Successful difelikefalin use in severe chronic kidney disease-associated pruritus in a patient with tertiary hyperparathyroidism: a case report

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Werzowa, Margit Hemetsberger This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5158635/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Feb, 2025 Read the published version in Case Reports in Nephrology → Version 1 posted You are reading this latest preprint version Abstract Background Chronic kidney disease-associated pruritus (CKD-aP) is a frequently experienced, unpleasant skin condition. Difelikefalin is indicated for the treatment of moderate-to-severe CKD-aP in adult patients on hemodialysis. Reports of difelikefalin effectiveness in complex patient cases encountered in routine clinical practice are rare. Case presentation The presented patient had a complex interplay of morbidities, most notably diabetes mellitus type 2, tertiary hyperparathyroidism, end-stage renal disease (ESRD), and CKD-associated mineral bone disease (CKD-MBD), all of which are associated with the development and severity of CKD-aP. The patient’s CKD-aP proved resistant to H 1 -receptor antagonists and gabapentin and showed no improvement after parathyroidectomy. Treatment with difelikefalin rapidly and sustainedly improved symptoms, with a brief recurrence of itch towards the end of each long interdialytic interval. Apart from a short episode of vertigo at initiation of treatment, no adverse events were observed over the long duration of treatment (more than two years). Conclusions Difelikefalin, an agonist of the kappa opioid receptor, acts independently of the itch-causing mechanisms associated with the comorbidities present in the patient, notably diabetes mellitus type 2, tertiary hyperparathyroidism, ESRD, and CKD-MBD. This may explain the sustained effectiveness of difelikefalin throughout the patient’s complex clinical history. Urology & Nephrology Chronic kidney disease difelikefalin uremic pruritus hyperparathyroidism case report Figures Figure 1 Background Chronic kidney disease-associated pruritus (CKD-aP) is a very unpleasant skin condition frequently experienced by patients with end-stage renal disease (ESRD). According to the Dialysis Outcomes and Practice Patterns Study (DOPPS), 37% of hemodialysis patients feel moderately (18%), severely (12%) or extremely (7%) affected by pruritus 1 and symptoms were shown to be chronic in most affected patients. 2 In a recent cohort study from the Austrian Dialysis and Transplant Registry, a CKD-aP prevalence of 14% for at least moderate and 4% for severe pruritus was extrapolated from the observed hemodialysis patients. 3 However, CKD-aP has not only been observed in ESRD but also in approximately one-third of patients with earlier, non-dialysis stages of CKD. 4 The location, duration, severity and perception of CKD-aP-associated itching varies from person to person. The condition is often bilaterally symmetrical and can be localized or generalized. Itching may periodically reoccur several times a day or persist permanently. 5, 6 Visible, secondary skin lesions may be present, ranging from scratch marks to prurigo nodularis to scarring. 7–9 CKD-aP often occurs along with other physical and psycho-emotional symptoms, including poor sleep quality, depression, fatigue, and pain. 10, 11 The DOPPS found a 1.2-fold higher cause-independent mortality rate and a 1.4-fold higher infection-related mortality rate in patients with severe CKD-aP compared to patients who were not at all bothered by pruritus. 1 The pathophysiology of CKD-aP is not yet fully understood. The condition is commonly described as a consequence of the accumulation of uremic toxins in the skin, and subsequent peripheral neuropathy, immune system dysregulation and/or opioid imbalance. 12 However, these mechanisms appear to be involved to varying degrees in different subsets of patients. In many patients, symptoms of itching only improve transiently or not at all when highly efficient hemodialysis (with increasing Kt/V and control of serum calcium, intact parathyroid hormone [iPTH] or phosphate) is initiated. 12 There is evidence that gabapentin as well as pregabalin used to treat the pain associated with peripheral neuropathy may improve CKD-aP, 13–15 but neurological adverse treatment-related events, such as mental status deterioration or an increased propensity to falls, were reported. 16, 17 Anti-histamines, administered to address the immune system dysregulation, were shown to have limited efficacy against CKD-aP. 12 Difelikefalin, a kappa opioid receptor agonist, was specifically developed to address the imbalance in the endogenous opioid system, i.e. the overexpression of mu opioid receptors and concomitant downregulation of kappa opioid receptors. 18 Kappa opioid receptor activation on peripheral sensory neurons and immune cells reduces itching and produces immunomodulatory, anti-inflammatory effects. 12, 18 Difelikefalin was first approved in the European Union in April 2022 and is indicated for the treatment of moderate-to-severe CKD-aP in adult patients on hemodialysis. 18 The rapid, sustained efficacy of difelikefalin was demonstrated in the randomized, controlled clinical KALM-1 and KALM-2 trials, in which results were consistent across diverse populations. 19–21 However, reports of difelikefalin effectiveness in the complex patient cases encountered in routine clinical practice are still rare. Therefore, we present the case of a patient with severe, H 1 -receptor antagonist and gabapentin refractory CKD-aP, tertiary hyperparathyroidism and associated bone disease, who showed rapid and sustained response to treatment with difelikefalin. Case presentation The female patient (year of birth: 1980, height: 160 cm; weight: 57 kg; smoker) first presented in 07/2016, after she was hospitalized with a knee injury. Routine laboratory workup at the orthopedics department found a Modification of Diet in Renal Disease (MDRD)-estimated glomerular filtration rate (eGFR) of 30 mL/min per 1.73 m 2 and hypercalcemia (total serum calcium 3.6 mmol/L), indicating possible CKD. Sonographic workup showed suspected kidney concrements. Table 1 shows relevant comorbidities and risk factors present in the patient. Table 1 Comorbidities and risk factors Comorbidity Comment Nephrolithiasis • First diagnosed in 06/2015 Nephrocalcinosis, severe interstitial fibrosis, tubular atrophy • Kidney biopsy in 08/2016 Primary hyperparathyroidism • Parathyroid adenoma • Parathyroidectomy left caudal on 01.08.2016 Secondary hyperparathyroidism • Secondary hyperparathyroidism in connection with chronic renal insufficiency • Large single-gland disease on the right dorsal • Second parathyroidectomy on 06.12.2023 with autotransplantation Diabetes mellitus type 2 • First diagnosed in 06/2019 • Insulin dependent COVID infection 04/2021, resolved End-stage renal disease • Chronic hemodialysis initiated 03/2022 Uremic pruritus • First experienced in 04/2021 Severe osteoporosis • DXA scan in 04/2023 • Alendronate 35 mg/week p.o. since 05/2023–12/2023 Chronic hyponatremia and hypokalemia Potential Bartter syndrome or Gitelman syndrome were excluded through genetic testing Nicotine abuse CKD-aP, chronic kidney disease-associated pruritus; iPTH, intact parathyroid hormone The orange line depicts the time of first appearance of CKD-aP symptoms in 04/2021. The green line depicts the time difelikefalin initiation in 06/2022. With an iPTH level of 7200 pg/mL (reference range: 12–88 pg/mL), primary hyperparathyroidism was suspected. A methoxy-isobutyl-isonitrile (MIBI)-scintigraphy of the thyroid showed MIBI retention in the area of the left caudal thyroid pole and a kidney biopsy revealed nephrocalcinosis, severe interstitial fibrosis and tubular atrophy. After confirmed diagnosis of primary hyperparathyroidism due to an adenoma of the right parathyroid gland, surgical resection of the adenoma was performed in 08/2016. After surgery, levels of serum calcium and iPTH rapidly improved to approx. 2 mmol/L and 150–600 pg/mL, respectively. Creatinine values were fluctuating between 2 and 3 mg/dL over a longer period of time. In 06/2019, diabetes mellitus type 2 was diagnosed, and insulin treatment was initiated shortly thereafter due to high HbA1c values (approx. 8%) despite oral antidiabetic therapy. In 04/2021, a significant deterioration of renal function and electrolytes (hypokalemia and hyponatremia) was observed following a severe COVID infection (the patient was not vaccinated). Bartter syndrome or Gitelman syndrome as possible causes for the observed hypokalemia and hyponatremia were excluded through genetic testing. CKD-aP was first observed at the time of the COVID infection. In 08/2021, a Cimino-Shunt was placed in the left forearm. Chronic hemodialysis was initiated in 03/2022. The patient was hyperphosphatemic and therefore initiated on a phosphate binder (sevelamer) upon start of hemodialysis. The patient suffered from moderate pruritus at that time. Figure 1 shows the patient’s relevant laboratory parameters and clinical events over time from the start of CKD-aP. Initiation of hemodialysis led to a transient improvement in pruritus intensity but by 05/2022 the condition deteriorated with a worst-itch numerical rating scale (WI-NRS) of 8–9 and a self-assessed disease severity (SADS) level C. Itching was worst during the night. H 1 -receptor antagonist therapy (diphenhydramine and cetirizine) and gabapentin did not lead to improvement of symptoms. Topical treatment including emollients and a polidocanol containing ointment also did not provide any relief and the patient showed massive scratch marks especially on the upper extremities. Therapy with intravenous difelikefalin at 0.5 mg/kg three times weekly at the end of each dialysis session was initiated in 06/2022 as part of an early access program in Austria. The patient’s relevant laboratory measurements nearest to initiation of difelikefalin were as follows: iPTH 973 pg/mL, serum calcium 2.60 mmol/L, albumin 3.9 g/dL, HbA1c 6.7%, alkaline phosphatase 386 U/L, phosphate 2.21 mmol/L. The patient experienced mild vertigo after the first two to three administrations but then experienced no further side effects. Pruritus decreased significantly within the first two weeks of therapy to WI-NRS 0 and SADS A. Of note, although the CKD-aP generally resolved after initiation of difelikefalin, the patient continues to regularly experience mild pruritus at the end of the long interdialytic interval over the weekends; these symptoms reliably disappear after administration of difelikefalin at the end of the first weekly dialysis session each Monday. The patient’s dialysis efficacy was adequate (Kt/V > 1.3) at all times. The C-reactive protein (CRP) level was constantly elevated. Concomitantly, iPTH levels were continuously increasing to 1200 pg/mL despite treatment with the calcimimetic etelcalcetide (12.5 mg intravenously at the end of each dialysis session). Sonographic examination of the right thyroid revealed a hypoechogenic structure at the dorsocaudal margin of the right thyroid lobe suspect of a parathyroid adenoma. Scintigraphic examination confirmed the diagnosis of tertiary hyperparathyroidism. A dual-energy X-ray absorptiometry (DXA) scan conducted in 04/2023 revealed severe osteoporosis with T-scores of -1.7 in the lumal spine, -3.0 in the femoral neck, and − 5.1 in the radius, a picture typical of bone disease associated with very high iPTH levels. 22 Bone-specific alkaline phosphatase levels were elevated to 719 U/L (reference range: 35–105 U/L) with an increased fraction of the bone-specific isoform (80%, reference range: 20–74%). An antiresorptive therapy with alendronate (35 mg orally once weekly) was initiated in 05/2023. Surgical resection of the parathyroid adenoma with autotransplantation of gland tissue to the right forearm was conducted in 12/2023. After the operation, iPTH levels fell sharply to 4 pg/mL and the patient developed severe hypocalcemia. She therefore received calcitriol and oral calcium supplements. Alendronate was discontinued. Phosphate binder use was stopped upon normalization of phosphate levels. The patient reported no improvement in the frequency or intensity of itching at the end of the long dialysis interval after parathyroidectomy. At the time of writing (September 2024), she is still receiving difelikefalin at the initial dose to control her pruritus without experiencing adverse effects. The patient still has residual kidney function with no need for ultrafiltration to maintain euvolemia. Discussion and Conclusions This is the case of a patient with a complex interplay of morbidities, most notably diabetes mellitus type 2, tertiary hyperparathyroidism, ESRD, and CKD-associated mineral bone disease (CKD-MBD). There is evidence that all of these morbidities are associated with the development and severity of CKD-aP. 5, 23–26 In a cohort study of 1951 non-dialysis CKD patients, diabetes, elevated serum iPTH, and reduced eGFR – among other factors – were associated with a higher risk of developing CKD-aP. An incremental reduction of eGFR of 10 mL/min per 1.73 m 2 was associated with a hazard ratio (HR) for CKD-aP of 1.16 (95% confidence interval [CI]: 1.10 to 1.23). Serum phosphate was not associated with incident CKD-aP, while low serum calcium (< 9 mg/dL) correlated with a reduced incidence of CKD-aP. 4 A recent cross-sectional study of 6221 patients also found that diabetes, as well as elevated phosphate and iPTH levels significantly correlated with higher CKD-aP disease severity. 27 An Austrian Dialysis and Transplant Registry analysis found that a CRP or iPTH level above the sample median (CRP > 0.5 mg/dL; iPTH > 300.5 pg/mL) was associated with more severe pruritus (CRP: odds ratio [OR] 1.61, 95% CI: 1.07–2.43; PTH: OR 1.50, 95% CI: 1.00–2.27). Absolute serum calcium above the cohort mean (> 8.63 mg/dL) was associated with a lower risk for moderate-to-severe pruritus (OR 0.62, 95% CI: 0.41–0.93), but statistical significance was lost when calcium values were corrected for serum albumin. Serum phosphate above the cohort mean (> 5.53 mg/dL) was not significantly associated with an increased risk of moderate-to-severe pruritus (odds ratio [OR] 1.19, 95% CI: 0.79–1.78, p = 0.433). 3 An association between elevated iPTH levels and CKD-aP severity was also found in other studies. 5, 24–26 Disappearance of uremic pruritus after parathyroidectomy has already been described in the 1960s 28, 29 and was later confirmed in a study by Chou et al. 30 in patients with pruritus and secondary hyperparathyroidism. However, there is also evidence indicating a lack of correlation between CKD-MBD and pruritus. DOPPS found no association between CKD-aP severity and levels of iPTH, calcium or phosphate. 31 In the phase 3 KALM-1 and KALM-2 trials of difelikefalin, serum phosphate levels did neither correlate with CKD-aP severity nor with response to difelikefalin. 19, 21 Local injection of PTH into the skin of dialysis patients also did not induce pruritus at the injection site. 32 The presented patient had persistently high levels of iPTH, alkaline phosphatase, phosphate, CRP, and creatinine, all of which further deteriorated when kidney function worsened in the spring and early summer of 2021 (Fig. 1 ). Around this time, the patient first noticed pruritus symptoms. When hemodialysis started in 02/2022, pruritus symptoms worsened, and the patient quickly required specific treatment for CKD-aP upon the appearance of severe scratch marks. The patient’s pruritus did, however, not improve substantially using H 1 -receptor antagonists and subsequently gabapentin. Therefore, treatment with difelikefalin was initiated and symptoms quickly and sustainedly improved. However, after each long interdialytic interval, a recurrence of the itch was observed, owing to the mean half-life of difelikefalin of 38 hours in hemodialysis patients. 33 At the time of writing, the duration of difelikefalin treatment is now more than two years with no notable adverse effects apart from a short and mild episode of vertigo at the time of initiation. Parathyroidectomy, followed by a substantial decrease in iPTH levels, did not alleviate pruritus symptoms. It was hypothesized that overstimulation of central mu-opioid receptors, antagonism of peripheral kappa-opioid receptors, or an imbalance of stimulation and antagonism of mu- and kappa opioid receptors causes itching. 18, 34, 35 The mechanism of action of difelikefalin via the kappa opioid receptor 12, 18 is thus directed at a mechanism of itch sensation that is independent of the comorbidities present in the patient, notably diabetes mellitus type 2, tertiary hyperparathyroidism, ESRD, and CKD-MBD. This may explain the sustained effectiveness of difelikefalin throughout the patient’s complex clinical history. In conclusion, this patient case shows the sustained effectiveness of difelikefalin in a complex patient with multiple relevant comorbidities affecting the occurrence and severity of CKD-aP. Difelikefalin acts via a pathway independent of CKD-associated causes of pruritus, such as elevated iPTH, calcium, CRP, and possibly phosphate, and thus seems to be able to sustain its effectiveness despite recurring deteriorations of these parameters. Abbreviations CI confidence interval CKD-aP chronic kidney disease-associated pruritus CKD-MBD chronic kidney disease-associated mineral bone disease DOPPS Dialysis Outcomes and Practice Patterns Study DXA dual-energy X-ray absorptiometry ESRD end-stage renal disease iPTH intact parathyroid hormone MDRD Modification of Diet in Renal Disease MIBI methoxy-isobutyl-isonitrile SADS self-assessed disease severity WI-NRS worst-itch numerical rating scale Declarations Ethics approval and consent to participate Ethics approval is not required for this report of a patient treated in clinical practice according with national guidelines. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Availability of data and materials This is a report of a patient treated in routine clinical practice and data not included in this article are protected by physician-patient privilege and subject to the patient’s consent to making it available. Further enquiries can be directed to the corresponding author. Conflicting interests JW has received speaker honoraria from CSL Vifor. MH has received consultancy fees from CSL Vifor. Funding The authors did not receive funding for the preparation of this case report. Authors’ Contributions The authors comply with the ICMJE criteria of authorship, have substantially contributed the acquisition and interpretation of data for the work; reviewed the work critically for important intellectual content; and provided final approval of the version to be published. 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The New England journal of medicine 1968; 279: 697-700. DOI: 10.1056/NEJM196809262791308. Chou FF, Ho JC, Huang SC and Sheen-Chen SM. A study on pruritus after parathyroidectomy for secondary hyperparathyroidism. J Am Coll Surg 2000; 190: 65-70. DOI: 10.1016/s1072-7515(99)00212-4. Rayner HC, Larkina M, Wang M, et al. International Comparisons of Prevalence, Awareness, and Treatment of Pruritus in People on Hemodialysis. Clinical Journal of the American Society of Nephrology 2017; 12: 2000-2007. DOI: 10.2215/cjn.03280317. Stahle-Backdahl M, Hagermark O, Lins LE, et al. Experimental and immunohistochemical studies on the possible role of parathyroid hormone in uraemic pruritus. Journal of internal medicine 1989; 225: 411-415. DOI: 10.1111/j.1365-2796.1989.tb00104.x. Stark JG, Noonan PK, Spencer RH, et al. Pharmacokinetics, Metabolism, and Excretion of Intravenous [14C]Difelikefalin in Healthy Subjects and Subjects on Hemodialysis. Clinical pharmacokinetics 2023; 62: 1231-1241. DOI: 10.1007/s40262-023-01262-2. Tey HL and Yosipovitch G. Targeted treatment of pruritus: a look into the future. British Journal of Dermatology 2011; 165: 5-17. DOI: 10.1111/j.1365-2133.2011.10217.x. Cowan A, Kehner GB and Inan S. Targeting itch with ligands selective for κ opioid receptors. Handb Exp Pharmacol 2015; 226: 291-314. DOI: 10.1007/978-3-662-44605-8_16. Additional Declarations The authors declare potential competing interests as follows: JW has received speaker honoraria from CSL Vifor. MH has received consultancy fees from CSL Vifor. Cite Share Download PDF Status: Published Journal Publication published 24 Feb, 2025 Read the published version in Case Reports in Nephrology → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5158635","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":359355624,"identity":"b623fd78-120f-4c3b-9abd-a37551129549","order_by":0,"name":"Johannes M. Werzowa","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDUlEQVRIiWNgGAWjYBACxgYeNBF+sChJWiQbIFokcGtC12JwgIAW5vbeg58Ld9jYM0gkH/v4o+KwvPHx5sMvZzDY1eF0WM+5ZOmZZ9ISGyTSkmdInDlsuO3MsTTLDQzJOG1hnJFjIM3bdjiBQTrHmMGw7Tbjths5ZoYPGJjxaTH+zdv2355BOv8zQ2LbbfvNM/K/AbXU49NiBrTlAGODdA4zw8G224kbJHKYH25gOIxbS88ZM2vetuTENvlnxowNZ/4nzzhzzIxxhsFxUGBjBYbtPca3edvs7Pl5Dj9m/FGRZtvf3vz4Y09FNT8uWwxhZrEhCbJJMBjg0sDAII9NkPkDbg2jYBSMglEwAgEAPWJWjWdUDgwAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-2507-1377","institution":"Clinical Division of Nephrology and Dialysis, 1st Medical Department, Hanusch Hospital, Heinrich-Collin-Straße 30, 1140 Vienna, Austria","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Johannes","middleName":"M.","lastName":"Werzowa","suffix":""},{"id":359355625,"identity":"65e8c7bb-ebbd-44c5-8a28-740711ff4bb3","order_by":1,"name":"Margit Hemetsberger","email":"","orcid":"https://orcid.org/0000-0003-1877-6838","institution":"hemetsberger medical services","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Margit","middleName":"","lastName":"Hemetsberger","suffix":""}],"badges":[],"createdAt":"2024-09-26 12:16:06","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":true,"vertebrateSubjectEthicalGuidelines":false,"coiExplicitlySet":false},"doi":"10.21203/rs.3.rs-5158635/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5158635/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1155/crin/6626611","type":"published","date":"2025-02-25T00:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":65782890,"identity":"a0a48bfa-64de-4706-9f4d-023612f54cba","added_by":"auto","created_at":"2024-10-02 15:24:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":29302,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRelevant laboratory parameters and clinical events over time\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCKD-aP, chronic kidney disease-associated pruritus; iPTH, intact parathyroid hormone\u003c/p\u003e\n\u003cp\u003eThe orange line depicts the time of first appearance of CKD-aP symptoms in 04/2021.\u003c/p\u003e\n\u003cp\u003eThe green line depicts the time difelikefalin initiation in 06/2022.\u003c/p\u003e","description":"","filename":"Picture1.png","url":"https://assets-eu.researchsquare.com/files/rs-5158635/v1/cec79417c10531ec0f76cf51.png"},{"id":99837584,"identity":"9b545c64-0ef4-44a4-be15-25e7c9f9fb28","added_by":"auto","created_at":"2026-01-08 19:44:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":515064,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5158635/v1/c8362526-e0b0-4668-847a-b1fcc035176a.pdf"}],"financialInterests":"The authors declare potential competing interests as follows: JW has received speaker honoraria from CSL Vifor. MH has received consultancy fees from CSL Vifor.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eSuccessful difelikefalin use in severe chronic kidney disease-associated pruritus in a patient with tertiary hyperparathyroidism: a case report\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eChronic kidney disease-associated pruritus (CKD-aP) is a very unpleasant skin condition frequently experienced by patients with end-stage renal disease (ESRD). According to the Dialysis Outcomes and Practice Patterns Study (DOPPS), 37% of hemodialysis patients feel moderately (18%), severely (12%) or extremely (7%) affected by pruritus\u003csup\u003e1\u003c/sup\u003e and symptoms were shown to be chronic in most affected patients.\u003csup\u003e2\u003c/sup\u003e In a recent cohort study from the Austrian Dialysis and Transplant Registry, a CKD-aP prevalence of 14% for at least moderate and 4% for severe pruritus was extrapolated from the observed hemodialysis patients.\u003csup\u003e3\u003c/sup\u003e However, CKD-aP has not only been observed in ESRD but also in approximately one-third of patients with earlier, non-dialysis stages of CKD.\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe location, duration, severity and perception of CKD-aP-associated itching varies from person to person. The condition is often bilaterally symmetrical and can be localized or generalized. Itching may periodically reoccur several times a day or persist permanently.\u003csup\u003e5, 6\u003c/sup\u003e Visible, secondary skin lesions may be present, ranging from scratch marks to prurigo nodularis to scarring.\u003csup\u003e7\u0026ndash;9\u003c/sup\u003e CKD-aP often occurs along with other physical and psycho-emotional symptoms, including poor sleep quality, depression, fatigue, and pain.\u003csup\u003e10, 11\u003c/sup\u003e The DOPPS found a 1.2-fold higher cause-independent mortality rate and a 1.4-fold higher infection-related mortality rate in patients with severe CKD-aP compared to patients who were not at all bothered by pruritus.\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe pathophysiology of CKD-aP is not yet fully understood. The condition is commonly described as a consequence of the accumulation of uremic toxins in the skin, and subsequent peripheral neuropathy, immune system dysregulation and/or opioid imbalance.\u003csup\u003e12\u003c/sup\u003e However, these mechanisms appear to be involved to varying degrees in different subsets of patients. In many patients, symptoms of itching only improve transiently or not at all when highly efficient hemodialysis (with increasing Kt/V and control of serum calcium, intact parathyroid hormone [iPTH] or phosphate) is initiated.\u003csup\u003e12\u003c/sup\u003e There is evidence that gabapentin as well as pregabalin used to treat the pain associated with peripheral neuropathy may improve CKD-aP,\u003csup\u003e13\u0026ndash;15\u003c/sup\u003e but neurological adverse treatment-related events, such as mental status deterioration or an increased propensity to falls, were reported.\u003csup\u003e16, 17\u003c/sup\u003e Anti-histamines, administered to address the immune system dysregulation, were shown to have limited efficacy against CKD-aP.\u003csup\u003e12\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDifelikefalin, a kappa opioid receptor agonist, was specifically developed to address the imbalance in the endogenous opioid system, i.e. the overexpression of mu opioid receptors and concomitant downregulation of kappa opioid receptors.\u003csup\u003e18\u003c/sup\u003e Kappa opioid receptor activation on peripheral sensory neurons and immune cells reduces itching and produces immunomodulatory, anti-inflammatory effects.\u003csup\u003e12, 18\u003c/sup\u003e Difelikefalin was first approved in the European Union in April 2022 and is indicated for the treatment of moderate-to-severe CKD-aP in adult patients on hemodialysis.\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe rapid, sustained efficacy of difelikefalin was demonstrated in the randomized, controlled clinical KALM-1 and KALM-2 trials, in which results were consistent across diverse populations.\u003csup\u003e19\u0026ndash;21\u003c/sup\u003e However, reports of difelikefalin effectiveness in the complex patient cases encountered in routine clinical practice are still rare. Therefore, we present the case of a patient with severe, H\u003csub\u003e1\u003c/sub\u003e-receptor antagonist and gabapentin refractory CKD-aP, tertiary hyperparathyroidism and associated bone disease, who showed rapid and sustained response to treatment with difelikefalin.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eThe female patient (year of birth: 1980, height: 160 cm; weight: 57 kg; smoker) first presented in 07/2016, after she was hospitalized with a knee injury. Routine laboratory workup at the orthopedics department found a Modification of Diet in Renal Disease (MDRD)-estimated glomerular filtration rate (eGFR) of 30 mL/min per 1.73 m\u003csup\u003e2\u003c/sup\u003e and hypercalcemia (total serum calcium 3.6 mmol/L), indicating possible CKD. Sonographic workup showed suspected kidney concrements. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows relevant comorbidities and risk factors present in the patient.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComorbidities and risk factors\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eComment\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNephrolithiasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; First diagnosed in 06/2015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNephrocalcinosis, severe interstitial fibrosis, tubular atrophy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Kidney biopsy in 08/2016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary hyperparathyroidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Parathyroid adenoma\u003c/p\u003e \u003cp\u003e\u0026bull; Parathyroidectomy left caudal on 01.08.2016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary hyperparathyroidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Secondary hyperparathyroidism in connection with chronic renal insufficiency\u003c/p\u003e \u003cp\u003e\u0026bull; Large single-gland disease on the right dorsal\u003c/p\u003e \u003cp\u003e\u0026bull; Second parathyroidectomy on 06.12.2023 with autotransplantation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus type 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; First diagnosed in 06/2019\u003c/p\u003e \u003cp\u003e\u0026bull; Insulin dependent\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOVID infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e04/2021, resolved\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnd-stage renal disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Chronic hemodialysis initiated 03/2022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUremic pruritus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; First experienced in 04/2021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere osteoporosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; DXA scan in 04/2023\u003c/p\u003e \u003cp\u003e\u0026bull; Alendronate 35 mg/week p.o. since 05/2023\u0026ndash;12/2023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic hyponatremia and hypokalemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePotential Bartter syndrome or Gitelman syndrome were excluded through genetic testing\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNicotine abuse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eCKD-aP, chronic kidney disease-associated pruritus; iPTH, intact parathyroid hormone\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eThe orange line depicts the time of first appearance of CKD-aP symptoms in 04/2021.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eThe green line depicts the time difelikefalin initiation in 06/2022.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWith an iPTH level of 7200 pg/mL (reference range: 12\u0026ndash;88 pg/mL), primary hyperparathyroidism was suspected. A methoxy-isobutyl-isonitrile (MIBI)-scintigraphy of the thyroid showed MIBI retention in the area of the left caudal thyroid pole and a kidney biopsy revealed nephrocalcinosis, severe interstitial fibrosis and tubular atrophy. After confirmed diagnosis of primary hyperparathyroidism due to an adenoma of the right parathyroid gland, surgical resection of the adenoma was performed in 08/2016. After surgery, levels of serum calcium and iPTH rapidly improved to approx. 2 mmol/L and 150\u0026ndash;600 pg/mL, respectively. Creatinine values were fluctuating between 2 and 3 mg/dL over a longer period of time.\u003c/p\u003e \u003cp\u003eIn 06/2019, diabetes mellitus type 2 was diagnosed, and insulin treatment was initiated shortly thereafter due to high HbA1c values (approx. 8%) despite oral antidiabetic therapy.\u003c/p\u003e \u003cp\u003eIn 04/2021, a significant deterioration of renal function and electrolytes (hypokalemia and hyponatremia) was observed following a severe COVID infection (the patient was not vaccinated). Bartter syndrome or Gitelman syndrome as possible causes for the observed hypokalemia and hyponatremia were excluded through genetic testing. CKD-aP was first observed at the time of the COVID infection. In 08/2021, a Cimino-Shunt was placed in the left forearm. Chronic hemodialysis was initiated in 03/2022. The patient was hyperphosphatemic and therefore initiated on a phosphate binder (sevelamer) upon start of hemodialysis. The patient suffered from moderate pruritus at that time. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the patient\u0026rsquo;s relevant laboratory parameters and clinical events over time from the start of CKD-aP. Initiation of hemodialysis led to a transient improvement in pruritus intensity but by 05/2022 the condition deteriorated with a worst-itch numerical rating scale (WI-NRS) of 8\u0026ndash;9 and a self-assessed disease severity (SADS) level C. Itching was worst during the night. H\u003csub\u003e1\u003c/sub\u003e-receptor antagonist therapy (diphenhydramine and cetirizine) and gabapentin did not lead to improvement of symptoms. Topical treatment including emollients and a polidocanol containing ointment also did not provide any relief and the patient showed massive scratch marks especially on the upper extremities.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTherapy with intravenous difelikefalin at 0.5 mg/kg three times weekly at the end of each dialysis session was initiated in 06/2022 as part of an early access program in Austria. The patient\u0026rsquo;s relevant laboratory measurements nearest to initiation of difelikefalin were as follows: iPTH 973 pg/mL, serum calcium 2.60 mmol/L, albumin 3.9 g/dL, HbA1c 6.7%, alkaline phosphatase 386 U/L, phosphate 2.21 mmol/L.\u003c/p\u003e \u003cp\u003eThe patient experienced mild vertigo after the first two to three administrations but then experienced no further side effects. Pruritus decreased significantly within the first two weeks of therapy to WI-NRS 0 and SADS A. Of note, although the CKD-aP generally resolved after initiation of difelikefalin, the patient continues to regularly experience mild pruritus at the end of the long interdialytic interval over the weekends; these symptoms reliably disappear after administration of difelikefalin at the end of the first weekly dialysis session each Monday. The patient\u0026rsquo;s dialysis efficacy was adequate (Kt/V\u0026thinsp;\u0026gt;\u0026thinsp;1.3) at all times. The C-reactive protein (CRP) level was constantly elevated.\u003c/p\u003e \u003cp\u003eConcomitantly, iPTH levels were continuously increasing to 1200 pg/mL despite treatment with the calcimimetic etelcalcetide (12.5 mg intravenously at the end of each dialysis session). Sonographic examination of the right thyroid revealed a hypoechogenic structure at the dorsocaudal margin of the right thyroid lobe suspect of a parathyroid adenoma. Scintigraphic examination confirmed the diagnosis of tertiary hyperparathyroidism. A dual-energy X-ray absorptiometry (DXA) scan conducted in 04/2023 revealed severe osteoporosis with T-scores of -1.7 in the lumal spine, -3.0 in the femoral neck, and \u0026minus;\u0026thinsp;5.1 in the radius, a picture typical of bone disease associated with very high iPTH levels.\u003csup\u003e22\u003c/sup\u003e Bone-specific alkaline phosphatase levels were elevated to 719 U/L (reference range: 35\u0026ndash;105 U/L) with an increased fraction of the bone-specific isoform (80%, reference range: 20\u0026ndash;74%). An antiresorptive therapy with alendronate (35 mg orally once weekly) was initiated in 05/2023. Surgical resection of the parathyroid adenoma with autotransplantation of gland tissue to the right forearm was conducted in 12/2023. After the operation, iPTH levels fell sharply to 4 pg/mL and the patient developed severe hypocalcemia. She therefore received calcitriol and oral calcium supplements. Alendronate was discontinued. Phosphate binder use was stopped upon normalization of phosphate levels. The patient reported no improvement in the frequency or intensity of itching at the end of the long dialysis interval after parathyroidectomy. At the time of writing (September 2024), she is still receiving difelikefalin at the initial dose to control her pruritus without experiencing adverse effects. The patient still has residual kidney function with no need for ultrafiltration to maintain euvolemia.\u003c/p\u003e "},{"header":"Discussion and Conclusions","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003cp\u003eThis is the case of a patient with a complex interplay of morbidities, most notably diabetes mellitus type 2, tertiary hyperparathyroidism, ESRD, and CKD-associated mineral bone disease (CKD-MBD). There is evidence that all of these morbidities are associated with the development and severity of CKD-aP.\u003csup\u003e5, 23\u0026ndash;26\u003c/sup\u003e In a cohort study of 1951 non-dialysis CKD patients, diabetes, elevated serum iPTH, and reduced eGFR \u0026ndash; among other factors \u0026ndash; were associated with a higher risk of developing CKD-aP. An incremental reduction of eGFR of 10 mL/min per 1.73 m\u003csup\u003e2\u003c/sup\u003e was associated with a hazard ratio (HR) for CKD-aP of 1.16 (95% confidence interval [CI]: 1.10 to 1.23). Serum phosphate was not associated with incident CKD-aP, while low serum calcium (\u0026lt;\u0026thinsp;9 mg/dL) correlated with a reduced incidence of CKD-aP.\u003csup\u003e4\u003c/sup\u003e A recent cross-sectional study of 6221 patients also found that diabetes, as well as elevated phosphate and iPTH levels significantly correlated with higher CKD-aP disease severity.\u003csup\u003e27\u003c/sup\u003e An Austrian Dialysis and Transplant Registry analysis found that a CRP or iPTH level above the sample median (CRP\u0026thinsp;\u0026gt;\u0026thinsp;0.5 mg/dL; iPTH\u0026thinsp;\u0026gt;\u0026thinsp;300.5 pg/mL) was associated with more severe pruritus (CRP: odds ratio [OR] 1.61, 95% CI: 1.07\u0026ndash;2.43; PTH: OR 1.50, 95% CI: 1.00\u0026ndash;2.27). Absolute serum calcium above the cohort mean (\u0026gt;\u0026thinsp;8.63 mg/dL) was associated with a lower risk for moderate-to-severe pruritus (OR 0.62, 95% CI: 0.41\u0026ndash;0.93), but statistical significance was lost when calcium values were corrected for serum albumin. Serum phosphate above the cohort mean (\u0026gt;\u0026thinsp;5.53 mg/dL) was not significantly associated with an increased risk of moderate-to-severe pruritus (odds ratio [OR] 1.19, 95% CI: 0.79\u0026ndash;1.78, p\u0026thinsp;=\u0026thinsp;0.433).\u003csup\u003e3\u003c/sup\u003e An association between elevated iPTH levels and CKD-aP severity was also found in other studies.\u003csup\u003e5, 24\u0026ndash;26\u003c/sup\u003e Disappearance of uremic pruritus after parathyroidectomy has already been described in the 1960s\u003csup\u003e28, 29\u003c/sup\u003e and was later confirmed in a study by Chou et al.\u003csup\u003e30\u003c/sup\u003e in patients with pruritus and secondary hyperparathyroidism.\u003c/p\u003e \u003cp\u003eHowever, there is also evidence indicating a lack of correlation between CKD-MBD and pruritus. DOPPS found no association between CKD-aP severity and levels of iPTH, calcium or phosphate.\u003csup\u003e31\u003c/sup\u003e In the phase 3 KALM-1 and KALM-2 trials of difelikefalin, serum phosphate levels did neither correlate with CKD-aP severity nor with response to difelikefalin.\u003csup\u003e19, 21\u003c/sup\u003e Local injection of PTH into the skin of dialysis patients also did not induce pruritus at the injection site.\u003csup\u003e32\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe presented patient had persistently high levels of iPTH, alkaline phosphatase, phosphate, CRP, and creatinine, all of which further deteriorated when kidney function worsened in the spring and early summer of 2021 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Around this time, the patient first noticed pruritus symptoms. When hemodialysis started in 02/2022, pruritus symptoms worsened, and the patient quickly required specific treatment for CKD-aP upon the appearance of severe scratch marks. The patient\u0026rsquo;s pruritus did, however, not improve substantially using H\u003csub\u003e1\u003c/sub\u003e-receptor antagonists and subsequently gabapentin. Therefore, treatment with difelikefalin was initiated and symptoms quickly and sustainedly improved. However, after each long interdialytic interval, a recurrence of the itch was observed, owing to the mean half-life of difelikefalin of 38 hours in hemodialysis patients.\u003csup\u003e33\u003c/sup\u003e At the time of writing, the duration of difelikefalin treatment is now more than two years with no notable adverse effects apart from a short and mild episode of vertigo at the time of initiation. Parathyroidectomy, followed by a substantial decrease in iPTH levels, did not alleviate pruritus symptoms.\u003c/p\u003e \u003cp\u003eIt was hypothesized that overstimulation of central mu-opioid receptors, antagonism of peripheral kappa-opioid receptors, or an imbalance of stimulation and antagonism of mu- and kappa opioid receptors causes itching.\u003csup\u003e18, 34, 35\u003c/sup\u003e The mechanism of action of difelikefalin via the kappa opioid receptor\u003csup\u003e12, 18\u003c/sup\u003e is thus directed at a mechanism of itch sensation that is independent of the comorbidities present in the patient, notably diabetes mellitus type 2, tertiary hyperparathyroidism, ESRD, and CKD-MBD. This may explain the sustained effectiveness of difelikefalin throughout the patient\u0026rsquo;s complex clinical history.\u003c/p\u003e \u003cp\u003eIn conclusion, this patient case shows the sustained effectiveness of difelikefalin in a complex patient with multiple relevant comorbidities affecting the occurrence and severity of CKD-aP. Difelikefalin acts via a pathway independent of CKD-associated causes of pruritus, such as elevated iPTH, calcium, CRP, and possibly phosphate, and thus seems to be able to sustain its effectiveness despite recurring deteriorations of these parameters.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCI confidence interval\u003c/p\u003e \u003cp\u003eCKD-aP chronic kidney disease-associated pruritus\u003c/p\u003e \u003cp\u003eCKD-MBD chronic kidney disease-associated mineral bone disease\u003c/p\u003e \u003cp\u003eDOPPS Dialysis Outcomes and Practice Patterns Study\u003c/p\u003e \u003cp\u003eDXA dual-energy X-ray absorptiometry\u003c/p\u003e \u003cp\u003eESRD end-stage renal disease\u003c/p\u003e \u003cp\u003eiPTH intact parathyroid hormone\u003c/p\u003e \u003cp\u003eMDRD Modification of Diet in Renal Disease\u003c/p\u003e \u003cp\u003eMIBI methoxy-isobutyl-isonitrile\u003c/p\u003e \u003cp\u003eSADS self-assessed disease severity\u003c/p\u003e \u003cp\u003eWI-NRS worst-itch numerical rating scale\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval is not required for this report of a patient treated in clinical practice according with national guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a report of a patient treated in routine clinical practice and data not included in this article are protected by physician-patient privilege and subject to the patient\u0026rsquo;s consent to making it available. Further enquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJW has received speaker honoraria from CSL Vifor. MH has received consultancy fees from CSL Vifor.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors did not receive funding for the preparation of this case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors comply with the ICMJE criteria of authorship, have substantially contributed the acquisition and interpretation of data for the work; reviewed the work critically for important intellectual content; and provided final approval of the version to be published. The authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSukul N, Karaboyas A, Csomor PA, et al. Self-reported Pruritus and Clinical, Dialysis-Related, and Patient-Reported Outcomes in Hemodialysis Patients. \u003cem\u003eKidney Medicine\u003c/em\u003e 2021; 3: 42-53.e41. DOI: 10.1016/j.xkme.2020.08.011.\u003c/li\u003e\n\u003cli\u003eSukul N, Zhao J, Pisoni RL, et al. Pruritus in Hemodialysis Patients: Longitudinal Associations With Clinical and Patient-Reported Outcomes. \u003cem\u003eAmerican Journal of Kidney Diseases\u003c/em\u003e. DOI: 10.1053/j.ajkd.2023.04.008.\u003c/li\u003e\n\u003cli\u003eEngler F, Kerschbaum J, Keller F, et al. 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Mai 2023).\u003c/li\u003e\n\u003cli\u003eShirazian S, Aina O, Park Y, et al. Chronic kidney disease-associated pruritus: impact on quality of life and current management challenges. \u003cem\u003eInt J Nephrol Renovasc Dis\u003c/em\u003e 2017; 10: 11-26. 20170123. DOI: 10.2147/IJNRD.S108045.\u003c/li\u003e\n\u003cli\u003eMathur VS, Lindberg J, Germain M, et al. A longitudinal study of uremic pruritus in hemodialysis patients. \u003cem\u003eClinical journal of the American Society of Nephrology : CJASN\u003c/em\u003e 2010; 5: 1410-1419. 2010/06/19. DOI: 10.2215/cjn.00100110.\u003c/li\u003e\n\u003cli\u003eMettang T and Kremer AE. Uremic pruritus. \u003cem\u003eKidney Int\u003c/em\u003e 2015; 87: 685-691. 20140108. DOI: 10.1038/ki.2013.454.\u003c/li\u003e\n\u003cli\u003eAgarwal R, Burton J, Gallieni M, et al. 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Chronic Kidney Disease-Associated Pruritus. \u003cem\u003eToxins\u003c/em\u003e 2021; 13: 527.\u003c/li\u003e\n\u003cli\u003eIshida JH, McCulloch CE, Steinman MA, et al. Gabapentin and Pregabalin Use and Association with Adverse Outcomes among Hemodialysis Patients. \u003cem\u003eJ Am Soc Nephrol\u003c/em\u003e 2018; 29: 1970-1978. 20180605. DOI: 10.1681/ASN.2018010096.\u003c/li\u003e\n\u003cli\u003eEuropean Medicines Agency. Kapruvia - Summary of Product Characteristics, https://www.ema.europa.eu/en/documents/product-information/kapruvia-epar-product-information_en.pdf (2022, accessed 09 November 2023).\u003c/li\u003e\n\u003cli\u003eFishbane S, Jamal A, Munera C, et al. A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus. \u003cem\u003eN Engl J Med\u003c/em\u003e 2020; 382: 222-232. 2019/11/09. DOI: 10.1056/NEJMoa1912770.\u003c/li\u003e\n\u003cli\u003eWooldridge T, Mccafferty K, Schoemig M, et al. Efficacy and safety of difelikefalin for moderate-to-severe chronic kidney disease\u0026ndash;associated pruritus: a global phase 3 study in hemodialysis patients (KALM-2). In: \u003cem\u003eAnnual Meeting of the American Society of Nephrology \u003c/em\u003e2020.\u003c/li\u003e\n\u003cli\u003eTopf J, Wooldridge T, McCafferty K, et al. Efficacy of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis of KALM-1 and KALM-2 Phase 3 Studies. \u003cem\u003eKidney Med\u003c/em\u003e 2022; 4: 100512. 20220628. DOI: 10.1016/j.xkme.2022.100512.\u003c/li\u003e\n\u003cli\u003eBilezikian JP, Khan AA, Potts JT, Jr. and Third International Workshop on the Management of Asymptomatic Primary H. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. \u003cem\u003eJ Clin Endocrinol Metab\u003c/em\u003e 2009; 94: 335-339. DOI: 10.1210/jc.2008-1763.\u003c/li\u003e\n\u003cli\u003ePisoni RL, Wikstr\u0026ouml;m B, Elder SJ, et al. Pruritus in haemodialysis patients: international results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). \u003cem\u003eNephrology Dialysis Transplantation\u003c/em\u003e 2006; 21: 3495-3505. DOI: 10.1093/ndt/gfl461.\u003c/li\u003e\n\u003cli\u003eZhao J-H, Zhu Q-S, Li Y-W and Wang L-L. Determinants of the intensity of uremic pruritus in patients receiving maintenance hemodialysis: A cross-sectional study. \u003cem\u003ePLOS ONE\u003c/em\u003e 2021; 16: e0245370. DOI: 10.1371/journal.pone.0245370.\u003c/li\u003e\n\u003cli\u003eRamakrishnan K, Bond TC, Claxton A, et al. Clinical characteristics and outcomes of end-stage renal disease patients with self-reported pruritus symptoms. \u003cem\u003eInt J Nephrol Renovasc Dis\u003c/em\u003e 2013; 7: 1-12. 2014/01/01. DOI: 10.2147/IJNRD.S52985.\u003c/li\u003e\n\u003cli\u003eWeisshaar E, Weiss M, Passlick-Deetjen J, et al. Laboratory and dialysis characteristics in hemodialysis patients suffering from chronic itch - results from a representative cross-sectional study. \u003cem\u003eBMC nephrology\u003c/em\u003e 2015; 16: 184. DOI: 10.1186/s12882-015-0177-3.\u003c/li\u003e\n\u003cli\u003eTitapiccolo JI, Lonati C, Goethel-Paal B, et al. Chronic kidney disease-associated pruritus (CKD-aP) is associated with worse quality of life and increased healthcare utilization among dialysis patients. \u003cem\u003eQual Life Res\u003c/em\u003e 2023; 32: 2939-2950. 20230603. DOI: 10.1007/s11136-023-03438-6.\u003c/li\u003e\n\u003cli\u003eKleeman CR, Massry SG, Popovtzer MM, et al. The disappearance of intractable pruritus after parathyroidectomy in uremic patients with secondary hyperparathyroidism. \u003cem\u003eTrans Assoc Am Physicians\u003c/em\u003e 1968; 81: 203-212.\u003c/li\u003e\n\u003cli\u003eMassry SG, Popovtzer MM, Coburn JW, et al. Intractable pruritus as a manifestation of secondary hyperparathyroidism in uremia. Disappearance of itching after subtotal parathyroidectomy. \u003cem\u003eThe New England journal of medicine\u003c/em\u003e 1968; 279: 697-700. DOI: 10.1056/NEJM196809262791308.\u003c/li\u003e\n\u003cli\u003eChou FF, Ho JC, Huang SC and Sheen-Chen SM. A study on pruritus after parathyroidectomy for secondary hyperparathyroidism. \u003cem\u003eJ Am Coll Surg\u003c/em\u003e 2000; 190: 65-70. DOI: 10.1016/s1072-7515(99)00212-4.\u003c/li\u003e\n\u003cli\u003eRayner HC, Larkina M, Wang M, et al. International Comparisons of Prevalence, Awareness, and Treatment of Pruritus in People on Hemodialysis. \u003cem\u003eClinical Journal of the American Society of Nephrology\u003c/em\u003e 2017; 12: 2000-2007. DOI: 10.2215/cjn.03280317.\u003c/li\u003e\n\u003cli\u003eStahle-Backdahl M, Hagermark O, Lins LE, et al. Experimental and immunohistochemical studies on the possible role of parathyroid hormone in uraemic pruritus. \u003cem\u003eJournal of internal medicine\u003c/em\u003e 1989; 225: 411-415. DOI: 10.1111/j.1365-2796.1989.tb00104.x.\u003c/li\u003e\n\u003cli\u003eStark JG, Noonan PK, Spencer RH, et al. Pharmacokinetics, Metabolism, and Excretion of Intravenous [14C]Difelikefalin in Healthy Subjects and Subjects on Hemodialysis. \u003cem\u003eClinical pharmacokinetics\u003c/em\u003e 2023; 62: 1231-1241. DOI: 10.1007/s40262-023-01262-2.\u003c/li\u003e\n\u003cli\u003eTey HL and Yosipovitch G. Targeted treatment of pruritus: a look into the future. \u003cem\u003eBritish Journal of Dermatology\u003c/em\u003e 2011; 165: 5-17. DOI: 10.1111/j.1365-2133.2011.10217.x.\u003c/li\u003e\n\u003cli\u003eCowan A, Kehner GB and Inan S. Targeting itch with ligands selective for \u0026kappa; opioid receptors. \u003cem\u003eHandb Exp Pharmacol\u003c/em\u003e 2015; 226: 291-314. DOI: 10.1007/978-3-662-44605-8_16.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Chronic kidney disease, difelikefalin, uremic pruritus, hyperparathyroidism, case report","lastPublishedDoi":"10.21203/rs.3.rs-5158635/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5158635/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eChronic kidney disease-associated pruritus (CKD-aP) is a frequently experienced, unpleasant skin condition. Difelikefalin is indicated for the treatment of moderate-to-severe CKD-aP in adult patients on hemodialysis. Reports of difelikefalin effectiveness in complex patient cases encountered in routine clinical practice are rare.\u003c/p\u003e\u003ch2\u003eCase presentation\u003c/h2\u003e \u003cp\u003eThe presented patient had a complex interplay of morbidities, most notably diabetes mellitus type 2, tertiary hyperparathyroidism, end-stage renal disease (ESRD), and CKD-associated mineral bone disease (CKD-MBD), all of which are associated with the development and severity of CKD-aP. The patient\u0026rsquo;s CKD-aP proved resistant to H\u003csub\u003e1\u003c/sub\u003e-receptor antagonists and gabapentin and showed no improvement after parathyroidectomy. Treatment with difelikefalin rapidly and sustainedly improved symptoms, with a brief recurrence of itch towards the end of each long interdialytic interval. Apart from a short episode of vertigo at initiation of treatment, no adverse events were observed over the long duration of treatment (more than two years).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eDifelikefalin, an agonist of the kappa opioid receptor, acts independently of the itch-causing mechanisms associated with the comorbidities present in the patient, notably diabetes mellitus type 2, tertiary hyperparathyroidism, ESRD, and CKD-MBD. This may explain the sustained effectiveness of difelikefalin throughout the patient\u0026rsquo;s complex clinical history.\u003c/p\u003e","manuscriptTitle":"Successful difelikefalin use in severe chronic kidney disease-associated pruritus in a patient with tertiary hyperparathyroidism: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-02 15:24:10","doi":"10.21203/rs.3.rs-5158635/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"01913635-e194-4f8b-875c-684d5fb00710","owner":[],"postedDate":"October 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":38238454,"name":"Urology \u0026 Nephrology"}],"tags":[],"updatedAt":"2026-01-08T19:44:32+00:00","versionOfRecord":{"articleIdentity":"rs-5158635","link":"https://doi.org/10.1155/crin/6626611","journal":{"identity":"case-reports-in-nephrology","isVorOnly":true,"title":"Case Reports in Nephrology"},"publishedOn":"2025-02-25 00:00:00","publishedOnDateReadable":"February 25th, 2025"},"versionCreatedAt":"2024-10-02 15:24:10","video":"","vorDoi":"10.1155/crin/6626611","vorDoiUrl":"https://doi.org/10.1155/crin/6626611","workflowStages":[]},"version":"v1","identity":"rs-5158635","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5158635","identity":"rs-5158635","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}