Inflammation and pruritus in haemodialysis patients
Giovambattista Virga1,,
Ivana Visentin2,
Vincenzo La Milia3 and
Antonio Bonadonna1
1 Nephrology and Dialysis Unit and
2 Laboratory, Provincial Hospital, Camposampiero, Padova and
3 Nephrology and Dialysis Unit, Provincial Hospital, Lecco, Italy
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Abstract
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Background. Pruritus is a common symptom among patients on haemodialysis (HD). We studied 68 HD patients to assess the role of iron deficiency, anaemia, inflammation and other common serum and dialysis parameters in pruritus.
Methods. The patients were questioned about the occurrence of pruritus at home, quantified according to frequency (never, occasionally and every day) and intensity (absent, moderate and severe). The blood and serum variables considered were: haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, hypochromic red blood cells (RBC), hyperchromic RBC, microcytic RBC, macrocytic RBC, reticulocytes, iron, ferritin, transferrin, transferrin saturation, C-reactive protein (CRP), urea, creatinine, calcium, phosphorus, albumin, total protein and glucose. We also analysed Kt/V, age and time on HD treatment. Patients were divided into 3 groups according to the frequency or intensity of their pruritus, and we analysed and compared the variables between the 3 groups.
Results. Half (50%) of the patients reported never having pruritus, 32.4% occasionally and 17.6% every day. Pruritus was moderate in 41.2% of them and severe in 8.8%. None of the parameters considered revealed any statistically relevant differences between the three pruritus frequency groups, except for mean serum transferrin level (mg/dl) (never=268±64 vs occasionally=244±40 vs every day=217±56, P<0.05). As for the intensity of the symptom, mean serum transferrin (268±64 vs 247±39 vs 174±31, P<0.001) and median ferritin levels (mg/dl) (83 (11420) vs 98 (111121) vs 293 (111471), P<0.05) showed statistically significant differences between the 3 groups, as did albumin levels (g/dl) (4.3±0.4 vs 4.2±0.4 vs 3.7±0.4, P<0.05). Median CRP values (mg/dl) tended to be higher in patients with more frequent (0.4 (0.35.5) vs 0.7 (0.311.4) vs 0.9 (0.313.5)) and more severe pruritus (0.4 (0.35.5) vs 0.7 (0.34.0) vs 2.1 (0.313.5)), but those differences were not statistically significant.
Conclusions. Iron deficiency and anaemia seem to play no part in HD-related pruritus, whereas lower serum transferrin and albumin levels and higher ferritin values are consistent with the possible role of inflammation in the development and severity of pruritus.
Keywords: haemodialysis; inflammation; iron; itching; pruritus; transferrin
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Introduction
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Pruritus is an unpleasant cutaneous sensation prompting a desire to scratch. It is a common and disturbing symptom among patients on haemodialysis (HD). The percentage of HD patients suffering from pruritus reportedly is higher than 50% [1].
Many different metabolic disorders, frequently associated with uraemia, are thought to coincide with the onset of pruritus in HD, but its aetiology still remains obscure. Parathormone was initially implicated in causing pruritus [2], but was subsequently found not to be involved [1,3]. The theory of altered bivalent ion metabolism, i.e. hypercalcaemia and hyperphosphoraemia [2], was not confirmed [1,3]. Other agents have been held responsible for uraemic pruritus, e.g. histamine [4] and serum bile acids [3], as have certain clinical conditions, such as iron-deficiency anaemia [5]. A relationship between dialysis adequacy and pruritus has been claimed in some studies [1] and rejected in others [3].
Apart from uraemia, many conditions (e.g. diabetes, thyrotoxicosis, liver diseases and malignant tumours) can cause pruritus, and among the haematological disorders, pruritus is common in patients affected by polycythaemia vera and iron-deficiency anaemia [6].
We studied our HD patients to assess the role of iron deficiency, anaemia, inflammation and other common serum and dialysis adequacy parameters in pruritus (deliberately disregarding aspects concerning different membranes and techniques).
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Subjects and methods
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Patients
All patients on HD at our centre (Nephrology and Dialysis Unit, Camposampiero) (n=71) were included in a cross-sectional study, but three were subsequently excluded due to oligophrenia (n=1), schizophrenia (n=1) and absence from the centre at the time of the study (n=1). The characteristics of our patient population are summarized in Table 1
. All patients underwent HD three times a week. The median duration of the HD sessions was 4.0 h (2.754.00). Five of the patients were diabetic. No patients presented with defined skin lesions such as psoriasis or atopic dermatitis.
Symptoms
The patients were questioned, by the same nephrologist, if they had pruritus during the previous 2 weeks. The symptoms were quantified according to frequency, using three possible answers (never, occasionally and every day), and according to intensity (absent, moderate and severe). No visual analog scale (VAS) was used in this study, since our aim was to consider only the subjective awareness of the symptom.
Variables
The patients' symptoms were recorded immediately before a mid-week HD session, while a blood sample was being taken. The following anaemia- and iron-related blood variables were considered: haemoglobin (Hb) (g/dl), haematocrit (Hct) (%), mean corpuscular volume (MCV) (µ3), mean corpuscular haemoglobin (MCH) (pg), mean corpuscular haemoglobin concentration (MCHC) (g/dl), hypochromic red cells (RBC) (%), hyperchromic RBC (%), microcytic RBC (%), macrocytic RBC (%), reticulocytes (%), serum iron (mg/dl), ferritin (mg/dl), transferrin (mg/dl) and transferrin saturation (TSAT) (%).
Other serum parameters considered were: C-reactive protein (CRP) (mg/dl), urea (mg/dl), creatinine (mg/dl), calcium (mg/dl), phosphorus (mg/dl), albumin (g/dl), total protein (g/dl) and glucose (mg/dl). We also recorded and analysed Kt/V, calculated according to Daugirdas' formula [7], age (years) and time on HD treatment (months).
Statistical analysis
Patients were divided into 3 groups according to the frequency or intensity of their pruritus, and we analysed the variables for differences between the 3 groups. Continuous variables were expressed as means±SD or as median values (range) if the distribution was not Gaussian. One-way ANOVA or the KruskalWallis rank test was used to evaluate differences between variables. Distribution normality was assessed by the KolmogorovSmirnov test. The null hypothesis was rejected for all tests with two-tailed alpha values of <0.05. The JMP 5.01 (SAS, Cary, NC, USA) software was used on Macintosh (Apple, Cupertino, CA, USA) hardware.
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Results
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Half of our patients (n=34) reported never having pruritus, 32.4% (n=22) had it occasionally and 17.6% (n=12) every day. Pruritus was moderate in 41.2% (n=28) of the patients who had the symptoms and severe in 8.8% (n=6).
The values for the parameters related to iron deficiency, e.g. iron, TSAT or hypochromicity of RBC, did not differ between patients with different frequency or intensity of pruritus (Tables 2
and 3
).
Ferritin was higher in patients with more severe pruritus, showing a statistically significant relationship with symptom intensity (Tables 2
and 3
, Figures 1
and 2
). These results do not seem to support an association between iron deficiency and pruritus.

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Fig. 1. Mean and median values of serum transferrin (mg/dl, left column) and ferritin (mg/dl, right column) in HD patients according to frequency of pruritus.
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Fig. 2. Mean and median values of serum transferrin (mg/dl, left column) and ferritin (mg/dl, right column) in HD patients according to severity of pruritus.
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Lower serum transferrin levels were found in patients with more frequent or more intense pruritus (Tables 2
and 3
, Figures 1
and 2
). Lower serum albumin values were found in patients with more severe pruritus (Tables 4
and 5
, Figure 3
).
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Table 4. Comparison of frequency of pruritus in HD patients in relation to parameters other than anaemia and iron status
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Table 5. Comparison of intensity of pruritus between HD patients in relation to parameters other than anaemia and iron status
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Median CRP values showed an upward trend in patients with more frequent and more severe pruritus, but did not reach statistical significance (P=0.11 and 0.057, respectively) (Tables 2
and 3
, Figure 4
).

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Fig. 4. Median values of serum CRP in HD patients according to frequency and intensity of pruritus. The thick black line represents the normal CRP value (<0.6 mg/dl).
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Discussion
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The aetiology and pathophysiology of pruritus in patients on HD are poorly understood. One of the most interesting of the numerous theories advanced on the process underlying pruritus is the histamine hypothesis' [4]. However, the improvement of pruritus in several of our HD patients receiving iron therapy prompted the suggestion that iron deficiency may directly affect uraemic pruritus.
Iron deficiency is a well-known cause of pruritus and skin inflammation [8], and hypochromic anaemia has been demonstrated to cause pruritus in non-uraemic patients [6].
Iron deficiency may be absolute or functional. The former occurs when body iron stores are depleted; in the latter, iron stores are abundant but the iron is not supplied to the marrow or used in erythropoiesis.
How to assess iron deficiency in HD patients still is a matter of debate and a combination of serum ferritin, TSAT and the hypochromic portion of RBC has been suggested as a measure [9]. Our findings relating to serum iron, TSAT, ferritin and the hypochromic RBC fraction seem to disprove the role of iron deficiency in the frequency and intensity of itching. Serum iron has a low specificity in diagnosing iron deficiency in HD patients, however, and only reduced serum ferritin provides unequivocal evidence of diminished iron stores (absolute deficiency). The reliability of TSAT in assessing absolute iron deficiency is still under discussion. The role of a functional iron deficiency in the development of pruritus in HD patients could be an interesting topic for research, because it is associated with the inflammatory status, though this is difficult to demonstrate (or measure).
Anaemia was proven by us to have no direct link with pruritus. The absence of any connection between pruritus and many common biochemical markers or patient age and time on HD treatment is hardly surprising, for the same finding has already been reported in many other papers [1,3,4].
Our results point to a role of inflammation in the development and severity of pruritus in HD patients. The statistically relevant differences in transferrin, ferritin and albumin levels between patients with more or less intense pruritus would suggest a relationship between inflammatory status and severity of pruritus.
The finding of an inverse relationship between pruritus and serum transferrin levels has not been reported before, nor has its link with other parameters relating to inflammation, such as serum albumin and ferritin. We found lower and lower mean serum transferrin levels corresponding to more frequent and more severe pruritus, suggesting that a biochemical phenomenon leading to a drop in transferrin may be involved in HD-related pruritus. We also found a trend towards higher CRP values in patients with increased frequency and severity of pruritus, though it failed to reach statistical significance.
All these aspects are consistent with a possible role of inflammation in the HD patients' pruritus. In fact, transferrin is a protein that invariably decreases with the acute-phase response [10], serum albumin is closely related to the systemic inflammatory response [11] and ferritin is a prominent positive acute-phase reactant [10]. Inflammation in HD patients can be induced by pathological conditions, e.g. infections and tumours. Biochemically, it can be generated by complement activation and cytokine release, effects also associated with bloodmembrane contact, that is between the blood cells and the artificial dialysis membrane [12]. Dermatological studies have demonstrated that an intradermal injection of complement activating products or cytokines induces local itching [13,14]. Among these factors, the most likely culprit is interleukin-2 (IL-2), which is secreted by activated T helper cells type 1 (Th1) [15]. In fact, ultraviolet phototherapy, which attenuates Th1 expression [16], is accompanied by relief of uraemic pruritus [17] and drugs such as thalidomide, which suppresses IL-2 production [18], are quite effective in the treatment of itching [19]. The hypothesis concerning the contributory role of histamine in the genesis of pruritus [4] may not necessarily be inconsistent with the possible influence of an inflammatory status, since histamine is also actively secreted by platelets in response to inflammatory stimuli [20]. If the contribution of inflammation to pruritus is confirmed, therapy with an anti-inflammatory agent may be warranted.
In conclusion, our results suggest that iron deficiency and anaemia play no part in HD-related pruritus, whereas our finding of more severe pruritus associated with low serum transferrin and albumin and high ferritin levels is consistent with a possible role of inflammation in the development and severity of pruritus. The intrinsic pathophysiological mechanism behind pruritus in HD patients requires further study.
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Notes
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Correspondence and offprint requests to: Dr Giovambattista Virga, Via Ongarello 8, Camposampiero, I-351128 Padova, Italy. Email: g.virga{at}iperv.it 
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Received for publication: 12.12.01
Revision received 10. 7.02.