Managing CKD-Associated Pruritus

Approximately 35 million US adults suffer from chronic kidney disease (CKD), including more than 808,000 with end-stage renal disease (ESRD). Among these patients, an estimated 50%-100% experience at least one cutaneous symptom.

“CKD has far-reaching implications that go way beyond the kidneys,” Uday Nori, MD, clinical professor of medicine and transplant nephrologist, The Ohio State University Wexner Medical Center, Columbus, Ohio, told Medscape Medical News. “CKD is a systemic disease that affects practically all the other organs, including the skin.”

This second article in a series on dermatologic manifestations of CKD focuses on pruritus, defined as an “unpleasant sensation that causes the desire to scratch.” CDK-associated pruritus refers specifically to itching that occurs without another comorbid condition that could explain it. One of the most common and debilitating dermatologic conditions, pruritus affects 15%-49% of patients with chronic renal failure and up to 85% of the dialysis population.

“Pruritus is probably the biggest dermatologic problem in patients with kidney disease,” Dirk Elston, MD, professor and chairman of the Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, South Carolina, told Medscape Medical News. “Its consequences are broad and devastating because it affects patients’ sleep and their quality of life while they’re awake.”

A growing body of research sheds light on potential causes and emerging treatments for this pervasive problem.

What Causes the Itch?

Development of CKD-associated pruritus varies widely in presentation. It may be episodic or constant, localized or generalized, and mild or severe. The face, back, forearm, and shunt arm are common sites of localized itching. Symptoms typically worsen at night, and affected areas may migrate over time. Xerosis is common in CKD, but not all patients with it experience severe itching.

For some, symptoms improve after dialysis, whereas for others, they worsen over time, often correlating with increased length of treatment.

The mechanisms underlying pruritus in CKD are unclear. Uremia remains the most common metabolic trigger, and systemic inflammation may play a central role.

According to Nori, the “itch response,” triggered by inflammation, is a reaction to a series of compounds (eg, histamine, prostaglandins, cytokines, neuropeptides, and proteases), which send “itch signals” to the central nervous system. Elevated C-reactive protein levels have been reported in patients with ESRD and uremic pruritus, supporting this potential association.

Leslie Robinson-Bostom, MD, professor of dermatology and director of the Division of Dermatopathology, Department of Dermatology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, told Medscape Medical News that systemic imbalances may also contribute: “Decreased kidney function reduces urinary phosphate excretion, which leads to increased serum phosphate. This, in turn, decreases calcium and increases parathyroid hormone levels.”

Additional contributing factors to CKD-associated pruritus may include:

• Pruritogenic toxins: aluminum, calcium, phosphate, parathyroid hormone
• Metabolic imbalances: elevated urea, beta-2 microglobulin, vitamin A, and magnesium levels; low serum albumin; high white blood cell counts
• Additional factors: xerosis, dermal mast cell proliferation, impaired elimination of pruritogens, uremic sensory neuropathy, and adverse drug reactions

Risk factors include anemia, low erythropoietin, elevated ferritin, and low transferrin. Common comorbidities such as diabetes, viral hepatitis, and endocrinopathies may exacerbate pruritus.

In recent years, attention has turned to dysregulation of opioid pathway as another potential contributor.

“Dysregulation of endogenous opioids may well be a driver of pruritus,” Robinson-Bostom suggested. According to this hypothesis, overstimulation of the mu-opioid pathway and antagonism of the kappa-opioid pathway may result in itching.

A Profound Impact on Patients’ Lives

“Itching affects every aspect and every minute of a person’s life,” Jenny Murase, MD, associate clinical professor of dermatology, University of California, San Francisco, told Medscape Medical News. “To be unable to sleep or concentrate, and to feel you don’t want to live in your own skin — these are incredibly debilitating.”

In a survey of 301 patients receiving maintenance dialysis, respondents ranked itching as the most distressing and disruptive symptom.

What makes it even harder is that the source of itching in patients with kidney disease is often invisible.

“It’s not like there’s a rash or like arthritis, where we can visualize swelling or redness at the painful joint,” said Murase, who also serves as director of Medical Consultative Dermatology and Patch Testing, Palo Alto Medical Foundation, Mountain View, California.

CKD-associated pruritus is associated with poor treatment adherence, worse outcomes, and complications such as depression and suicidal ideation. Prompt recognition and treatment are critical, as is ruling out other causes for pruritus in CKD. These include liver disease, thyroid disease, primary dermatologic conditions, infestations (eg, lice or bedbugs), hypercalcemia, lymphoma, polycythemia vera, posthepatic neuralgia, and HIV.

Stepwise Treatment Strategies

Management of CKD-associated pruritus involves a “stepwise approach.” Nephrologists should begin by ensuring that patients meet Kidney Disease: Improving Global Outcomes targets for dialysis clearance and mineral and bone disease treatment.

Next, patients should be counseled to avoid triggers that can exacerbate CKD-associated pruritus like extreme temperatures, stress, and prolonged bathing. It can be helpful to keep the skin cool, maintain hydration, limit bathing to under 20 minutes with lukewarm water, and apply soap only to oily and intertriginous areas.

Topical treatments are often the next step. These can include the following:

• Emollients: paraffin or glycerol
• Topical analgesics: capsaicin or pramoxine
• Immunomodulators: tacrolimus (use with caution in renal transplant patients, as this agent can increase skin cancer risk)

Although antihistamines are commonly prescribed, some studies of these agents have yielded “disappointing” results. Sedating antihistamines may be modestly effective but can cause oversedation, especially in the elderly.

Patients who don’t respond to these measures can be treated with gabapentin or pregabalin. A systematic review found both to be superior to placebo. However, these agents can have adverse effects, including dizziness, drowsiness, and somnolence.

Additional approaches include mast cell stabilizers (hydroxyzine, cromolyn sodium, and nicotinamide) and opioid receptor modulators. Since an imbalance of mu- and kappa-opioid receptors is a hypothesized mechanism of CKD-associated pruritus, treatments targeting this pathway (difelikefalin, nalfurafine, and nalbuphine) have shown promise.

Elston noted that phototherapy is sometimes helpful in this indication, as it modulates the immune response via alteration of cytokine production. Broadband ultraviolet B has shown the most efficacy, although all ultraviolet light therapies carry the risk for sunburn and tanning.

Additional medications with limited but encouraging evidence include antidepressants (mirtazapine, paroxetine, fluvoxamine, and sertraline), aprepitant (a substance P agonist), and serlopitant (a neurokinin-1 receptor antagonist granted Breakthrough Therapy Designation by the FDA for treatment of pruritus associated with prurigo nodularis).

A Promising New Biologic

Nemolizumab, an interleukin-31 (IL-31) receptor alpha-antagonist, is “the newest and most promising drug to be investigated,” according to Elston.

Currently FDA-approved for moderate-to-severe atopic dermatitis and prurigo nodularis, nemolizumab potentially has broader utility given that it targets IL-31, an “itch cytokine” implicated in multiple pruritic disorders. 

Murase and colleagues published a case series following 60 patients — 14 with renal insufficiency — who suffered from severe and recalcitrant pruritus. On average, patients had failed 13 prior therapies. Following treatment with nemolizumab, all but two of the patients achieved a ≥ 2-point reduction on the Peak Pruritus Numerical Rating Scale and/or a 50% reduction from baseline. The medication was well tolerated, with 7.5% of patients reporting adverse events. No serious adverse events were reported.

“I believe nephrologists will be very happy when they hear about this medication,” Murase said. “It can be life-changing for their patients, and it works very rapidly, often within 48 hours after the first loading dose.”

The Benefits of a Multidisciplinary Approach

Research suggests that nephrologists may underestimate the prevalence of pruritus among their patients. This may be due to a lack of communication from their patients. In a study of more than 35,000 patients on dialysis, nearly one fifth had not reported itching to any healthcare provider.

Several reasons may account for this reticence, including patients’ resilience to symptoms, language ability, lack of time, and assumptions that their provider may not regard itching as a problem. A study including nephrologists, nurses, and patients with CKD found that underreporting and undertreatment of pruritus often stemmed from limited knowledge, ambivalence regarding the importance of itching, and a need for specific prompts during consultation.

Physicians should proactively ask patients with CKD and ESRD about itching using validated tools such as the General Itch Questionnaire and the Visual Analog Scale. Additional scales to assess specific domains of pruritus, including sleep impairment and psychological impact, are provided in a paper by Manuel P. Pereira, MD, and colleagues.

All the experts interviewed for this article agree on the importance of adopting a multidisciplinary approach in these patients. Dermatologists, nephrologists, nurses, pharmacists, dietitians, and mental health professionals can work together to manage symptoms and improve overall outcomes.

Robinson-Bostom, Nori, and Elston declared having no relevant financial relationships. Murase is on the speakers bureau for Regeneron, Genzyme/Sanofi, Galderma, and UCB; advisory boards for Regeneron, Genzyme/Sanofi, UCB, Arcutis, and Bristol Myers Squibb; and consulting for AbbVie, UCB, Sanofi-Regeneron, and UpToDate.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape Medical News and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).