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

doi:10.21203/rs.3.rs-5158635/v1

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Case Report

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

https://doi.org/10.21203/rs.3.rs-5158635/v1

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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 H₁-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

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 pruritus¹ 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, H₁-receptor antagonist and gabapentin refractory CKD-aP, tertiary hyperparathyroidism and associated bone disease, who showed rapid and sustained response to treatment with difelikefalin.

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 m² 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. H₁-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.

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 m² 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 H₁-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.

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

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. 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.

Acknowledgements

Not applicable.

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The authors declare potential competing interests as follows: JW has received speaker honoraria from CSL Vifor. MH has received consultancy fees from CSL Vifor.

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

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