate that the blood pressure is too low for the patient. In addition, the blood pressure goal (like the proteinuria goal) is only a surrogate end point, and if kidney function declines even though the surrogate end points are attained, then those end points should be reevaluated.

Tailoring blood pressure goals to the individual patient dovetails with the recent suggestion that blood pressure should not be perceived as a rigid dichotomy of “hypertension” vs “normal.”²⁷ There is, in general, a continuous correlation between blood pressure, beginning at low levels, and the risk of cardiorenal disease, and choosing an optimal blood pressure goal for an individual patient requires an ongoing assessment of benefits, risks, and side effects.

STARTING ANTIHYPERTENSIVE THERAPY

The question of which antihypertensive drug to try first is moot in chronic kidney disease because almost all patients need multiple medicines to reach their blood pressure goals.

The Seventh Joint National Committee recommended an ACE inhibitor for initial therapy in hypertensive patients with chronic kidney disease,²² although an ARB is a reasonable first choice for those with type 2 diabetes.^5,6

Diuretics potentiate the effects of ACE inhibitors and ARBs and are generally prescribed concomitantly or as the second choice.

A beta-blocker may be recommended as a third medicine (when needed), to provide a complementary class of antihypertensive, to address the high incidence of concomitant coronary artery disease and systolic dysfunction, and because of evidence that sympathetic excess contributes to the hypertension and progression of chronic kidney disease.^28,29 The National Kidney Foundation³⁰ suggests that the dose of beta-blocker be increased if the heart rate is greater than 84.

INTENSIFYING RENIN-ANGIOTENSIN-ALDOSTERONE INHIBITION: WHICH DRUGS, AND WHEN?

When hypertension and proteinuria persist despite the use of an ACE inhibitor or an ARB, additional inhibition of the renin-angiotensin-aldosterone system is generally recommended to lower both the blood pressure and the protein excretion. Increasing the dose of ACE inhibitor or ARB,^31–34 combining an ACE inhibitor and an ARB,²⁰ or adding an aldosterone receptor antagonist to either an ACE inhibitor or an ARB^11–13 have all been shown to reduce proteinuria (as a surrogate end point), and several studies have, importantly, found that these combinations preserve kidney function over time.^13,20

However, lacking long-term studies that compare these options, we cannot insist upon specific treatment choices or sequences in these situations.

An approach based on serum potassium and volume status

For example, if a patient has obvious signs of volume excess (eg, edema, jugular venous distention, rales) and the serum potassium concentration is less than about 5.0 or 5.5 mEq/L, then an aldosterone receptor antagonist may logically be added or increased in dose.

Aldosterone is more than a kidney hormone

Increasing the diuretic or renin-angiotensin-aldosterone inhibition

For patients who have obvious signs of volume excess and a serum potassium level greater than 5.0 mEq/L, the dosage of kaliuretic (potassium-excreting) diuretic (usually a loop diuretic in chronic kidney disease) can be increased. Although kaliuretic diuretics do not specifically lower proteinuria, they will help control volume and blood pressure and, by lowering the serum potassium level, facilitate the subsequent augmention of renin-angiotensin-aldosterone inhibition.

When a hypertensive patient does not seem to have excess volume or tachycardia and the serum potassium level is less than about 5.5 mEq/L, then additional renin-angiotensin-aldosterone inhibition is indicated.¹⁶ This may be accomplished either by increasing the ACE inhibitor or the ARB to its maximal antihypertensive dose or by starting combination therapy.

Starting a calcium channel blocker

When the serum potassium level is higher than about 5.5 mEq/L, further inhibition of the renin-angiotensin-aldosterone system is contraindicated, and a nondihydropyridine calcium channel blocker can be added for its anti-hypertensive and antiproteinuric effects.^16,36

When nondihydropyridine calcium channel blockers are contraindicated due to their antiinotropic effect, an attractive alternative may be to cautiously increase the dose of kaliuretic diuretics. Given the high prevalence of (often covert) volume excess in chronic kidney disease, empiric diuresis may lower blood pressure, particularly in patients already receiving several vasodilators.³⁷ Moreover, as mentioned, by reducing serum potassium, kaliuretic diuretics help allow for a subsequent increase in renin-angiotensin-aldosterone inhibition.

IF BLOOD PRESSURE IS NORMAL, BUT PROTEINURIA PERSISTS

Because lowering blood pressure does not necessarily reduce protein excretion, some patients achieve their blood pressure goal but still have excessive proteinuria. Proponents of the dual-goal approach suggest that these patients require further treatment modifications to reach the proteinuria goal and their optimal renal prognosis.

A cautious increase in renin-angiotensin-aldosterone inhibition is possible but is likely to be limited by low blood pressure. When applicable, any nonessential antihypertensive drug that does not specifically reduce proteinuria (ie, dihydropyridine calcium channel blockers and central and direct vasodilators) should first be discontinued. This allows additional renin-angiotensin-aldosterone inhibition to reduce proteinuria without causing hypotension.

In addition, “ultra-high” doses of these drugs—two or more times the maximal antihypertensive dose—appear to reduce proteinuria without further reducing blood pressure.^31–34

Various combinations of an ACE inhibitor, an ARB, and an aldosterone receptor antagonist (and possibly a renin inhibitor) may also be prescribed, striving for more complete suppression of the renin-angiotensin-aldosterone system, with dose adjustments to prevent hypotension.

KEEPING SERUM POTASSIUM AT SAFE LEVELS

Intensive inhibition of the renin-angiotensin-aldosterone system, via higher doses or combination therapy, increases the risk of hyperkalemia. This risk must be addressed energetically to prevent a potentially life-threatening complication.

When prescribed by nephrologists in clinical studies, renin-angiotensin-aldosterone inhibition has proven safe, with minimal adverse events (including hyperkalemia), even with high doses,^32–34 in stage 4 chronic kidney disease (ie, with a glomerular filtration rate of 15 to 29 mL/min/1.73m², inclusively)⁷ and with combination therapy.^11–13,20

However, the increased incidence of hyperkalemia reported with spironolactone in patients with congestive heart failure following publication of the Randomized Aldactone Evaluation Study³⁸ suggests that safety in clinical studies should not be extrapolated to mean safety in routine, community use. Patients with chronic kidney disease should not be given high doses or combinations of these drugs unless the treating physician is experienced in the prevention and treatment of hyperkalemia; typically such therapy should be guided by a nephrologist.

When serum potassium levels exceed 5.6 mEq/L, renin-angiotensin-aldosterone inhibitors should be decreased in dose or discontinued.³⁹ Ideally, the drug or drugs should be restarted (to provide the potential benefits of these classes of drugs) when hyperkalemia has resolved, but this requires not only resolution of hyperkalemia but also steps to prevent this serious problem from recurring. The serum potassium level should be checked frequently, particularly after any increase in renin-angiotensin-aldosterone inhibition.

Treating hyperkalemia

Potential treatments for hyperkalemia include dietary restriction, sodium bicarbonate,³⁹ fludrocortisone (Florinef),⁴⁰ kaliuretic diuretics, and sodium polystyrene sulfonate (Kayexalate). Nonsteroidal anti-inflammatory drugs should be avoided.

Dietary restriction should be particularly emphasized: if potassium intake is decreased to the same extent as renin-angiotensin-aldosterone inhibitors reduce its excretion, then the serum potassium level will remain acceptable. All dietary supplements whose contents are not precisely known should be proscribed. A list of high-potassium foods to avoid should be given with the initial prescription for the drug. If briefly reviewed at each visit, with feedback given based on measured serum potassium levels, dietary treatment is typically effective (personal observation).

Fludrocortisone is an option when dietary potassium restriction fails.

An increase in the dose of diuretic is typically required with fludrocortisone to prevent sodium retention. The combination of dietary potassium restriction, fludrocortisone (0.1 mg/day, 3–5 days a week), and furosemide (Lasix) allowed high doses of an ACE inhibitor or a combination of an ACE inhibitor and an ARB to be given in 132 patients with chronic kidney disease.⁴⁰ Over several years, their mean peak potassium level was 4.87 mEq/L, and no instance of acute hyperkalemia requiried stopping the ACE inhibitor or ARB.

However, fludrocortisone is an aldosterone analogue with potentially long-term aldosterone-mediated injurious effects on heart and renal function, even though only low doses were required in the three-pronged approach to hyperkalemia.⁴⁰ The long-term effect of a regimen of an ACE inhibitor plus an ARB plus fludrocortisone on cardiac and renal outcomes is unknown and of concern.

Therefore, fludrocortisone should probably be avoided in patients with systolic heart dysfunction and should be used cautiously in general. Its use might be limited to patients with proteinuric chronic kidney disease that progresses despite therapy, particularly when that progression is in the context of inability to give significant renin-angiotensin-aldosterone inhibition because of hyperkalemia.

MORE STUDY NEEDED

Chronic kidney disease treatment is becoming increasingly complex, with a lengthening list of potentially effective drugs, difficult-to-reach goals, and a less structured approach. This complexity is magnified by issues of potassium homeostasis and interindividual variations in response to renin-angiotensin-aldosterone inhibition.

More prospective studies are needed to confirm the benefits of targeting proteinuria along with blood pressure and the metrics of the goals in tandem, but, based on available information, the dual-goal approach has been recommended for proteinuric patients,^10,15–18 and evidence is accumulating for greater renal protection from larger doses of renin-angiotensin-aldosterone inhibitors and from using these drugs in combination.

When angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor blockers (ARBs) were introduced, we hoped that these drugs would slow or stop the inexorable progression of chronic kidney disease. This hasn’t come to pass: the incidence of end-stage renal disease continued to increase throughout the 1990s, and although it may have finally reached a plateau, it remains unacceptably high.¹ One reason may be that, used singly, drugs that block the renin-angiotensin-aldosterone system are only moderately successful, as approximately 20% to 40% of patients still reach unfavorable renal end points such as doubling of the serum creatinine level or dialysis.^2–7

See related editorial

In view of these disappointing results, some experts are advocating a new strategy in which they advise that both blood pressure and urinary albumin excretion be lowered to specific goals. To achieve these goals, we will generally have to give higher doses of ACE inhibitors and ARBs alone or use a combination of these and other drugs that block the renin-angiotensin-aldosterone system at various sites.

This article describes how the dual-goal approach, with a focus on renin-angiotensin-aldosterone system inhibition, may be applied in the therapy of proteinuric chronic kidney disease. This appears to be a reasonable approach, based on current evidence, to address the epidemic of renal failure. However, further studies are needed to establish the effectiveness of this approach, and the risk of hyperkalemia following aggressive inhibition of the renin-angiotensin-aldosterone system poses a significant management problem.

ALBUMIN MAY BE TOXIC

While hypertension has long been associated with poor renal outcomes, urinary albumin has more recently been implicated by observational and experimental evidence as a tubular-interstitial toxin that may also accelerate the progression of renal disease.

For example, in both the Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) study⁸ and the Ramipril Efficacy in Nephropathy study,⁴ baseline proteinuria was almost linearly related to worse renal outcomes. In RENAAL, patients who excreted more than about 3 g of albumin per day had an 8.1-fold higher risk of progressing to end-stage renal disease.⁸ Moreover, the more that protein excretion could be reduced, the better the renal outcomes, down to a level of about 500 mg/day.⁸

Of importance, lowering blood pressure did not always decrease protein excretion—nearly 40% of patients had a dissociation between the two.⁹ In fact, prescribing a single ACE inhibitor or ARB while targeting only blood pressure has not predictably reduced protein excretion to 500 mg/day (the proposed goal).^2–7

Although albumin has not been conclusively proven to be a renal toxin, targeting the reduction of proteinuria may also succeed if urinary albumin simply serves as a marker of the success of chronic kidney disease treatment and reflects prognosis.

A DUAL-GOAL APPROACH

In view of the observational and experimental evidence, many experts^10,15–18 are advocating a dual-goal approach that stresses lowering both blood pressure and urinary protein (albumin) excretion. The recommended goal for systolic blood pressure is less than 120 to 125 mm Hg; the goal for proteinuria is less than 300 to 500 mg/24 hours,^16,17,19 aiming to slow the decline in glomerular filtration rate to less than 2 mL/ min/year.^11,20

The strategy of targeting both proteinuria and blood pressure has recently received further support. In a prospective randomized controlled study,²¹ nondiabetic patients with proteinuria received either an ACE inhibitor or an ARB. In one group, the dose was adjusted to lower the blood pressure to less than 130/80 mm/Hg; in the other group, the dose was adjusted to lower the blood pressure to 130/80 and to reduce protein excretion maximally. Only about half as many patients in the group with the dual-goal strategy reached the composite primary end point (doubling of serum creatinine, end-stage renal disease, or death) over a median of 3.7 years of follow-up, as compared with those treated by targeting the blood pressure alone.

In retrospect, the suboptimal success in the earlier landmark studies^2–7 may have derived from the failure of ACE inhibitors and ARBs, used by themselves at moderate doses, to either lower the blood pressure to the recently advised goal (the actual results obtained varied from about 128 to about 145 mm Hg systolic) or, perhaps, to reduce proteinuria to the goal level.

Not all nephrologists currently pursue the stringent proteinuria goal of 500 mg per day—the targeted reduction of proteinuria requires further prospective evidence to support it. However, nephrologists do commonly follow the broad theme that antihypertensive therapy in proteinuric chronic kidney disease should accentuate medicines that protect the kidney beyond their antihypertensive effect (Table 1), and that proteinuria is an important metric that, at the very least, reflects the response to therapy and prognosis.

BLOCKING RENIN-ANGIOTENSIN- ALDOSTERONE MORE COMPLETELY

These issues may be addressed by more complete inhibition of the renin-angiotensin-aldosterone system, now achievable with the addition of aldosterone receptor antagonists and direct renin inhibitors to the ACE inhibitors and ARBs. Although we lack long-term studies of the relative efficacy of these medicines alone or in various combinations, the multistep sequence of the renin-angiotensin-aldosterone system allows for the possibility that more complete suppression via coordinated pharmacologic attention to multiple sites will yield beneficial results.

Combining an ACE inhibitor and an ARB

Even in the absence of ACE, angiotensin II is also produced by other kinases and therefore is not completely suppressed by an ACE inhibitor. For this and other reasons, there are theoretical advantages to adding an ARB to an ACE inhibitor.

In the Combination Treatment of Angiotensin 2 Receptor Blocker and Angiotensin-Converting-Enzyme Inhibitor in Non-Diabetic Renal Disease (COOPERATE) study,²⁰ the combination of an ACE inhibitor and an ARB protected the kidneys better than either medicine alone, not only in terms of less protein in the urine but also in terms of significantly fewer patients progressing to the primary end points of doubling of serum creatinine or end-stage renal disease after 3 years of follow-up (11% of patients on combination therapy vs 23% on single therapy).

Aldosterone receptor antagonists or renin inhibitors plus ACE inhibitors and ARBs

Aldosterone escape is common during long-term therapy with ACE inhibitors and ARBs, and an aldosterone-receptor antagonist reduces proteinuria^11–13 and stabilizes kidney function¹³ in a manner additive to that of ACE inhibitors and ARBs.

Direct renin inhibitors overcome the reactive rises in renin activity and in angiotensin II that complicate therapy with ACE inhibitors and ARBs, and they also reduce urinary aldosterone excretion.¹⁴

When to consider combination therapy

Inhibition of the renin-angiotensin-aldosterone system at multiple sites may be considered in cases of persistent hypertension or proteinuria, or of progression of chronic kidney disease despite single-drug therapy, or more broadly, with increasing evidence that combination therapy may preserve the glomerular filtration rate.^13,20 This article suggests one way to apply the several available renin-angiotensin-aldosterone inhibitors, keeping in mind extensive interindividual variations, uncertain responses, and the absence of a linear evidence-based strategy known to be broadly successful.

INITIAL CONSIDERATION: WHAT IS THE BLOOD PRESSURE GOAL?

Determining the blood pressure goal for a patient may not be as straightforward as usually assumed. Typically, advisories suggest a discrete goal; for example, the Seventh Joint National Committee²² recommended a systolic blood pressure of 130 mm Hg or lower for patients with chronic kidney disease or diabetes. However, if we weigh the risks and benefits, we find that the situation is more nuanced. The blood pressure goal should vary among patients, depending on age, amount of proteinuria, whether the patient can tolerate the lowered blood pressure, and whether lowering the blood pressure to this goal stabilizes kidney function.

Long-term follow-up of the Modification of Diet in Renal Disease (MDRD) study demonstrated a benefit of setting the goal mean arterial pressure to less than 92 mm Hg (about 125 mm Hg systolic) regardless of proteinuria.²³ In addition, a meta-analysis suggested that nondiabetic proteinuric patients benefit from even lower systolic blood pressures (110–119 mm Hg).¹⁹

In older patients

However, in the MDRD study, the goal of approximately 125 mm Hg systolic pertained only to patients no older than 60 years.²³ The goal was increased to about 130 mm Hg for patients 61 to 70 years old. In addition, major clinical studies of chronic kidney disease have excluded patients older than 70 years.^2–7,23

Therapy for chronic kidney disease in this older age group is essentially unstudied, and we should be cautious about extrapolating results of aggressive blood pressure-lowering (and renin-angiotensin-aldosterone inhibition) from younger patients to older patients, who may have extensive vascular disease.^24,25

For patients older than 70 years, guidance is perhaps best provided by the Systolic Hypertension in the Elderly Program (SHEP), which found that lowering systolic blood pressure to an average of 143 mm Hg reduced the incidence of stroke and cardiovascular disease.²⁶ The SHEP study does not establish the optimal blood pressure goal for preventing progressive chronic kidney disease (or even cardiovascular disease) in the older age group. However, this is the lowest systolic pressure yet shown to be generally safe and associated with any improved outcome for these patients.

Additional studies are needed to evaluate whether this blood pressure level provides the best outcomes in patients with chronic kidney disease, or whether even lower blood pressures in the elderly are safe and will further improve either renal or cardiovascular outcomes.

In younger patients

In contrast, younger patients without diabetes or vascular disease may, in theory, be candidates for even lower blood pressure. No major study of chronic kidney disease isolated patients from about 20 to 40 years old for analysis, precluding direct evidence-based guidelines for this cohort at this time.

However, some of these patients may have had premorbid systolic blood pressures of 90 to 110 mm Hg, so systolic pressures of 110 to 120 mm Hg would be “hypertensive” by 10 to 30 mm Hg for them. It is possible that some patients in this cohort will tolerate a systolic pressure lower than 110 mm Hg, and that the lower blood pressure may provide additional long-term renal protection for them. This notion is theoretical, however, and has not been verified by clinical studies.

No one pressure fits all

In summary, an initial target systolic pressure for proteinuric patients, based on available evidence, might be less than 130 mm Hg for patients 61 to 70 years old,²³ less than 125 mm Hg for patients younger than 61 years,²³ and perhaps as low as 110 to 119 mm Hg for non-diabetic patients.¹⁹ Caution is advised against targeting systolic blood pressure less than 140 mm Hg for patients older than 70 years.

These are only initial goals and should be reevaluated as treatment progresses. The achieved blood pressure must be clinically tolerated—symptoms of tissue hypoperfusion indicate that the blood pressure is too low for the patient. In addition, the blood pressure goal (like the proteinuria goal) is only a surrogate end point, and if kidney function declines even though the surrogate end points are attained, then those end points should be reevaluated.

Tailoring blood pressure goals to the individual patient dovetails with the recent suggestion that blood pressure should not be perceived as a rigid dichotomy of “hypertension” vs “normal.”²⁷ There is, in general, a continuous correlation between blood pressure, beginning at low levels, and the risk of cardiorenal disease, and choosing an optimal blood pressure goal for an individual patient requires an ongoing assessment of benefits, risks, and side effects.

STARTING ANTIHYPERTENSIVE THERAPY

The question of which antihypertensive drug to try first is moot in chronic kidney disease because almost all patients need multiple medicines to reach their blood pressure goals.

The Seventh Joint National Committee recommended an ACE inhibitor for initial therapy in hypertensive patients with chronic kidney disease,²² although an ARB is a reasonable first choice for those with type 2 diabetes.^5,6

Diuretics potentiate the effects of ACE inhibitors and ARBs and are generally prescribed concomitantly or as the second choice.

A beta-blocker may be recommended as a third medicine (when needed), to provide a complementary class of antihypertensive, to address the high incidence of concomitant coronary artery disease and systolic dysfunction, and because of evidence that sympathetic excess contributes to the hypertension and progression of chronic kidney disease.^28,29 The National Kidney Foundation³⁰ suggests that the dose of beta-blocker be increased if the heart rate is greater than 84.

INTENSIFYING RENIN-ANGIOTENSIN-ALDOSTERONE INHIBITION: WHICH DRUGS, AND WHEN?

When hypertension and proteinuria persist despite the use of an ACE inhibitor or an ARB, additional inhibition of the renin-angiotensin-aldosterone system is generally recommended to lower both the blood pressure and the protein excretion. Increasing the dose of ACE inhibitor or ARB,^31–34 combining an ACE inhibitor and an ARB,²⁰ or adding an aldosterone receptor antagonist to either an ACE inhibitor or an ARB^11–13 have all been shown to reduce proteinuria (as a surrogate end point), and several studies have, importantly, found that these combinations preserve kidney function over time.^13,20

However, lacking long-term studies that compare these options, we cannot insist upon specific treatment choices or sequences in these situations.

An approach based on serum potassium and volume status

For example, if a patient has obvious signs of volume excess (eg, edema, jugular venous distention, rales) and the serum potassium concentration is less than about 5.0 or 5.5 mEq/L, then an aldosterone receptor antagonist may logically be added or increased in dose.

Aldosterone is more than a kidney hormone

Increasing the diuretic or renin-angiotensin-aldosterone inhibition

For patients who have obvious signs of volume excess and a serum potassium level greater than 5.0 mEq/L, the dosage of kaliuretic (potassium-excreting) diuretic (usually a loop diuretic in chronic kidney disease) can be increased. Although kaliuretic diuretics do not specifically lower proteinuria, they will help control volume and blood pressure and, by lowering the serum potassium level, facilitate the subsequent augmention of renin-angiotensin-aldosterone inhibition.

When a hypertensive patient does not seem to have excess volume or tachycardia and the serum potassium level is less than about 5.5 mEq/L, then additional renin-angiotensin-aldosterone inhibition is indicated.¹⁶ This may be accomplished either by increasing the ACE inhibitor or the ARB to its maximal antihypertensive dose or by starting combination therapy.

Starting a calcium channel blocker

When the serum potassium level is higher than about 5.5 mEq/L, further inhibition of the renin-angiotensin-aldosterone system is contraindicated, and a nondihydropyridine calcium channel blocker can be added for its anti-hypertensive and antiproteinuric effects.^16,36

When nondihydropyridine calcium channel blockers are contraindicated due to their antiinotropic effect, an attractive alternative may be to cautiously increase the dose of kaliuretic diuretics. Given the high prevalence of (often covert) volume excess in chronic kidney disease, empiric diuresis may lower blood pressure, particularly in patients already receiving several vasodilators.³⁷ Moreover, as mentioned, by reducing serum potassium, kaliuretic diuretics help allow for a subsequent increase in renin-angiotensin-aldosterone inhibition.

IF BLOOD PRESSURE IS NORMAL, BUT PROTEINURIA PERSISTS

Because lowering blood pressure does not necessarily reduce protein excretion, some patients achieve their blood pressure goal but still have excessive proteinuria. Proponents of the dual-goal approach suggest that these patients require further treatment modifications to reach the proteinuria goal and their optimal renal prognosis.

A cautious increase in renin-angiotensin-aldosterone inhibition is possible but is likely to be limited by low blood pressure. When applicable, any nonessential antihypertensive drug that does not specifically reduce proteinuria (ie, dihydropyridine calcium channel blockers and central and direct vasodilators) should first be discontinued. This allows additional renin-angiotensin-aldosterone inhibition to reduce proteinuria without causing hypotension.

In addition, “ultra-high” doses of these drugs—two or more times the maximal antihypertensive dose—appear to reduce proteinuria without further reducing blood pressure.^31–34

Various combinations of an ACE inhibitor, an ARB, and an aldosterone receptor antagonist (and possibly a renin inhibitor) may also be prescribed, striving for more complete suppression of the renin-angiotensin-aldosterone system, with dose adjustments to prevent hypotension.

KEEPING SERUM POTASSIUM AT SAFE LEVELS

Intensive inhibition of the renin-angiotensin-aldosterone system, via higher doses or combination therapy, increases the risk of hyperkalemia. This risk must be addressed energetically to prevent a potentially life-threatening complication.

When prescribed by nephrologists in clinical studies, renin-angiotensin-aldosterone inhibition has proven safe, with minimal adverse events (including hyperkalemia), even with high doses,^32–34 in stage 4 chronic kidney disease (ie, with a glomerular filtration rate of 15 to 29 mL/min/1.73m², inclusively)⁷ and with combination therapy.^11–13,20

However, the increased incidence of hyperkalemia reported with spironolactone in patients with congestive heart failure following publication of the Randomized Aldactone Evaluation Study³⁸ suggests that safety in clinical studies should not be extrapolated to mean safety in routine, community use. Patients with chronic kidney disease should not be given high doses or combinations of these drugs unless the treating physician is experienced in the prevention and treatment of hyperkalemia; typically such therapy should be guided by a nephrologist.

When serum potassium levels exceed 5.6 mEq/L, renin-angiotensin-aldosterone inhibitors should be decreased in dose or discontinued.³⁹ Ideally, the drug or drugs should be restarted (to provide the potential benefits of these classes of drugs) when hyperkalemia has resolved, but this requires not only resolution of hyperkalemia but also steps to prevent this serious problem from recurring. The serum potassium level should be checked frequently, particularly after any increase in renin-angiotensin-aldosterone inhibition.

Treating hyperkalemia

Potential treatments for hyperkalemia include dietary restriction, sodium bicarbonate,³⁹ fludrocortisone (Florinef),⁴⁰ kaliuretic diuretics, and sodium polystyrene sulfonate (Kayexalate). Nonsteroidal anti-inflammatory drugs should be avoided.

Dietary restriction should be particularly emphasized: if potassium intake is decreased to the same extent as renin-angiotensin-aldosterone inhibitors reduce its excretion, then the serum potassium level will remain acceptable. All dietary supplements whose contents are not precisely known should be proscribed. A list of high-potassium foods to avoid should be given with the initial prescription for the drug. If briefly reviewed at each visit, with feedback given based on measured serum potassium levels, dietary treatment is typically effective (personal observation).

Fludrocortisone is an option when dietary potassium restriction fails.

An increase in the dose of diuretic is typically required with fludrocortisone to prevent sodium retention. The combination of dietary potassium restriction, fludrocortisone (0.1 mg/day, 3–5 days a week), and furosemide (Lasix) allowed high doses of an ACE inhibitor or a combination of an ACE inhibitor and an ARB to be given in 132 patients with chronic kidney disease.⁴⁰ Over several years, their mean peak potassium level was 4.87 mEq/L, and no instance of acute hyperkalemia requiried stopping the ACE inhibitor or ARB.

However, fludrocortisone is an aldosterone analogue with potentially long-term aldosterone-mediated injurious effects on heart and renal function, even though only low doses were required in the three-pronged approach to hyperkalemia.⁴⁰ The long-term effect of a regimen of an ACE inhibitor plus an ARB plus fludrocortisone on cardiac and renal outcomes is unknown and of concern.

Therefore, fludrocortisone should probably be avoided in patients with systolic heart dysfunction and should be used cautiously in general. Its use might be limited to patients with proteinuric chronic kidney disease that progresses despite therapy, particularly when that progression is in the context of inability to give significant renin-angiotensin-aldosterone inhibition because of hyperkalemia.

MORE STUDY NEEDED

Chronic kidney disease treatment is becoming increasingly complex, with a lengthening list of potentially effective drugs, difficult-to-reach goals, and a less structured approach. This complexity is magnified by issues of potassium homeostasis and interindividual variations in response to renin-angiotensin-aldosterone inhibition.

More prospective studies are needed to confirm the benefits of targeting proteinuria along with blood pressure and the metrics of the goals in tandem, but, based on available information, the dual-goal approach has been recommended for proteinuric patients,^10,15–18 and evidence is accumulating for greater renal protection from larger doses of renin-angiotensin-aldosterone inhibitors and from using these drugs in combination.