Nephrology

[UPDATED]SILVER SPRING, MD. – Vytorin should be approved for preventing major vascular events in patients who have chronic kidney disease but are not on dialysis, according to a unanimous vote by a Food and Drug Administration advisory panel.

The panel also voted 10-6, however, that the safety and effectiveness data did not support approval of the combination of 10 mg of ezetimibe with 20 mg of simvastatin for the same indication in patients with end-stage renal disease who are on dialysis.

Their votes at the Nov. 2 meeting were based on the results of the Study of Heart and Renal Protection (SHARP), which evaluated the effects of reducing LDL cholesterol on the risk of coronary vascular disease in patients with chronic kidney disease who are at an increased risk of cardiovascular morbidity and mortality. About two-thirds of the patients in the trial were not on dialysis at baseline, and in these patients, there was a 23% reduction in the primary end point – the risk of a major vascular event (nonfatal MI or cardiac death, stroke, or a revascularization procedure that excluded dialysis access-related procedures) – compared with those on placebo over a mean of 5 years (Lancet 2011;377:2181-92).

But in the patients who were on dialysis at baseline, the risk was reduced by about 6% over placebo. Panelists who did not support approval in this group cited the lower degree of effectiveness, and the fact that end stage renal disease patients on dialysis are very different from predialysis patients – and that patients with ESRD in the United States are different than those elsewhere. They noted that only 4% of the patients in SHARP were in the United States, and management and outcomes of patients with ESRD are different in the United States than in other parts of the world.

Dr. Lamont Weide, chief of diabetes and endocrinology, at the University of Missouri, Kansas City, backed approval for predialysis patients, but not for those on dialysis. Like several other panelists, he also considered the results of two previous large studies of about 4,000 CKD patients on dialysis, which found no significant beneficial effects of treatment with other statins on cardiovascular outcomes. While these were three different studies with different agents and different entry criteria, he said that the results go in the same direction as SHARP, in a large group of patients "without any clear indication of benefit." Those studies were the 4D study (N. Engl. J. Med. 2005;353:238-48) and the AURORA study (N. Engl J. Med. 2009;360:1395-407).

Also splitting her votes, Dr. Julia Lewis, professor of medicine in the department of nephrology, Vanderbilt University, Nashville, referred to those two trials and added that she considers her dialysis patients considerably different than her clinic patients who are not on dialysis. She commended the SHARP study and investigators for "providing what I think is going to be a wonderful addition to the care of CKD patients. It is going to change care of CKD patients and prevent the bad [cardiovascular] outcomes that affect them," she said.

In the study overall, the risk of major vascular events was reduced by 16% among those treated with the combination as compared to those on placebo, which was primarily driven by a reduction in the revascularization component. Cancers and all-cause mortality were similar in treated patients and those on placebo, and the panel agreed there were no new safety concerns at the dose studied. (About one-quarter of those enrolled died during the study.)

Merck, the manufacturer of ezetimibe (Zetia) and Vytorin, filed for approval of the claim that 10 mg of ezetimibe plus 20 mg of simvastatin (in the fixed-dose combination pill or taken separately) reduces the risk of major cardiovascular events in patients with chronic kidney disease on the basis of the SHARP results. SHARP was funded by Merck and Schering-Plough, but was independently conducted by the Oxford (England) University Clinical Trials Service Unit. Ezetimibe was used to make it possible to use a lower dose of simvastatin in the CKD patients, who are at a greater risk of myopathy and other adverse effects of statins.

Panelists emphasized that the 10 mg of ezetimibe with the 20-mg dose of simvastatin was the dose combination studied and was shown to be safe, and that doses should not be increased in this population of patients.

The two drugs are only approved for lipid-lowering indications: Ezetimibe, a selective inhibitor of the absorption of intestinal cholesterol and related phytosterol marketed as Zetia, was approved by the FDA in 2002; Vytorin, a combination of ezetimibe and the HMG-CoA reductase inhibitor simvastatin was approved in 2004; simvastatin was approved in 1991.

 

The mean age of the patients in the SHARP trial was 61 years; they did not have a history of MI or coronary revascularization.

The six panelists who voted in favor of approval for patient not yet on dialysis and those on dialysis included Dr. William Hiatt, professor of medicine, division of cardiology, at the University of Colorado, Denver, voted in favor of approval for both populations, based on the overall trial results. The differences between the two populations could be explained in the Vytorin label, and "the consistency between the vascular and atherosclerotic events led me to believe that the overall trial had integrity and the various components of the primary outcome were relatively consistent," he said. "To deny an indication to extend to patients who are on chronic hemodialysis ... would not respect the totality of the data," he added.

Dr. Lawrence Hunsicker, professor of medicine in the nephrology division, and emeritus medical director of organ transplantation, University of Iowa, Iowa City, also voted in favor of approval for both groups, but added that the FDA should ensure that advertising and detailing of the product should reflect that "the data are far more clear for patients not on dialysis."

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of disclosures, although in some cases, they are given a waiver-but not at this meeting.

[UPDATED]SILVER SPRING, MD. – Vytorin should be approved for preventing major vascular events in patients who have chronic kidney disease but are not on dialysis, according to a unanimous vote by a Food and Drug Administration advisory panel.

The panel also voted 10-6, however, that the safety and effectiveness data did not support approval of the combination of 10 mg of ezetimibe with 20 mg of simvastatin for the same indication in patients with end-stage renal disease who are on dialysis.

Their votes at the Nov. 2 meeting were based on the results of the Study of Heart and Renal Protection (SHARP), which evaluated the effects of reducing LDL cholesterol on the risk of coronary vascular disease in patients with chronic kidney disease who are at an increased risk of cardiovascular morbidity and mortality. About two-thirds of the patients in the trial were not on dialysis at baseline, and in these patients, there was a 23% reduction in the primary end point – the risk of a major vascular event (nonfatal MI or cardiac death, stroke, or a revascularization procedure that excluded dialysis access-related procedures) – compared with those on placebo over a mean of 5 years (Lancet 2011;377:2181-92).

But in the patients who were on dialysis at baseline, the risk was reduced by about 6% over placebo. Panelists who did not support approval in this group cited the lower degree of effectiveness, and the fact that end stage renal disease patients on dialysis are very different from predialysis patients – and that patients with ESRD in the United States are different than those elsewhere. They noted that only 4% of the patients in SHARP were in the United States, and management and outcomes of patients with ESRD are different in the United States than in other parts of the world.

Dr. Lamont Weide, chief of diabetes and endocrinology, at the University of Missouri, Kansas City, backed approval for predialysis patients, but not for those on dialysis. Like several other panelists, he also considered the results of two previous large studies of about 4,000 CKD patients on dialysis, which found no significant beneficial effects of treatment with other statins on cardiovascular outcomes. While these were three different studies with different agents and different entry criteria, he said that the results go in the same direction as SHARP, in a large group of patients "without any clear indication of benefit." Those studies were the 4D study (N. Engl. J. Med. 2005;353:238-48) and the AURORA study (N. Engl J. Med. 2009;360:1395-407).

Also splitting her votes, Dr. Julia Lewis, professor of medicine in the department of nephrology, Vanderbilt University, Nashville, referred to those two trials and added that she considers her dialysis patients considerably different than her clinic patients who are not on dialysis. She commended the SHARP study and investigators for "providing what I think is going to be a wonderful addition to the care of CKD patients. It is going to change care of CKD patients and prevent the bad [cardiovascular] outcomes that affect them," she said.

In the study overall, the risk of major vascular events was reduced by 16% among those treated with the combination as compared to those on placebo, which was primarily driven by a reduction in the revascularization component. Cancers and all-cause mortality were similar in treated patients and those on placebo, and the panel agreed there were no new safety concerns at the dose studied. (About one-quarter of those enrolled died during the study.)

Merck, the manufacturer of ezetimibe (Zetia) and Vytorin, filed for approval of the claim that 10 mg of ezetimibe plus 20 mg of simvastatin (in the fixed-dose combination pill or taken separately) reduces the risk of major cardiovascular events in patients with chronic kidney disease on the basis of the SHARP results. SHARP was funded by Merck and Schering-Plough, but was independently conducted by the Oxford (England) University Clinical Trials Service Unit. Ezetimibe was used to make it possible to use a lower dose of simvastatin in the CKD patients, who are at a greater risk of myopathy and other adverse effects of statins.

Panelists emphasized that the 10 mg of ezetimibe with the 20-mg dose of simvastatin was the dose combination studied and was shown to be safe, and that doses should not be increased in this population of patients.

The two drugs are only approved for lipid-lowering indications: Ezetimibe, a selective inhibitor of the absorption of intestinal cholesterol and related phytosterol marketed as Zetia, was approved by the FDA in 2002; Vytorin, a combination of ezetimibe and the HMG-CoA reductase inhibitor simvastatin was approved in 2004; simvastatin was approved in 1991.

 

The mean age of the patients in the SHARP trial was 61 years; they did not have a history of MI or coronary revascularization.

The six panelists who voted in favor of approval for patient not yet on dialysis and those on dialysis included Dr. William Hiatt, professor of medicine, division of cardiology, at the University of Colorado, Denver, voted in favor of approval for both populations, based on the overall trial results. The differences between the two populations could be explained in the Vytorin label, and "the consistency between the vascular and atherosclerotic events led me to believe that the overall trial had integrity and the various components of the primary outcome were relatively consistent," he said. "To deny an indication to extend to patients who are on chronic hemodialysis ... would not respect the totality of the data," he added.

Dr. Lawrence Hunsicker, professor of medicine in the nephrology division, and emeritus medical director of organ transplantation, University of Iowa, Iowa City, also voted in favor of approval for both groups, but added that the FDA should ensure that advertising and detailing of the product should reflect that "the data are far more clear for patients not on dialysis."

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of disclosures, although in some cases, they are given a waiver-but not at this meeting.

[UPDATED]SILVER SPRING, MD. – Vytorin should be approved for preventing major vascular events in patients who have chronic kidney disease but are not on dialysis, according to a unanimous vote by a Food and Drug Administration advisory panel.

The panel also voted 10-6, however, that the safety and effectiveness data did not support approval of the combination of 10 mg of ezetimibe with 20 mg of simvastatin for the same indication in patients with end-stage renal disease who are on dialysis.

Their votes at the Nov. 2 meeting were based on the results of the Study of Heart and Renal Protection (SHARP), which evaluated the effects of reducing LDL cholesterol on the risk of coronary vascular disease in patients with chronic kidney disease who are at an increased risk of cardiovascular morbidity and mortality. About two-thirds of the patients in the trial were not on dialysis at baseline, and in these patients, there was a 23% reduction in the primary end point – the risk of a major vascular event (nonfatal MI or cardiac death, stroke, or a revascularization procedure that excluded dialysis access-related procedures) – compared with those on placebo over a mean of 5 years (Lancet 2011;377:2181-92).

But in the patients who were on dialysis at baseline, the risk was reduced by about 6% over placebo. Panelists who did not support approval in this group cited the lower degree of effectiveness, and the fact that end stage renal disease patients on dialysis are very different from predialysis patients – and that patients with ESRD in the United States are different than those elsewhere. They noted that only 4% of the patients in SHARP were in the United States, and management and outcomes of patients with ESRD are different in the United States than in other parts of the world.

Dr. Lamont Weide, chief of diabetes and endocrinology, at the University of Missouri, Kansas City, backed approval for predialysis patients, but not for those on dialysis. Like several other panelists, he also considered the results of two previous large studies of about 4,000 CKD patients on dialysis, which found no significant beneficial effects of treatment with other statins on cardiovascular outcomes. While these were three different studies with different agents and different entry criteria, he said that the results go in the same direction as SHARP, in a large group of patients "without any clear indication of benefit." Those studies were the 4D study (N. Engl. J. Med. 2005;353:238-48) and the AURORA study (N. Engl J. Med. 2009;360:1395-407).

Also splitting her votes, Dr. Julia Lewis, professor of medicine in the department of nephrology, Vanderbilt University, Nashville, referred to those two trials and added that she considers her dialysis patients considerably different than her clinic patients who are not on dialysis. She commended the SHARP study and investigators for "providing what I think is going to be a wonderful addition to the care of CKD patients. It is going to change care of CKD patients and prevent the bad [cardiovascular] outcomes that affect them," she said.

In the study overall, the risk of major vascular events was reduced by 16% among those treated with the combination as compared to those on placebo, which was primarily driven by a reduction in the revascularization component. Cancers and all-cause mortality were similar in treated patients and those on placebo, and the panel agreed there were no new safety concerns at the dose studied. (About one-quarter of those enrolled died during the study.)

Merck, the manufacturer of ezetimibe (Zetia) and Vytorin, filed for approval of the claim that 10 mg of ezetimibe plus 20 mg of simvastatin (in the fixed-dose combination pill or taken separately) reduces the risk of major cardiovascular events in patients with chronic kidney disease on the basis of the SHARP results. SHARP was funded by Merck and Schering-Plough, but was independently conducted by the Oxford (England) University Clinical Trials Service Unit. Ezetimibe was used to make it possible to use a lower dose of simvastatin in the CKD patients, who are at a greater risk of myopathy and other adverse effects of statins.

Panelists emphasized that the 10 mg of ezetimibe with the 20-mg dose of simvastatin was the dose combination studied and was shown to be safe, and that doses should not be increased in this population of patients.

The two drugs are only approved for lipid-lowering indications: Ezetimibe, a selective inhibitor of the absorption of intestinal cholesterol and related phytosterol marketed as Zetia, was approved by the FDA in 2002; Vytorin, a combination of ezetimibe and the HMG-CoA reductase inhibitor simvastatin was approved in 2004; simvastatin was approved in 1991.

 

The mean age of the patients in the SHARP trial was 61 years; they did not have a history of MI or coronary revascularization.

The six panelists who voted in favor of approval for patient not yet on dialysis and those on dialysis included Dr. William Hiatt, professor of medicine, division of cardiology, at the University of Colorado, Denver, voted in favor of approval for both populations, based on the overall trial results. The differences between the two populations could be explained in the Vytorin label, and "the consistency between the vascular and atherosclerotic events led me to believe that the overall trial had integrity and the various components of the primary outcome were relatively consistent," he said. "To deny an indication to extend to patients who are on chronic hemodialysis ... would not respect the totality of the data," he added.

Dr. Lawrence Hunsicker, professor of medicine in the nephrology division, and emeritus medical director of organ transplantation, University of Iowa, Iowa City, also voted in favor of approval for both groups, but added that the FDA should ensure that advertising and detailing of the product should reflect that "the data are far more clear for patients not on dialysis."

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of disclosures, although in some cases, they are given a waiver-but not at this meeting.

If you get up more than once every night to empty your bladder, you should tell your doctor. He or she may be able to do something about it.

Many people get this problem as they get older. It even has a medical name: nocturia (noct = night, uria = urination). However, it is not something you just have to put up with.

What causes nocturia?

Potential causes are many, and most people have a combination of them.

A large urine output can be a sign of a number of diseases. Diabetes, for example, is high on the list and not something you should ignore.

Less room in the bladder, overactive bladder, or an enlarged prostate gland can also make you have to go to the bathroom more often. There are drugs that can help with this. Another common cause is urinary tract infection.

Poor sleep. If you keep waking up for other reasons, you may be getting up just because you are awake. Your doctor may be able to suggest treatments to help you sleep better.

Dear Diary…

To help figure out what is causing the problem, your doctor may ask you to keep a “voiding diary” (a urination diary) for a few days to a week. This means you’ll have to measure everything that comes out—every time—and write down the amount and time. Some people use a special plastic measuring container that fits in the toilet.

Some common-sense advice

• Don’t drink a lot before you go to bed, especially alcoholic or caffeinated drinks.
• If you take a diuretic (water pill) for your blood pressure or heart, don’t take it right before you go to bed.
• If your feet and ankles swell, try wearing compression stockings during the day, and sitting with your legs up in the afternoon.
• Get some moderate exercise every day, such as walking.
• Bed is for sleeping. Avoid reading or watching TV when you’re in bed. Keep the bedroom dark and quiet, if possible. And if it’s cold, put another blanket on the bed.

Be safe

To avoid the risk of tripping and falling down on the way to and from the bathroom, make sure that the path is clear before you go to bed. Clean up the clutter. Get rid of throw rugs. Keep a nightlight on so you can see where you are going. Try to discourage your dog or cat from sleeping in the path you’re going to take. Wear slippers that don’t slip.

It may not be possible to make the problem go away completely, but you may be able to improve it. And if you can sleep better, you’ll probably feel better in the daytime too.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.

For patient information on hundreds of health topics, see the Web site, www.clevelandclinic.org/health.

If you get up more than once every night to empty your bladder, you should tell your doctor. He or she may be able to do something about it.

Many people get this problem as they get older. It even has a medical name: nocturia (noct = night, uria = urination). However, it is not something you just have to put up with.

What causes nocturia?

Potential causes are many, and most people have a combination of them.

A large urine output can be a sign of a number of diseases. Diabetes, for example, is high on the list and not something you should ignore.

Less room in the bladder, overactive bladder, or an enlarged prostate gland can also make you have to go to the bathroom more often. There are drugs that can help with this. Another common cause is urinary tract infection.

Poor sleep. If you keep waking up for other reasons, you may be getting up just because you are awake. Your doctor may be able to suggest treatments to help you sleep better.

Dear Diary…

To help figure out what is causing the problem, your doctor may ask you to keep a “voiding diary” (a urination diary) for a few days to a week. This means you’ll have to measure everything that comes out—every time—and write down the amount and time. Some people use a special plastic measuring container that fits in the toilet.

Some common-sense advice

• Don’t drink a lot before you go to bed, especially alcoholic or caffeinated drinks.
• If you take a diuretic (water pill) for your blood pressure or heart, don’t take it right before you go to bed.
• If your feet and ankles swell, try wearing compression stockings during the day, and sitting with your legs up in the afternoon.
• Get some moderate exercise every day, such as walking.
• Bed is for sleeping. Avoid reading or watching TV when you’re in bed. Keep the bedroom dark and quiet, if possible. And if it’s cold, put another blanket on the bed.

Be safe

To avoid the risk of tripping and falling down on the way to and from the bathroom, make sure that the path is clear before you go to bed. Clean up the clutter. Get rid of throw rugs. Keep a nightlight on so you can see where you are going. Try to discourage your dog or cat from sleeping in the path you’re going to take. Wear slippers that don’t slip.

It may not be possible to make the problem go away completely, but you may be able to improve it. And if you can sleep better, you’ll probably feel better in the daytime too.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.

For patient information on hundreds of health topics, see the Web site, www.clevelandclinic.org/health.

If you get up more than once every night to empty your bladder, you should tell your doctor. He or she may be able to do something about it.

Many people get this problem as they get older. It even has a medical name: nocturia (noct = night, uria = urination). However, it is not something you just have to put up with.

What causes nocturia?

Potential causes are many, and most people have a combination of them.

A large urine output can be a sign of a number of diseases. Diabetes, for example, is high on the list and not something you should ignore.

Less room in the bladder, overactive bladder, or an enlarged prostate gland can also make you have to go to the bathroom more often. There are drugs that can help with this. Another common cause is urinary tract infection.

Poor sleep. If you keep waking up for other reasons, you may be getting up just because you are awake. Your doctor may be able to suggest treatments to help you sleep better.

Dear Diary…

To help figure out what is causing the problem, your doctor may ask you to keep a “voiding diary” (a urination diary) for a few days to a week. This means you’ll have to measure everything that comes out—every time—and write down the amount and time. Some people use a special plastic measuring container that fits in the toilet.

Some common-sense advice

• Don’t drink a lot before you go to bed, especially alcoholic or caffeinated drinks.
• If you take a diuretic (water pill) for your blood pressure or heart, don’t take it right before you go to bed.
• If your feet and ankles swell, try wearing compression stockings during the day, and sitting with your legs up in the afternoon.
• Get some moderate exercise every day, such as walking.
• Bed is for sleeping. Avoid reading or watching TV when you’re in bed. Keep the bedroom dark and quiet, if possible. And if it’s cold, put another blanket on the bed.

Be safe

To avoid the risk of tripping and falling down on the way to and from the bathroom, make sure that the path is clear before you go to bed. Clean up the clutter. Get rid of throw rugs. Keep a nightlight on so you can see where you are going. Try to discourage your dog or cat from sleeping in the path you’re going to take. Wear slippers that don’t slip.

It may not be possible to make the problem go away completely, but you may be able to improve it. And if you can sleep better, you’ll probably feel better in the daytime too.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.

For patient information on hundreds of health topics, see the Web site, www.clevelandclinic.org/health.

Nocturia is common, but elderly patients infrequently volunteer this complaint, and even when they do, some clinicians may dismiss it as simply a part of aging. Nevertheless, nocturia causes significant distress and impairment of quality of life. It is associated with very serious consequences such as depression, social isolation, and a higher risk of death.

In this article, we review the concepts behind frequent nighttime voiding in older adults. We will start with two case scenarios to aid in understanding these concepts; near the end of the article, we will discuss the most appropriate management strategies for these two patients.

CASE SCENARIOS

Case 1: An 82-year-old man with fatigue

An 82-year-old obese white man with a history of hypertension, diabetes, and benign prostatic hyperplasia comes in to see his primary care provider, complaining of fatigue. He wakes up tired and has difficulty completing his daytime tasks. He gets up every 1 to 2 hours at night to urinate and has slow urinary flow and a feeling of incomplete bladder emptying.

See related patient education material

He says his wife has been increasingly bothered by his loud snoring. Recently, he had a car accident when he fell asleep while driving.

Case 2: An 85-year-old woman with incontinence

An 85-year-old white woman is in her family physician’s office with a primary complaint of waking up at least four times at night to urinate, and often ends up soaking her bed or adult diapers. She is bothered by urinary urgency and frequency during the day as well. She denies dysuria and hematuria.

She has a history of hypertension and urinary incontinence, and she has seven children. Her current medications are diltiazem (Cardizem), metoprolol (Toprol), and oxybutynin (Ditropan).

In these two cases, what would account for the nocturia? What would be the best way to help these patients?

THE NORM, NOT THE EXCEPTION

Although nocturia is defined as an awakening by the need to urinate even once in a night, many experts consider that it begins to be clinically significant only when the patient voids at least twice during the night.¹

In older adults, nocturia is the norm rather than the exception. Studies done between 1990 and 2009 found that 68.9% to 93% of men age 70 and older get up at least once a night to void. The prevalence in women is somewhat lower, at 74.1% to 77.1%.² Clinically significant nocturia is present in a majority of the elderly: more than 60% of both men and women.³

An Austrian study⁴ reported that elderly men got up to urinate a mean of 2.8 times per night, while women got up significantly more often—3.1 times. Women were also bothered more by this symptom, and their quality of life was significantly more decreased.

In another study,⁵ whites had a significantly higher nocturia ratio (ratio of nighttime urine volume to the 24-hour urine volume) than Asians. Asians, on the other hand, had a significantly higher nocturnal bladder capacity index than whites. (See below for definitions of the various indices of nocturia.) This information implies that nocturia may be a more prominent problem for elderly whites than for other racial groups.

In an epidemiologic study in Sweden,⁶ the death rate was as much as twice as high in both men and women who had three or more nocturnal voids, even after taking into account the influence of cardiac disease, diabetes mellitus, and stroke.

If nocturia is not addressed in the physician-patient encounter, patients may try to “self-manage” it by restricting their fluid intake or by limiting their social exposure,⁷ with limited success and with unwanted social isolation.

WHAT CAUSES NOCTURIA?

In almost all cases of nocturia in elderly people, the cause is multifactorial (Table 1).

Advancing age is primary among these factors. Age-related structural changes in the urinary system include decreased functional bladder capacity, a decreased maximum urinary flow rate,⁶ a decreased ability to postpone urination,⁸ and an age-related increase in postvoiding residual urine volume.⁹ The aging kidney is also less able to concentrate urine. Also implicated are histologic changes in the detrusor muscle¹⁰ that lead to diminished bladder compliance and, together with detrusor overactivity, result in increased urinary frequency.

Nocturnal polyuria or nocturnal urine overproduction is common in patients with nocturia.¹¹

Although the pathophysiology of nocturnal polyuria is still unclear, some investigators believe that low levels of antidiuretic hormone (ADH) at night are involved, reflecting an alteration in the circadian rhythm seen in diurnal plasma arginine vasopressin levels.¹² In patients with nocturnal polyuria, ADH levels drop to very low or undetectable levels at night, which increases nocturnal urine output. In some extreme cases, the low to absent levels of ADH increase nocturnal voiding to 85% of the total 24-hour urine volume.¹³

Other causes of nocturnal polyuria include mobilization of fluids in patients with edema,¹⁴ and autonomic dysfunction. Other biochemical changes that contribute to nocturia include a decrease in nighttime plasma melatonin levels, an increase in nighttime plasma catecholamine levels, an increase in nighttime plasma natriuretic peptide levels, an increase in blood pressure, and an increase in total urine volume.¹⁵

A decreased ability to store urine also leads to nocturia. This is caused by decreased nocturnal bladder capacity, more irritative symptoms, and comorbid conditions such as overactive bladder, pelvic floor laxity resulting in pelvic organ prolapse, and, in men, benign prostatic hyperplasia.

Neural inputs to the bladder can also be impaired, as in patients who have diabetes mellitus or spinal stenosis, leading to chronic urinary retention, detrusor dysfunction, nocturia, and incontinence.

 

WHICH PATIENTS ARE AT RISK?

Nocturia is associated with a number of risk factors (Table 2).

Obesity is associated with a higher incidence of moderate to severe nocturia.¹⁵ Studies have shown that the higher the body mass index, the greater the number of nighttime voids, especially in women.¹⁶

Habitually eating at night, with poor daytime appetite, is shown to be associated with increased nighttime diuresis.

Obstructive sleep apnea¹⁷ and untreated depressive symptoms such as frequent napping¹⁸ are also associated with moderate to severe nocturia.¹⁹

Higher systolic blood pressures are associated with more urine production at night. Plasma ADH regulation is also altered, which contributes to nocturnal polyuria.²¹

Other comorbid conditions associated with nocturia include recurrent cystitis, lung disease, congestive heart failure, neurodegenerative conditions (eg, Alzheimer disease and parkinsonism), and chronic kidney disease.²¹

Drugs associated with nocturia include cholinesterase inhibitors (for dementia),²² beta-blockers,²³ and calcium channel blockers.²⁴

Lifestyle factors. Alcohol and coffee have shown either no or only a mild diuretic effect. Smoking has not been shown to be associated with nocturia.¹⁵

Seasonal differences also exist, with increased frequency of nocturia in the winter.²⁵

WHAT ARE THE CLINICAL CONSEQUENCES OF NOCTURIA?

Nocturia’s effects are varied and are very important to address (Table 3).

Quality of life can be profoundly affected, and if nocturia is left untreated, it may lead to morbidity and even death. Elderly patients may feel simultaneously debilitated, frustrated, distressed, and puzzled. Nocturia may also increase their fear of falling and may negatively affect personal relationships.²⁶

Falls, injuries. Nocturia exposes elderly patients to injuries such as hip fractures due to falling, significantly increasing the incidence of this injury.²⁶ This occurs as elderly patients get up from bed and walk to the bathroom to void.²⁷ In addition, during the day, superficial and fragmented sleep leads to daytime sleepiness and impaired perception and balance, also increasing the risk of falls.²⁸ The complications of immobility and the need for surgery in many cases lead to debility, increased risk of infections, decubitus ulcers, and death. The risk of hip fractures can lead elderly patients with nocturia to associate this symptom with a fear of falling and can alter their concept of their own age (“Nocturia makes me feel old”),²⁹ further diminishing quality of life.

The estimated medical cost of nocturia-associated falls in the elderly is about $1.5 billion per year, part of the $61 billion in lost productivity due to nocturia in adults.³⁰

Long-term complications (eg, debilitation, poor sleep, obesity, decreased energy), increase the overall mortality rate, especially in patients who report voiding more than three times per night.²⁹ Elderly patients with nocturia also have a greater need for emergency care.³¹

Nocturia also complicates other comorbid conditions, such as dementia, which increases the risk of urinary incontinence.³² In patients who have had a stroke, nocturia is the most frequent lower urinary tract symptom, and represents a major impact on daily life.³³

Sleep disturbance is another important consequence. In one survey,³⁴ nocturia was cited as a cause of poor sleep four times more often than the cause cited next most often, ie, pain. Because the elderly patient is awakened from sleep numerous times throughout the night, nocturia leads to more fatigue,³⁵ lower energy levels, and poorer quality of sleep.³⁶ Depression may be linked to poor sleep, as men with two or more nocturnal episodes were shown to be six times more likely to experience depression.

The patient is not the only person who loses sleep: so do the patient’s family members or sleeping partner.⁷ It is therefore not surprising that sleep disruption caused by nocturia has been cited as a principal reason for admitting older relatives to care homes.³⁷

The risk of death is higher for elderly patients with coronary heart disease if they have nocturia. The causative link is the hemodynamic changes (increases in blood pressure and heart rate) that accompany awakening and arising, which may cause cardiovascular strain and lead to cardiovascular events. The 12-year survival rate has been shown to be significantly lower in patients with nighttime voiding, making nocturia a highly significant independent predictor of death in coronary heart disease patients.³⁸

HOW TO EVALUATE AN OLDER ADULT WHO PRESENTS WITH NOCTURIA

A thorough history and physical examination are crucial in diagnosing nocturia. The goal is to identify any treatable underlying condition, such as diabetes mellitus, obstructive sleep apnea, diabetes insipidus, overactive bladder, benign prostatic hyperplasia, urinary tract infection, and congestive heart failure. Laboratory tests and imaging studies can help rule out these underlying conditions.

Other important facets in the history that must be elicited are medication use, patterns of fluid intake, and a history of other urinary complaints.³⁹

A voiding diary and indices of nocturia

A voiding diary is extremely useful and should be used whenever possible. Episodes of incontinence, time of voids, volume voided, and frequency and volume of fluid intake are recorded. From the raw data, one can determine the following:

Total nocturnal urine volume, ie, the sum volume of the nighttime voids

Maximum voided volume, ie, the largest single recorded volume voided in a 24-hour period

Nocturia index, ie, the total nocturnal urine volume divided by the maximum voided volume. A nocturia index greater than 1 shows that nocturnal urine production is greater than the functional bladder capacity. Clinically significant nocturia is observed in patients with a nocturia index of 2.1 or greater.

Nocturnal polyuria index, ie, total nocturnal urine volume divided by the 24-hour urine output. A nocturnal polyuria index higher than 33% implies nocturnal polyuria.⁴⁰

Nocturnal bladder capacity index, ie, the actual number of nightly voids minus the predicted number of nightly voids, which in turn is calculated as the nocturia index minus 1.

It is especially important to encourage patients to make a voiding diary, as some patients may find this cumbersome, and compliance can be low unless its importance is emphasized. A diary over 7 days usually gives meaningful data. The results from the diary typically confirm the presence of nocturnal polyuria or a decrease in bladder capacity, influencing management.⁴¹

 

WHAT ARE THE TREATMENT OPTIONS?

Therapy must be directed at the primary cause, addressing any underlying conditions that can contribute to nocturia. Examples³⁹:

• Tight control of blood sugar for patients with diabetes mellitus
• Treatment of diabetes insipidus
• Referral for patients with primary polydipsia
• Management of hypercalcemia and hypokalemia
• A survey of medications
• Treatment of infections.

Nonpharmacologic measures

Tailored behavioral therapy can also be instituted, but the patient needs to have realistic expectations, as these measures are rarely effective alone.

Avoiding nighttime fluid intake, including alcohol and caffeine, has shown promise.

Wearing compression stockings and elevating the legs in the afternoon decrease the retention of fluid that otherwise would return to the circulation at night.

Identifying and eliminating nighttime influences that disturb sleep has variable efficacy. The use of continuous positive airway pressure helps to treat sleep apnea. Moderate exercise, reducing nonsleep time spent in bed,⁴² and sleeping in a warm bed⁴³ to decrease cold diuresis have also been shown to improve sleep quality.⁴⁴ Patients with nocturia may have a disrupted circadian rhythm, and phototherapy may help resynchronize the diurnal rhythm and melatonin secretion.

Pharmacotherapy

Pharmacotherapy of nocturia includes desmopressin (DDAVP) to manage nocturnal polyuria and antimuscarinic agents to manage the patient’s decreased ability to store urine. Alpha-blockers such as tamsulosin (Flomax) and 5-alpha-reductase inhibitors such as finasteride (Proscar) are used for men with benign prostatic hyperplasia. Novel and second-line therapies include diuretics such as furosemide (Lasix), cyclooxygenase-2 inhibitors, as well as botulinum toxin injected directly into the detrusor muscle for overactive bladder.⁴⁵

Desmopressin in a low oral dose (0.1–0.4 mg) at bedtime can be initiated and the response assessed. Patients with nocturnal polyuria and disorders of the vasopressin system have been found to be more sensitive to desmopressin therapy.⁴⁶ Fluid retention and hyponatremia can complicate therapy, and desmopressin must be avoided in patients with liver cirrhosis, renal failure, or congestive heart failure.⁴⁷

Antimuscarinic agents are effective for patients who have lower urinary tract symptoms and for those with a diminished ability to store urine. They act by decreasing both voluntary and involuntary bladder contractions by blocking muscarinic receptors on the detrusor muscle. This reduces the bladder’s ability to contract and the urge to urinate, thereby increasing bladder capacity.⁴⁸ These agents include oxybutynin (Ditropan), tolterodine (Detrol), solifenacin (Vesicare), and propiverine (not available in the United States).

Diuretics are being used as second-line agents or for patients who cannot tolerate desmopressin.⁴⁹ Hydrochlorothiazide is taken 8 hours before bedtime to prevent water accumulation before the early sleeping hours.⁵⁰ Furosemide has also led to a reduction in the mean number of nocturnal voids.⁵¹ The effect of these drugs on nocturia are especially beneficial to patients with concomitant hypertension or cardiovascular disease.

Cyclo-oxygenase-2 inhibitors such as celecoxib (Celebrex)⁵² and other nonsteroidal anti-inflammatory drugs such as diclofenac (Voltaren, others)⁵³ and loxoprofen (not available in the United States)⁵⁴ have been shown to decrease urine production, detrusor muscle tone, and inflammation, especially in men with benign prostatic hyperplasia.

Botulinum toxin has been used, usually in patients refractory to first-line treatment.⁴⁴

Referral to specialists is guided by underlying causes. Referral to a pulmonologist or sleep specialist may be helpful if the patient has obstructive sleep apnea. Referral to a urologist may be prudent if the patient has benign prostatic hyperplasia, and a gynecologist can address issues such as pelvic relaxation.

Table 4 summarizes the treatment strategies for nocturia.

CASES REVISITED

The first patient described above has nocturia caused by several concomitant diseases, ie, hypertension, diabetes, benign prostatic hyperplasia, and obstructive sleep apnea. In addition to controlling his blood pressure and blood sugar, his primary care provider referred him to a pulmonologist, who confirmed obstructive sleep apnea with polysomnography and prescribed nightly use of a continuous positive airway pressure apparatus. A few weeks later, the patient’s nocturia had improved significantly, and his level of fatigue had decreased.

Apart from hypertension, the second patient’s nocturia was mostly attributed to her existing urinary incontinence. Recognizing that her current antihypertensive regimen may worsen nocturia, her family physician changed it to enalapril (Vasotec) and doxazosin (Cardura) and counseled her to restrict her fluid intake 2 hours before bedtime. She was also referred to a gynecologist, who found a moderate degree of cystocele and treated her with a collagen injection. Her nocturia improved significantly.

Nocturia is common, but elderly patients infrequently volunteer this complaint, and even when they do, some clinicians may dismiss it as simply a part of aging. Nevertheless, nocturia causes significant distress and impairment of quality of life. It is associated with very serious consequences such as depression, social isolation, and a higher risk of death.

In this article, we review the concepts behind frequent nighttime voiding in older adults. We will start with two case scenarios to aid in understanding these concepts; near the end of the article, we will discuss the most appropriate management strategies for these two patients.

CASE SCENARIOS

Case 1: An 82-year-old man with fatigue

An 82-year-old obese white man with a history of hypertension, diabetes, and benign prostatic hyperplasia comes in to see his primary care provider, complaining of fatigue. He wakes up tired and has difficulty completing his daytime tasks. He gets up every 1 to 2 hours at night to urinate and has slow urinary flow and a feeling of incomplete bladder emptying.

See related patient education material

He says his wife has been increasingly bothered by his loud snoring. Recently, he had a car accident when he fell asleep while driving.

Case 2: An 85-year-old woman with incontinence

An 85-year-old white woman is in her family physician’s office with a primary complaint of waking up at least four times at night to urinate, and often ends up soaking her bed or adult diapers. She is bothered by urinary urgency and frequency during the day as well. She denies dysuria and hematuria.

She has a history of hypertension and urinary incontinence, and she has seven children. Her current medications are diltiazem (Cardizem), metoprolol (Toprol), and oxybutynin (Ditropan).

In these two cases, what would account for the nocturia? What would be the best way to help these patients?

THE NORM, NOT THE EXCEPTION

Although nocturia is defined as an awakening by the need to urinate even once in a night, many experts consider that it begins to be clinically significant only when the patient voids at least twice during the night.¹

In older adults, nocturia is the norm rather than the exception. Studies done between 1990 and 2009 found that 68.9% to 93% of men age 70 and older get up at least once a night to void. The prevalence in women is somewhat lower, at 74.1% to 77.1%.² Clinically significant nocturia is present in a majority of the elderly: more than 60% of both men and women.³

An Austrian study⁴ reported that elderly men got up to urinate a mean of 2.8 times per night, while women got up significantly more often—3.1 times. Women were also bothered more by this symptom, and their quality of life was significantly more decreased.

In another study,⁵ whites had a significantly higher nocturia ratio (ratio of nighttime urine volume to the 24-hour urine volume) than Asians. Asians, on the other hand, had a significantly higher nocturnal bladder capacity index than whites. (See below for definitions of the various indices of nocturia.) This information implies that nocturia may be a more prominent problem for elderly whites than for other racial groups.

In an epidemiologic study in Sweden,⁶ the death rate was as much as twice as high in both men and women who had three or more nocturnal voids, even after taking into account the influence of cardiac disease, diabetes mellitus, and stroke.

If nocturia is not addressed in the physician-patient encounter, patients may try to “self-manage” it by restricting their fluid intake or by limiting their social exposure,⁷ with limited success and with unwanted social isolation.

WHAT CAUSES NOCTURIA?

In almost all cases of nocturia in elderly people, the cause is multifactorial (Table 1).

Advancing age is primary among these factors. Age-related structural changes in the urinary system include decreased functional bladder capacity, a decreased maximum urinary flow rate,⁶ a decreased ability to postpone urination,⁸ and an age-related increase in postvoiding residual urine volume.⁹ The aging kidney is also less able to concentrate urine. Also implicated are histologic changes in the detrusor muscle¹⁰ that lead to diminished bladder compliance and, together with detrusor overactivity, result in increased urinary frequency.

Nocturnal polyuria or nocturnal urine overproduction is common in patients with nocturia.¹¹

Although the pathophysiology of nocturnal polyuria is still unclear, some investigators believe that low levels of antidiuretic hormone (ADH) at night are involved, reflecting an alteration in the circadian rhythm seen in diurnal plasma arginine vasopressin levels.¹² In patients with nocturnal polyuria, ADH levels drop to very low or undetectable levels at night, which increases nocturnal urine output. In some extreme cases, the low to absent levels of ADH increase nocturnal voiding to 85% of the total 24-hour urine volume.¹³

Other causes of nocturnal polyuria include mobilization of fluids in patients with edema,¹⁴ and autonomic dysfunction. Other biochemical changes that contribute to nocturia include a decrease in nighttime plasma melatonin levels, an increase in nighttime plasma catecholamine levels, an increase in nighttime plasma natriuretic peptide levels, an increase in blood pressure, and an increase in total urine volume.¹⁵

A decreased ability to store urine also leads to nocturia. This is caused by decreased nocturnal bladder capacity, more irritative symptoms, and comorbid conditions such as overactive bladder, pelvic floor laxity resulting in pelvic organ prolapse, and, in men, benign prostatic hyperplasia.

Neural inputs to the bladder can also be impaired, as in patients who have diabetes mellitus or spinal stenosis, leading to chronic urinary retention, detrusor dysfunction, nocturia, and incontinence.

 

WHICH PATIENTS ARE AT RISK?

Nocturia is associated with a number of risk factors (Table 2).

Obesity is associated with a higher incidence of moderate to severe nocturia.¹⁵ Studies have shown that the higher the body mass index, the greater the number of nighttime voids, especially in women.¹⁶

Habitually eating at night, with poor daytime appetite, is shown to be associated with increased nighttime diuresis.

Obstructive sleep apnea¹⁷ and untreated depressive symptoms such as frequent napping¹⁸ are also associated with moderate to severe nocturia.¹⁹

Higher systolic blood pressures are associated with more urine production at night. Plasma ADH regulation is also altered, which contributes to nocturnal polyuria.²¹

Other comorbid conditions associated with nocturia include recurrent cystitis, lung disease, congestive heart failure, neurodegenerative conditions (eg, Alzheimer disease and parkinsonism), and chronic kidney disease.²¹

Drugs associated with nocturia include cholinesterase inhibitors (for dementia),²² beta-blockers,²³ and calcium channel blockers.²⁴

Lifestyle factors. Alcohol and coffee have shown either no or only a mild diuretic effect. Smoking has not been shown to be associated with nocturia.¹⁵

Seasonal differences also exist, with increased frequency of nocturia in the winter.²⁵

WHAT ARE THE CLINICAL CONSEQUENCES OF NOCTURIA?

Nocturia’s effects are varied and are very important to address (Table 3).

Quality of life can be profoundly affected, and if nocturia is left untreated, it may lead to morbidity and even death. Elderly patients may feel simultaneously debilitated, frustrated, distressed, and puzzled. Nocturia may also increase their fear of falling and may negatively affect personal relationships.²⁶

Falls, injuries. Nocturia exposes elderly patients to injuries such as hip fractures due to falling, significantly increasing the incidence of this injury.²⁶ This occurs as elderly patients get up from bed and walk to the bathroom to void.²⁷ In addition, during the day, superficial and fragmented sleep leads to daytime sleepiness and impaired perception and balance, also increasing the risk of falls.²⁸ The complications of immobility and the need for surgery in many cases lead to debility, increased risk of infections, decubitus ulcers, and death. The risk of hip fractures can lead elderly patients with nocturia to associate this symptom with a fear of falling and can alter their concept of their own age (“Nocturia makes me feel old”),²⁹ further diminishing quality of life.

The estimated medical cost of nocturia-associated falls in the elderly is about $1.5 billion per year, part of the $61 billion in lost productivity due to nocturia in adults.³⁰

Long-term complications (eg, debilitation, poor sleep, obesity, decreased energy), increase the overall mortality rate, especially in patients who report voiding more than three times per night.²⁹ Elderly patients with nocturia also have a greater need for emergency care.³¹

Nocturia also complicates other comorbid conditions, such as dementia, which increases the risk of urinary incontinence.³² In patients who have had a stroke, nocturia is the most frequent lower urinary tract symptom, and represents a major impact on daily life.³³

Sleep disturbance is another important consequence. In one survey,³⁴ nocturia was cited as a cause of poor sleep four times more often than the cause cited next most often, ie, pain. Because the elderly patient is awakened from sleep numerous times throughout the night, nocturia leads to more fatigue,³⁵ lower energy levels, and poorer quality of sleep.³⁶ Depression may be linked to poor sleep, as men with two or more nocturnal episodes were shown to be six times more likely to experience depression.

The patient is not the only person who loses sleep: so do the patient’s family members or sleeping partner.⁷ It is therefore not surprising that sleep disruption caused by nocturia has been cited as a principal reason for admitting older relatives to care homes.³⁷

The risk of death is higher for elderly patients with coronary heart disease if they have nocturia. The causative link is the hemodynamic changes (increases in blood pressure and heart rate) that accompany awakening and arising, which may cause cardiovascular strain and lead to cardiovascular events. The 12-year survival rate has been shown to be significantly lower in patients with nighttime voiding, making nocturia a highly significant independent predictor of death in coronary heart disease patients.³⁸

HOW TO EVALUATE AN OLDER ADULT WHO PRESENTS WITH NOCTURIA

A thorough history and physical examination are crucial in diagnosing nocturia. The goal is to identify any treatable underlying condition, such as diabetes mellitus, obstructive sleep apnea, diabetes insipidus, overactive bladder, benign prostatic hyperplasia, urinary tract infection, and congestive heart failure. Laboratory tests and imaging studies can help rule out these underlying conditions.

Other important facets in the history that must be elicited are medication use, patterns of fluid intake, and a history of other urinary complaints.³⁹

A voiding diary and indices of nocturia

A voiding diary is extremely useful and should be used whenever possible. Episodes of incontinence, time of voids, volume voided, and frequency and volume of fluid intake are recorded. From the raw data, one can determine the following:

Total nocturnal urine volume, ie, the sum volume of the nighttime voids

Maximum voided volume, ie, the largest single recorded volume voided in a 24-hour period

Nocturia index, ie, the total nocturnal urine volume divided by the maximum voided volume. A nocturia index greater than 1 shows that nocturnal urine production is greater than the functional bladder capacity. Clinically significant nocturia is observed in patients with a nocturia index of 2.1 or greater.

Nocturnal polyuria index, ie, total nocturnal urine volume divided by the 24-hour urine output. A nocturnal polyuria index higher than 33% implies nocturnal polyuria.⁴⁰

Nocturnal bladder capacity index, ie, the actual number of nightly voids minus the predicted number of nightly voids, which in turn is calculated as the nocturia index minus 1.

It is especially important to encourage patients to make a voiding diary, as some patients may find this cumbersome, and compliance can be low unless its importance is emphasized. A diary over 7 days usually gives meaningful data. The results from the diary typically confirm the presence of nocturnal polyuria or a decrease in bladder capacity, influencing management.⁴¹

 

WHAT ARE THE TREATMENT OPTIONS?

Therapy must be directed at the primary cause, addressing any underlying conditions that can contribute to nocturia. Examples³⁹:

• Tight control of blood sugar for patients with diabetes mellitus
• Treatment of diabetes insipidus
• Referral for patients with primary polydipsia
• Management of hypercalcemia and hypokalemia
• A survey of medications
• Treatment of infections.

Nonpharmacologic measures

Tailored behavioral therapy can also be instituted, but the patient needs to have realistic expectations, as these measures are rarely effective alone.

Avoiding nighttime fluid intake, including alcohol and caffeine, has shown promise.

Wearing compression stockings and elevating the legs in the afternoon decrease the retention of fluid that otherwise would return to the circulation at night.

Identifying and eliminating nighttime influences that disturb sleep has variable efficacy. The use of continuous positive airway pressure helps to treat sleep apnea. Moderate exercise, reducing nonsleep time spent in bed,⁴² and sleeping in a warm bed⁴³ to decrease cold diuresis have also been shown to improve sleep quality.⁴⁴ Patients with nocturia may have a disrupted circadian rhythm, and phototherapy may help resynchronize the diurnal rhythm and melatonin secretion.

Pharmacotherapy

Pharmacotherapy of nocturia includes desmopressin (DDAVP) to manage nocturnal polyuria and antimuscarinic agents to manage the patient’s decreased ability to store urine. Alpha-blockers such as tamsulosin (Flomax) and 5-alpha-reductase inhibitors such as finasteride (Proscar) are used for men with benign prostatic hyperplasia. Novel and second-line therapies include diuretics such as furosemide (Lasix), cyclooxygenase-2 inhibitors, as well as botulinum toxin injected directly into the detrusor muscle for overactive bladder.⁴⁵

Desmopressin in a low oral dose (0.1–0.4 mg) at bedtime can be initiated and the response assessed. Patients with nocturnal polyuria and disorders of the vasopressin system have been found to be more sensitive to desmopressin therapy.⁴⁶ Fluid retention and hyponatremia can complicate therapy, and desmopressin must be avoided in patients with liver cirrhosis, renal failure, or congestive heart failure.⁴⁷

Antimuscarinic agents are effective for patients who have lower urinary tract symptoms and for those with a diminished ability to store urine. They act by decreasing both voluntary and involuntary bladder contractions by blocking muscarinic receptors on the detrusor muscle. This reduces the bladder’s ability to contract and the urge to urinate, thereby increasing bladder capacity.⁴⁸ These agents include oxybutynin (Ditropan), tolterodine (Detrol), solifenacin (Vesicare), and propiverine (not available in the United States).

Diuretics are being used as second-line agents or for patients who cannot tolerate desmopressin.⁴⁹ Hydrochlorothiazide is taken 8 hours before bedtime to prevent water accumulation before the early sleeping hours.⁵⁰ Furosemide has also led to a reduction in the mean number of nocturnal voids.⁵¹ The effect of these drugs on nocturia are especially beneficial to patients with concomitant hypertension or cardiovascular disease.

Cyclo-oxygenase-2 inhibitors such as celecoxib (Celebrex)⁵² and other nonsteroidal anti-inflammatory drugs such as diclofenac (Voltaren, others)⁵³ and loxoprofen (not available in the United States)⁵⁴ have been shown to decrease urine production, detrusor muscle tone, and inflammation, especially in men with benign prostatic hyperplasia.

Botulinum toxin has been used, usually in patients refractory to first-line treatment.⁴⁴

Referral to specialists is guided by underlying causes. Referral to a pulmonologist or sleep specialist may be helpful if the patient has obstructive sleep apnea. Referral to a urologist may be prudent if the patient has benign prostatic hyperplasia, and a gynecologist can address issues such as pelvic relaxation.

Table 4 summarizes the treatment strategies for nocturia.

CASES REVISITED

The first patient described above has nocturia caused by several concomitant diseases, ie, hypertension, diabetes, benign prostatic hyperplasia, and obstructive sleep apnea. In addition to controlling his blood pressure and blood sugar, his primary care provider referred him to a pulmonologist, who confirmed obstructive sleep apnea with polysomnography and prescribed nightly use of a continuous positive airway pressure apparatus. A few weeks later, the patient’s nocturia had improved significantly, and his level of fatigue had decreased.

Apart from hypertension, the second patient’s nocturia was mostly attributed to her existing urinary incontinence. Recognizing that her current antihypertensive regimen may worsen nocturia, her family physician changed it to enalapril (Vasotec) and doxazosin (Cardura) and counseled her to restrict her fluid intake 2 hours before bedtime. She was also referred to a gynecologist, who found a moderate degree of cystocele and treated her with a collagen injection. Her nocturia improved significantly.

Nocturia is common, but elderly patients infrequently volunteer this complaint, and even when they do, some clinicians may dismiss it as simply a part of aging. Nevertheless, nocturia causes significant distress and impairment of quality of life. It is associated with very serious consequences such as depression, social isolation, and a higher risk of death.

In this article, we review the concepts behind frequent nighttime voiding in older adults. We will start with two case scenarios to aid in understanding these concepts; near the end of the article, we will discuss the most appropriate management strategies for these two patients.

CASE SCENARIOS

Case 1: An 82-year-old man with fatigue

An 82-year-old obese white man with a history of hypertension, diabetes, and benign prostatic hyperplasia comes in to see his primary care provider, complaining of fatigue. He wakes up tired and has difficulty completing his daytime tasks. He gets up every 1 to 2 hours at night to urinate and has slow urinary flow and a feeling of incomplete bladder emptying.

See related patient education material

He says his wife has been increasingly bothered by his loud snoring. Recently, he had a car accident when he fell asleep while driving.

Case 2: An 85-year-old woman with incontinence

An 85-year-old white woman is in her family physician’s office with a primary complaint of waking up at least four times at night to urinate, and often ends up soaking her bed or adult diapers. She is bothered by urinary urgency and frequency during the day as well. She denies dysuria and hematuria.

She has a history of hypertension and urinary incontinence, and she has seven children. Her current medications are diltiazem (Cardizem), metoprolol (Toprol), and oxybutynin (Ditropan).

In these two cases, what would account for the nocturia? What would be the best way to help these patients?

THE NORM, NOT THE EXCEPTION

Although nocturia is defined as an awakening by the need to urinate even once in a night, many experts consider that it begins to be clinically significant only when the patient voids at least twice during the night.¹

In older adults, nocturia is the norm rather than the exception. Studies done between 1990 and 2009 found that 68.9% to 93% of men age 70 and older get up at least once a night to void. The prevalence in women is somewhat lower, at 74.1% to 77.1%.² Clinically significant nocturia is present in a majority of the elderly: more than 60% of both men and women.³

An Austrian study⁴ reported that elderly men got up to urinate a mean of 2.8 times per night, while women got up significantly more often—3.1 times. Women were also bothered more by this symptom, and their quality of life was significantly more decreased.

In another study,⁵ whites had a significantly higher nocturia ratio (ratio of nighttime urine volume to the 24-hour urine volume) than Asians. Asians, on the other hand, had a significantly higher nocturnal bladder capacity index than whites. (See below for definitions of the various indices of nocturia.) This information implies that nocturia may be a more prominent problem for elderly whites than for other racial groups.

In an epidemiologic study in Sweden,⁶ the death rate was as much as twice as high in both men and women who had three or more nocturnal voids, even after taking into account the influence of cardiac disease, diabetes mellitus, and stroke.

If nocturia is not addressed in the physician-patient encounter, patients may try to “self-manage” it by restricting their fluid intake or by limiting their social exposure,⁷ with limited success and with unwanted social isolation.

WHAT CAUSES NOCTURIA?

In almost all cases of nocturia in elderly people, the cause is multifactorial (Table 1).

Advancing age is primary among these factors. Age-related structural changes in the urinary system include decreased functional bladder capacity, a decreased maximum urinary flow rate,⁶ a decreased ability to postpone urination,⁸ and an age-related increase in postvoiding residual urine volume.⁹ The aging kidney is also less able to concentrate urine. Also implicated are histologic changes in the detrusor muscle¹⁰ that lead to diminished bladder compliance and, together with detrusor overactivity, result in increased urinary frequency.

Nocturnal polyuria or nocturnal urine overproduction is common in patients with nocturia.¹¹

Although the pathophysiology of nocturnal polyuria is still unclear, some investigators believe that low levels of antidiuretic hormone (ADH) at night are involved, reflecting an alteration in the circadian rhythm seen in diurnal plasma arginine vasopressin levels.¹² In patients with nocturnal polyuria, ADH levels drop to very low or undetectable levels at night, which increases nocturnal urine output. In some extreme cases, the low to absent levels of ADH increase nocturnal voiding to 85% of the total 24-hour urine volume.¹³

Other causes of nocturnal polyuria include mobilization of fluids in patients with edema,¹⁴ and autonomic dysfunction. Other biochemical changes that contribute to nocturia include a decrease in nighttime plasma melatonin levels, an increase in nighttime plasma catecholamine levels, an increase in nighttime plasma natriuretic peptide levels, an increase in blood pressure, and an increase in total urine volume.¹⁵

A decreased ability to store urine also leads to nocturia. This is caused by decreased nocturnal bladder capacity, more irritative symptoms, and comorbid conditions such as overactive bladder, pelvic floor laxity resulting in pelvic organ prolapse, and, in men, benign prostatic hyperplasia.

Neural inputs to the bladder can also be impaired, as in patients who have diabetes mellitus or spinal stenosis, leading to chronic urinary retention, detrusor dysfunction, nocturia, and incontinence.

 

WHICH PATIENTS ARE AT RISK?

Nocturia is associated with a number of risk factors (Table 2).

Obesity is associated with a higher incidence of moderate to severe nocturia.¹⁵ Studies have shown that the higher the body mass index, the greater the number of nighttime voids, especially in women.¹⁶

Habitually eating at night, with poor daytime appetite, is shown to be associated with increased nighttime diuresis.

Obstructive sleep apnea¹⁷ and untreated depressive symptoms such as frequent napping¹⁸ are also associated with moderate to severe nocturia.¹⁹

Higher systolic blood pressures are associated with more urine production at night. Plasma ADH regulation is also altered, which contributes to nocturnal polyuria.²¹

Other comorbid conditions associated with nocturia include recurrent cystitis, lung disease, congestive heart failure, neurodegenerative conditions (eg, Alzheimer disease and parkinsonism), and chronic kidney disease.²¹

Drugs associated with nocturia include cholinesterase inhibitors (for dementia),²² beta-blockers,²³ and calcium channel blockers.²⁴

Lifestyle factors. Alcohol and coffee have shown either no or only a mild diuretic effect. Smoking has not been shown to be associated with nocturia.¹⁵

Seasonal differences also exist, with increased frequency of nocturia in the winter.²⁵

WHAT ARE THE CLINICAL CONSEQUENCES OF NOCTURIA?

Nocturia’s effects are varied and are very important to address (Table 3).

Quality of life can be profoundly affected, and if nocturia is left untreated, it may lead to morbidity and even death. Elderly patients may feel simultaneously debilitated, frustrated, distressed, and puzzled. Nocturia may also increase their fear of falling and may negatively affect personal relationships.²⁶

Falls, injuries. Nocturia exposes elderly patients to injuries such as hip fractures due to falling, significantly increasing the incidence of this injury.²⁶ This occurs as elderly patients get up from bed and walk to the bathroom to void.²⁷ In addition, during the day, superficial and fragmented sleep leads to daytime sleepiness and impaired perception and balance, also increasing the risk of falls.²⁸ The complications of immobility and the need for surgery in many cases lead to debility, increased risk of infections, decubitus ulcers, and death. The risk of hip fractures can lead elderly patients with nocturia to associate this symptom with a fear of falling and can alter their concept of their own age (“Nocturia makes me feel old”),²⁹ further diminishing quality of life.

The estimated medical cost of nocturia-associated falls in the elderly is about $1.5 billion per year, part of the $61 billion in lost productivity due to nocturia in adults.³⁰

Long-term complications (eg, debilitation, poor sleep, obesity, decreased energy), increase the overall mortality rate, especially in patients who report voiding more than three times per night.²⁹ Elderly patients with nocturia also have a greater need for emergency care.³¹

Nocturia also complicates other comorbid conditions, such as dementia, which increases the risk of urinary incontinence.³² In patients who have had a stroke, nocturia is the most frequent lower urinary tract symptom, and represents a major impact on daily life.³³

Sleep disturbance is another important consequence. In one survey,³⁴ nocturia was cited as a cause of poor sleep four times more often than the cause cited next most often, ie, pain. Because the elderly patient is awakened from sleep numerous times throughout the night, nocturia leads to more fatigue,³⁵ lower energy levels, and poorer quality of sleep.³⁶ Depression may be linked to poor sleep, as men with two or more nocturnal episodes were shown to be six times more likely to experience depression.

The patient is not the only person who loses sleep: so do the patient’s family members or sleeping partner.⁷ It is therefore not surprising that sleep disruption caused by nocturia has been cited as a principal reason for admitting older relatives to care homes.³⁷

The risk of death is higher for elderly patients with coronary heart disease if they have nocturia. The causative link is the hemodynamic changes (increases in blood pressure and heart rate) that accompany awakening and arising, which may cause cardiovascular strain and lead to cardiovascular events. The 12-year survival rate has been shown to be significantly lower in patients with nighttime voiding, making nocturia a highly significant independent predictor of death in coronary heart disease patients.³⁸

HOW TO EVALUATE AN OLDER ADULT WHO PRESENTS WITH NOCTURIA

A thorough history and physical examination are crucial in diagnosing nocturia. The goal is to identify any treatable underlying condition, such as diabetes mellitus, obstructive sleep apnea, diabetes insipidus, overactive bladder, benign prostatic hyperplasia, urinary tract infection, and congestive heart failure. Laboratory tests and imaging studies can help rule out these underlying conditions.

Other important facets in the history that must be elicited are medication use, patterns of fluid intake, and a history of other urinary complaints.³⁹

A voiding diary and indices of nocturia

A voiding diary is extremely useful and should be used whenever possible. Episodes of incontinence, time of voids, volume voided, and frequency and volume of fluid intake are recorded. From the raw data, one can determine the following:

Total nocturnal urine volume, ie, the sum volume of the nighttime voids

Maximum voided volume, ie, the largest single recorded volume voided in a 24-hour period

Nocturia index, ie, the total nocturnal urine volume divided by the maximum voided volume. A nocturia index greater than 1 shows that nocturnal urine production is greater than the functional bladder capacity. Clinically significant nocturia is observed in patients with a nocturia index of 2.1 or greater.

Nocturnal polyuria index, ie, total nocturnal urine volume divided by the 24-hour urine output. A nocturnal polyuria index higher than 33% implies nocturnal polyuria.⁴⁰

Nocturnal bladder capacity index, ie, the actual number of nightly voids minus the predicted number of nightly voids, which in turn is calculated as the nocturia index minus 1.

It is especially important to encourage patients to make a voiding diary, as some patients may find this cumbersome, and compliance can be low unless its importance is emphasized. A diary over 7 days usually gives meaningful data. The results from the diary typically confirm the presence of nocturnal polyuria or a decrease in bladder capacity, influencing management.⁴¹

 

WHAT ARE THE TREATMENT OPTIONS?

Therapy must be directed at the primary cause, addressing any underlying conditions that can contribute to nocturia. Examples³⁹:

• Tight control of blood sugar for patients with diabetes mellitus
• Treatment of diabetes insipidus
• Referral for patients with primary polydipsia
• Management of hypercalcemia and hypokalemia
• A survey of medications
• Treatment of infections.

Nonpharmacologic measures

Tailored behavioral therapy can also be instituted, but the patient needs to have realistic expectations, as these measures are rarely effective alone.

Avoiding nighttime fluid intake, including alcohol and caffeine, has shown promise.

Wearing compression stockings and elevating the legs in the afternoon decrease the retention of fluid that otherwise would return to the circulation at night.

Identifying and eliminating nighttime influences that disturb sleep has variable efficacy. The use of continuous positive airway pressure helps to treat sleep apnea. Moderate exercise, reducing nonsleep time spent in bed,⁴² and sleeping in a warm bed⁴³ to decrease cold diuresis have also been shown to improve sleep quality.⁴⁴ Patients with nocturia may have a disrupted circadian rhythm, and phototherapy may help resynchronize the diurnal rhythm and melatonin secretion.

Pharmacotherapy

Pharmacotherapy of nocturia includes desmopressin (DDAVP) to manage nocturnal polyuria and antimuscarinic agents to manage the patient’s decreased ability to store urine. Alpha-blockers such as tamsulosin (Flomax) and 5-alpha-reductase inhibitors such as finasteride (Proscar) are used for men with benign prostatic hyperplasia. Novel and second-line therapies include diuretics such as furosemide (Lasix), cyclooxygenase-2 inhibitors, as well as botulinum toxin injected directly into the detrusor muscle for overactive bladder.⁴⁵

Desmopressin in a low oral dose (0.1–0.4 mg) at bedtime can be initiated and the response assessed. Patients with nocturnal polyuria and disorders of the vasopressin system have been found to be more sensitive to desmopressin therapy.⁴⁶ Fluid retention and hyponatremia can complicate therapy, and desmopressin must be avoided in patients with liver cirrhosis, renal failure, or congestive heart failure.⁴⁷

Antimuscarinic agents are effective for patients who have lower urinary tract symptoms and for those with a diminished ability to store urine. They act by decreasing both voluntary and involuntary bladder contractions by blocking muscarinic receptors on the detrusor muscle. This reduces the bladder’s ability to contract and the urge to urinate, thereby increasing bladder capacity.⁴⁸ These agents include oxybutynin (Ditropan), tolterodine (Detrol), solifenacin (Vesicare), and propiverine (not available in the United States).

Diuretics are being used as second-line agents or for patients who cannot tolerate desmopressin.⁴⁹ Hydrochlorothiazide is taken 8 hours before bedtime to prevent water accumulation before the early sleeping hours.⁵⁰ Furosemide has also led to a reduction in the mean number of nocturnal voids.⁵¹ The effect of these drugs on nocturia are especially beneficial to patients with concomitant hypertension or cardiovascular disease.

Cyclo-oxygenase-2 inhibitors such as celecoxib (Celebrex)⁵² and other nonsteroidal anti-inflammatory drugs such as diclofenac (Voltaren, others)⁵³ and loxoprofen (not available in the United States)⁵⁴ have been shown to decrease urine production, detrusor muscle tone, and inflammation, especially in men with benign prostatic hyperplasia.

Botulinum toxin has been used, usually in patients refractory to first-line treatment.⁴⁴

Referral to specialists is guided by underlying causes. Referral to a pulmonologist or sleep specialist may be helpful if the patient has obstructive sleep apnea. Referral to a urologist may be prudent if the patient has benign prostatic hyperplasia, and a gynecologist can address issues such as pelvic relaxation.

Table 4 summarizes the treatment strategies for nocturia.

CASES REVISITED

The first patient described above has nocturia caused by several concomitant diseases, ie, hypertension, diabetes, benign prostatic hyperplasia, and obstructive sleep apnea. In addition to controlling his blood pressure and blood sugar, his primary care provider referred him to a pulmonologist, who confirmed obstructive sleep apnea with polysomnography and prescribed nightly use of a continuous positive airway pressure apparatus. A few weeks later, the patient’s nocturia had improved significantly, and his level of fatigue had decreased.

Apart from hypertension, the second patient’s nocturia was mostly attributed to her existing urinary incontinence. Recognizing that her current antihypertensive regimen may worsen nocturia, her family physician changed it to enalapril (Vasotec) and doxazosin (Cardura) and counseled her to restrict her fluid intake 2 hours before bedtime. She was also referred to a gynecologist, who found a moderate degree of cystocele and treated her with a collagen injection. Her nocturia improved significantly.

A 44-year-old woman with end-stage liver disease presents with a painful, ischemic, necrotic lesion on her right lateral and medial thigh (Figure  1). Several months ago, while being evaluated in the hospital for liver transplantation, she developed bacteremia, anion-gap metabolic acidosis, hepatorenal syndrome, and acute renal failure. She began continuous hemodialysis, which lasted for about 1 month, ending 35 days after the renal failure resolved.

Current laboratory values:

• Serum calcium concentration 7.8 mg/dL (reference range 8.5–10.5)
• Phosphorus 6.4 mg/dL (2.5–4.5)
• Corrected calcium-phosphorus product 55
• Parathyroid hormone 275 pg/mL (10–60)
• 25-hydroxyvitamin D 7.4 ng/mL (31–80).

Q: Given the patient’s history, which of the following does her skin lesion likely represent?

• Necrotizing fasciitis
• Calciphylaxis
• Disseminated intravascular coagulation
• Anticoagulant-induced skin necrosis

A: Calciphylaxis, or calcific uremic arteriolopathy, is the most likely. It is rare in people with normal renal function, and still rare but somewhat less so in end-stage renal disease patients undergoing chronic hemodialysis.

WHAT CAUSED IT IN OUR PATIENT?

The cause of calciphylaxis is unknown. Theories have focused on protein C and parathyroid hormone. Putative precipitating factors include acute tubular necrosis, albumin infusion with paracentesis, deficiency of protein C or S, hyperparathyroidism, hyperphosphatemia, hypercalcemia, vitamin D supplementation, steroids, trauma, and warfarin use.

Our patient had a history of hypothyroidism, ulcerative colitis, and end-stage liver disease due to primary sclerosing cholangitis, but no previous history of renal disease.

At the time of her acute renal failure, her calcium-phosphorus level was 55, parathyroid hormone level 274 pg/mL (normal 10–60), and protein C level 26% (normal 76%–147%). At the time the skin lesions were discovered, her protein C level had dropped to 14%; her parathyroid level had returned to normal.

Her home medications included furosemide (Lasix), levothyroxine (Synthroid), mesalamine (Pentasa), azathioprine (Imuran), ursodiol (Actigall), spironolactone (Aldactone), and omeprazole (Prilosec).

NONHEALING LESIONS

The skin lesions are characteristically erythematous and tender, with mottling of the skin early in the course. As the lesions progress, they develop central necrosis and deep ulcerations with eschar formation. The ulcers have irregular borders and do not heal. Histopathologic study typically shows epidermis with ischemic necrosis and calcium deposition along elastic fibers on Von Kossa calcium stains (Figure 2).

The skin lesions of calciphylaxis usually occur in areas of increased adipose tissue. The lesions may not manifest until several weeks after the initial insult (ie, the elevated calcium-phosphate level). Skin biopsy is recommended if a necrotic skin lesion is identified in a patient with an elevated calcium-phosphate level or in a patient with risk factors for renal, liver, or parathyroid disease.

PROGNOSIS IS POOR

Treatment is supportive. Intensive wound care (with surgical evaluation for skin grafting), hyperbaric oxygen, and possibly tissue plasminogen activator (if there is evidence of a hypercoagulable state and occlusive vasculopathy) may be the most beneficial. Identifying the underlying cause and regulating the calcium-phosphorus product level with diet, phosphate binders, bisphosphonates, and sodium thiosulfate are also important in wound healing. Cinacalcet (Sensipar) and parathyroidectomy should be considered in cases of secondary hyperparathyroidism.

Calciphylaxis is important to recognize early in its course and may require a multidisciplinary approach to treatment. Its prognosis is poor, with death rates ranging from 40% to 60%.

Our patient developed recurrent hepatorenal syndrome and sepsis and eventually died of septic shock.

A 44-year-old woman with end-stage liver disease presents with a painful, ischemic, necrotic lesion on her right lateral and medial thigh (Figure  1). Several months ago, while being evaluated in the hospital for liver transplantation, she developed bacteremia, anion-gap metabolic acidosis, hepatorenal syndrome, and acute renal failure. She began continuous hemodialysis, which lasted for about 1 month, ending 35 days after the renal failure resolved.

Current laboratory values:

• Serum calcium concentration 7.8 mg/dL (reference range 8.5–10.5)
• Phosphorus 6.4 mg/dL (2.5–4.5)
• Corrected calcium-phosphorus product 55
• Parathyroid hormone 275 pg/mL (10–60)
• 25-hydroxyvitamin D 7.4 ng/mL (31–80).

Q: Given the patient’s history, which of the following does her skin lesion likely represent?

• Necrotizing fasciitis
• Calciphylaxis
• Disseminated intravascular coagulation
• Anticoagulant-induced skin necrosis

A: Calciphylaxis, or calcific uremic arteriolopathy, is the most likely. It is rare in people with normal renal function, and still rare but somewhat less so in end-stage renal disease patients undergoing chronic hemodialysis.

WHAT CAUSED IT IN OUR PATIENT?

The cause of calciphylaxis is unknown. Theories have focused on protein C and parathyroid hormone. Putative precipitating factors include acute tubular necrosis, albumin infusion with paracentesis, deficiency of protein C or S, hyperparathyroidism, hyperphosphatemia, hypercalcemia, vitamin D supplementation, steroids, trauma, and warfarin use.

Our patient had a history of hypothyroidism, ulcerative colitis, and end-stage liver disease due to primary sclerosing cholangitis, but no previous history of renal disease.

At the time of her acute renal failure, her calcium-phosphorus level was 55, parathyroid hormone level 274 pg/mL (normal 10–60), and protein C level 26% (normal 76%–147%). At the time the skin lesions were discovered, her protein C level had dropped to 14%; her parathyroid level had returned to normal.

Her home medications included furosemide (Lasix), levothyroxine (Synthroid), mesalamine (Pentasa), azathioprine (Imuran), ursodiol (Actigall), spironolactone (Aldactone), and omeprazole (Prilosec).

NONHEALING LESIONS

The skin lesions are characteristically erythematous and tender, with mottling of the skin early in the course. As the lesions progress, they develop central necrosis and deep ulcerations with eschar formation. The ulcers have irregular borders and do not heal. Histopathologic study typically shows epidermis with ischemic necrosis and calcium deposition along elastic fibers on Von Kossa calcium stains (Figure 2).

The skin lesions of calciphylaxis usually occur in areas of increased adipose tissue. The lesions may not manifest until several weeks after the initial insult (ie, the elevated calcium-phosphate level). Skin biopsy is recommended if a necrotic skin lesion is identified in a patient with an elevated calcium-phosphate level or in a patient with risk factors for renal, liver, or parathyroid disease.

PROGNOSIS IS POOR

Treatment is supportive. Intensive wound care (with surgical evaluation for skin grafting), hyperbaric oxygen, and possibly tissue plasminogen activator (if there is evidence of a hypercoagulable state and occlusive vasculopathy) may be the most beneficial. Identifying the underlying cause and regulating the calcium-phosphorus product level with diet, phosphate binders, bisphosphonates, and sodium thiosulfate are also important in wound healing. Cinacalcet (Sensipar) and parathyroidectomy should be considered in cases of secondary hyperparathyroidism.

Calciphylaxis is important to recognize early in its course and may require a multidisciplinary approach to treatment. Its prognosis is poor, with death rates ranging from 40% to 60%.

Our patient developed recurrent hepatorenal syndrome and sepsis and eventually died of septic shock.

A 44-year-old woman with end-stage liver disease presents with a painful, ischemic, necrotic lesion on her right lateral and medial thigh (Figure  1). Several months ago, while being evaluated in the hospital for liver transplantation, she developed bacteremia, anion-gap metabolic acidosis, hepatorenal syndrome, and acute renal failure. She began continuous hemodialysis, which lasted for about 1 month, ending 35 days after the renal failure resolved.

Current laboratory values:

• Serum calcium concentration 7.8 mg/dL (reference range 8.5–10.5)
• Phosphorus 6.4 mg/dL (2.5–4.5)
• Corrected calcium-phosphorus product 55
• Parathyroid hormone 275 pg/mL (10–60)
• 25-hydroxyvitamin D 7.4 ng/mL (31–80).

Q: Given the patient’s history, which of the following does her skin lesion likely represent?

• Necrotizing fasciitis
• Calciphylaxis
• Disseminated intravascular coagulation
• Anticoagulant-induced skin necrosis

A: Calciphylaxis, or calcific uremic arteriolopathy, is the most likely. It is rare in people with normal renal function, and still rare but somewhat less so in end-stage renal disease patients undergoing chronic hemodialysis.

WHAT CAUSED IT IN OUR PATIENT?

The cause of calciphylaxis is unknown. Theories have focused on protein C and parathyroid hormone. Putative precipitating factors include acute tubular necrosis, albumin infusion with paracentesis, deficiency of protein C or S, hyperparathyroidism, hyperphosphatemia, hypercalcemia, vitamin D supplementation, steroids, trauma, and warfarin use.

Our patient had a history of hypothyroidism, ulcerative colitis, and end-stage liver disease due to primary sclerosing cholangitis, but no previous history of renal disease.

At the time of her acute renal failure, her calcium-phosphorus level was 55, parathyroid hormone level 274 pg/mL (normal 10–60), and protein C level 26% (normal 76%–147%). At the time the skin lesions were discovered, her protein C level had dropped to 14%; her parathyroid level had returned to normal.

Her home medications included furosemide (Lasix), levothyroxine (Synthroid), mesalamine (Pentasa), azathioprine (Imuran), ursodiol (Actigall), spironolactone (Aldactone), and omeprazole (Prilosec).

NONHEALING LESIONS

The skin lesions are characteristically erythematous and tender, with mottling of the skin early in the course. As the lesions progress, they develop central necrosis and deep ulcerations with eschar formation. The ulcers have irregular borders and do not heal. Histopathologic study typically shows epidermis with ischemic necrosis and calcium deposition along elastic fibers on Von Kossa calcium stains (Figure 2).

The skin lesions of calciphylaxis usually occur in areas of increased adipose tissue. The lesions may not manifest until several weeks after the initial insult (ie, the elevated calcium-phosphate level). Skin biopsy is recommended if a necrotic skin lesion is identified in a patient with an elevated calcium-phosphate level or in a patient with risk factors for renal, liver, or parathyroid disease.

PROGNOSIS IS POOR

Treatment is supportive. Intensive wound care (with surgical evaluation for skin grafting), hyperbaric oxygen, and possibly tissue plasminogen activator (if there is evidence of a hypercoagulable state and occlusive vasculopathy) may be the most beneficial. Identifying the underlying cause and regulating the calcium-phosphorus product level with diet, phosphate binders, bisphosphonates, and sodium thiosulfate are also important in wound healing. Cinacalcet (Sensipar) and parathyroidectomy should be considered in cases of secondary hyperparathyroidism.

Calciphylaxis is important to recognize early in its course and may require a multidisciplinary approach to treatment. Its prognosis is poor, with death rates ranging from 40% to 60%.

Our patient developed recurrent hepatorenal syndrome and sepsis and eventually died of septic shock.