Beyond CKD-Associated Pruritus: Paraneoplastic Itch Revealing CLL/SLL in ESRD: A Case Report

Introduction

Pruritus serves as a physiological defense mechanism against harmful and dangerous environmental factors [1–4]. Itching-related signals are transmitted by neurons and can originate in either the central or peripheral nervous system, ultimately reaching the free nerve endings in the skin, triggering an intense urge to rub or scratch the affected area to achieve relief [5,6]. The itch–scratch cycle, besides its well-documented contribution to cutaneous damage, is a distressing symptom negatively affecting quality of life (QoL) [4,7–10]. While transient pruritus is a common sensory experience in the general population, chronic or pathological itching is frequently associated with dermatologic conditions, such as atopic dermatitis and eczema, as well as systemic disorders involving metabolic, immunological, or endocrine dysregulation [10,11].

Chronic kidney disease-associated pruritus (CKD-aP) is a clinical diagnosis with 58–90% prevalence in patients undergoing chronic renal replacement therapy (RRT) [2,12,13]. Moderate-to-severe pruritus is expected to affect 40–55% of hemodialysis (HD) patients and 56% of those treated by peritoneal dialysis (PD) [12–14]. In patients undergoing dialysis, pruritus may arise either from uremia, hyperphosphatemia, and inflammation, or from the chronic dryness of the skin characteristic of chronic kidney disease (CKD) [7,15].

Although CKD-aP is the most common cause of chronic itch in dialysis patients, persistent, treatment-resistant pruritus – particularly when hematologic abnormalities are present – should raise the suspicion of potential systemic or paraneoplastic etiologies.

Our patient’s chronic pruritus had no clear renal etiology. Initially, it was managed as an idiopathic pruritus by a dermatologist for over a year. Chronic lymphocytic leukemia manifesting primarily as refractory pruritus in peritoneal dialysis patients is exceedingly rare, and only sporadic case reports have suggested an association; there remains no established guidance for evaluating pruritus as a paraneoplastic phenomenon in this population. During routine hematological evaluations related to dialysis management, lymphopenia was incidentally identified, prompting further investigation and ultimately leading to a hematological consultation, thus hastening the diagnostic process.

Paraneoplastic pruritus can precede a malignancy diagnosis by weeks to months, as lymphoma-associated itching has been reported in up to 30% of patients and can be an early warning sign. Reviews also document that malignancy-related pruritus often lacks primary skin lesions, aligning with our patient’s presentation.

By discussing this unusual presentation, we propose that pruritus refractory to standard treatments in dialysis patients – especially when combined with pancytopenia – should be integrated into future diagnostic algorithms and clinical guidelines, ensuring earlier hematologic evaluation and timely intervention.

Case Report

A 66-year-old man with stage 5 CKD of idiopathic origin, supported exclusively on PD as his primary RRT for the past 6 months, presented with gradual worsening of symptoms.

He had a history of obesity (BMI: 31 kg/m2) and asymptomatic gallstones, diagnosed incidentally via abdominal ultrasonography with no scheduled cholecystectomy. He also had secondary hyperparathyroidism with parathyroid hormone (PTH) level of 25.5 pmol/L (normal range 1.6–6.9 pmol/L), consistent with prolonged renal dysfunction. A comprehensive diagnostic workup conducted prior to and following PD catheter insertion (performed in June 2020) revealed mild anemia, mild neutrophilia and eosinophilia, hypoproteinemia, and hypogammaglobulinemia. Abdominal ultrasonography showed no significant abnormalities, and the dialysis dose appeared to be sufficient.

Six months after peritoneal dialysis initiation, he developed persistent pruritus, primarily affecting the extremities. The most pronounced excoriations – linear, erythematous lesions predominantly affecting the calves – are shown in Figure 1.

Laboratory tests at that time revealed that urea and phosphate levels were within the expected range for a dialysis patient, thus ruling out chronic kidney disease-associated pruritus (CKD-aP). A dermatological evaluation led to a diagnosis of idiopathic pruritus, initially managed with dermocosmetics and antihistamines, but these provided only temporary relief. At no point was a primary dermatologic rash identified, supporting the notion that the itch was systemic in nature. Initially, it remained localized to the calves and arms, but eventually spread to involve the trunk and back, becoming generalized. As symptoms persisted, vascular assessments were performed, only to rule out venous insufficiency. Differential diagnoses considered at this stage included cholestasis, peripheral neuropathy, and metabolic pruritus, all of which were ruled out based on liver function tests, neurological examination, and adequate dialysis parameters, respectively. Over time, the pruritus worsened, coinciding with the onset of fatigue and lower-limb edema, complicating the clinical picture. Figure 2 illustrates the chronological appearance of the symptoms.

November 2021: The patient contracted moderate COVID-19, treated outside our center with systemic steroids (methylprednisolone, 16 mg twice daily). His pruritus temporarily subsided during this period but reoccurred shortly after steroid discontinuation.

April 2022: Given the symptom worsening, initial dermatology treatment was intensified with oral methylprednisolone (16 mg twice daily) and rupatadine (10 mg daily), offering partial symptom control. However, the underlying cause remained unclear, necessitating further diagnostic evaluation.

June 2021–July 2022: At that time, leukopenia was noted and initially attributed to viral infection following the patient’s COVID-19 illness. However, the prolonged period of leukopenia raised concern for an underlying hematologic disorder.

July 2022 – Kidney Transplant Evaluation: As part of the patient’s pre-transplant assessment, abdominal ultrasonography was performed, revealing splenomegaly and free fluid in the peritoneal cavity. These findings, combined with concurrent leukopenia, thrombocytopenia, and palpable subclavicular lymphadenopathy, prompted further hematological assessment. A follow-up CT confirmed generalized lymphadenopathy and hepatosplenomegaly, leading to temporary disqualification from transplant candidacy pending further diagnostic workup.

October 2023: The patient was admitted with progressive gastrointestinal symptoms, including anorexia, nausea, dyspepsia, and early satiety. X-ray imaging showed mediastinal widening and abdominal lymphadenopathy. CT scans (Figure 3) confirmed the findings.

April 2024: A bone marrow biopsy was performed, revealing >90% infiltration by CD20+, CD23+, CD79+ B cells with weak/focal CD5 expression and no CD34+ blasts. TP53 mutation was not detected, and the IGHV gene was mutated and productive – both markers are associated with a more favorable prognosis. No features of Richter transformation or p53 overexpression were present. Staging at diagnosis was consistent with advanced disease (Rai stage III-IV, Binet stage C), based on generalized lymphadenopathy, hepatosplenomegaly, leukopenia, and thrombocytopenia.

Given the patient’s advanced renal dysfunction and dialysis dependence, the hematology care team determined that initiating standard chemotherapy posed a significant risk of toxicity due to altered drug clearance. Furthermore, active malignancy disqualified the patient from the previously considered renal transplantation. Thus, the decision was made to adopt a supportive management approach with symptomatic treatment, accompanied by close nephrological and hematological monitoring, rather than the targeted therapy.

The patient’s condition evolved over several months, culminating in the identification of hepatosplenomegaly, widespread lymphadenopathy, and a definitive diagnosis of CLL/SLL, as shown in Table 1. To provide further clinical context, Figure 4 illustrates the longitudinal changes in leukocyte count. This case highlights a diagnostically complex and clinically rare presentation of CLL manifesting primarily as pruritus in a dialysis patient – a phenomenon that remains rarely described in the literature. This case underscores the importance of hematologic vigilance in evaluating persistent pruritus and suggests the need for an interdisciplinary approach when symptoms remain unexplained despite appropriate renal management.

Discussion

This case report illustrates a rare and diagnostically challenging presentation of CLL in a patient with ESRD undergoing peritoneal dialysis (PD), initially misattributed to mineral disturbances typical for CKD. While pruritus is a commonly experienced symptom in dialysis patients – reported in up to two-thirds of patients and often attributed to CKD-aP – its persistence despite standard therapy, particularly when accompanied by hematologic abnormalities, should prompt a broader diagnostic evaluation [2,8,10,14,16–18].

In our patient, moderate-to-severe pruritus persisted despite optimized dialysis parameters, topical treatments, and empirical therapy with antihistamines and oral corticosteroids. This clinical course was atypical for CKD-aP, which generally responds to conventional symptom management [3,4,9,15,19]. The concurrent presence of leukopenia and thrombocytopenia further supported the suspicion of an underlying systemic process. In the absence of uremic complications or dialysis inadequacy, these findings warranted investigation for a hematologic malignancy [3,10,17,18].

Although CLL has been described as a potential cause of renal dysfunction or glomerular injury [20–23], it is infrequently reported as the initial cause of pruritus in dialysis patients. A small number of case reports have documented hematologic malignancies presenting with treatment-refractory pruritus. Lelonek et al found that over 50% of patients with another hematological malignancy, polycythemia vera, experienced aquagenic pruritus prior to hematologic diagnosis, reinforcing the notion of pruritus as a possible paraneoplastic signal [24]. Despite increasing awareness of paraneoplastic itch in hematology and dermatology, its presence is rarely prioritized in the differential diagnosis of pruritus among dialysis patients. This may reflect diagnostic anchoring to CKD-aP, particularly in patients with known renal disease.

Our case is further distinguished by the unknown etiology of CKD, the absence of dialysis inadequacy or rash, and the fact that pruritus remained the sole clinical symptom for over a year. To the best of our knowledge, this is the first reported case of biopsy-confirmed CLL/SLL in a dialysis patient presenting with isolated pruritus over an extended period, without constitutional symptoms, lymphadenopathy, or organomegaly at onset.

Pruritus in hematologic malignancies is believed to arise from immune dysregulation, cytokine imbalance – particularly involving interleukins such as IL-6 and IL-31 – and altered neural signaling pathways [7,9,10,18,25,26]. Yosipovitch et al (2010) observed that pruritus preceded lymphoma diagnosis in a significant subset of patients, in some cases by several months [18]. These findings collectively emphasize the potential for itch to be an early, yet underrecognized, paraneoplastic manifestation in systemic disease [25–28].

In our case, the clinical trajectory of persistent pruritus without dermatologic pathology, the gradual appearance of cytopenias, and eventual radiologic evidence of lymphoproliferative disease, highlights the need to reassess persistent idiopathic pruritus in dialysis patients, particularly when hematologic abnormalities co-occur [27,28].

The nonspecific symptomatology and overlap with CKD-aP contributed to the delayed diagnosis of malignancy. Delays were further compounded by COVID-19–related disruptions in nephrology and hematology care, which further impacted specialist referrals and access to imaging [29,30].

In this patient, laboratory abnormalities raised concern, but the diagnosis of CLL was ultimately confirmed only after the pre-transplant imaging revealed hepatosplenomegaly and generalized lymphadenopathy, followed by bone marrow biopsy and immunophenotyping (CD5+, CD19+, and CD23+ clonal B cells). The absence of monoclonal gammopathy or paraproteinemia further supported a lymphoid etiology.

The coexistence of CLL/SLL and ESDR imposed significant therapeutic limitations. Chemotherapy posed a substantial risk of toxicity due to impaired renal clearance [31–33], and active malignancy rendered the patient ineligible for kidney transplantation. Therefore, the therapeutic approach focused on symptom control and multidisciplinary monitoring.

Although novel agents such as difelikefalin or gabapentinoids may provide relief in CKD-aP [4,10,17,19,34–36], their safety in patients with concurrent hematologic malignancies remains uncertain. Our experience underscores the need for further research on supportive care strategies tailored to patients with overlapping renal dysfunction and hematologic malignancy.

The association between CKD and lymphoproliferative disorders warrants further study. ESRD patients exhibit higher rates of monoclonal B-cell lymphocytosis (MBL), likely due to chronic immune activation and impaired B-cell regulation [37–41]. In this case, the absence of a clear cause for CKD raises the possibility that undiagnosed early-stage CLL or MBL may have contributed to the renal decline, although this remains speculative in the absence of renal histopathology [22,37–41].

Notably, no kidney biopsy was performed earlier to assess for leukemic infiltration or immune-mediated glomerular injury in this patient, limiting our ability to establish a definitive causal link between CLL and renal failure in our patient. Nonetheless, CLL/SLL has been reported to affect the kidneys via direct infiltration or paraneoplastic mechanisms [20–22,31,39,42].

Dialysis-related immune dysfunction may have also influenced disease progression, given the altered lymphocyte profiles observed in this population [40,42,43]. Due to the diagnosis of CLL/SLL, close hematologic surveillance was initiated. While observation remains the standard of care for asymptomatic early-stage CLL, patients with ESRD require more frequent assessment for cytopenias, lymphadenopathy, or signs of Richter’s transformation [21,32,33,38,40,44].

From a clinical perspective, our case report recognizes the importance of comprehensive malignancy screening in patients with chronic pruritus of unknown pathology, particularly when systemic symptoms or hematological abnormalities arise. A multidisciplinary diagnostic strategy involving nephrology, dermatology, and hematology could be implemented in chronic dialysis patients with idiopathic generalized pruritus. Future research or guidelines explicitly recognizing paraneoplastic pruritus as a red flag may benefit this unique and high-risk population.

Conclusions

This case report underscores the importance of reassessing presumed CKD-aP in dialysis patients when pruritus is refractory to standard interventions. Hematologic evaluation should be considered in patients with unexplained cytopenias, persistent systemic symptoms, or atypical pruritus patterns. The findings in this case emphasize the potential interplay between CKD and hematologic disorders, raising questions about the role of dialysis-related immune dysfunction in lymphoproliferative disease evolution.