Thomas Mettang

Low-dose intradermal versus intramuscular hepatitis B vaccination in patients with end-stage renal failure : a preliminary study

Patients with end-stage renal disease (ESRD) are at high risk of hepatitis B infection. Only 50-60% of the patients respond adequately to the routinely performed intramuscular (i.m.) hepatitis B vaccination. We examined whether low dose intradermal (i.d.) application of the vaccine is equivalent to regular i.m. administration. Thirty-two patients with ESRD of different etiologies were investigated at the onset of dialysis treatment [11 patients on continuous ambulatory peritoneal dialysis (CAPD) and 21 patients on hemodialysis (HD)]. Patients were vaccinated at month 0, 1, 3 and 6 with either 40 micrograms HBs Ag (2 ml Engerix B, 14 patients) i.m. or with 10 micrograms HBsAg (0.5 ml Engerix B, 18 patients) i.d. The i.m. vaccination was applied in the deltoid muscle, while for i.d. vaccination the vaccine was injected into the skin of the deltoid region. Six weeks after the last vaccination anti-HBs titers were measured. 61% (11 patients) of the patients vaccinated i.d. and 64% (9 patients) of the patients vaccinated i.m. developed protective titers. Neither the height of the titers nor the proportion of patients responding to the vaccination differed significantly between the two vaccination schedules. No difference regarding the height of titers achieved or the rate of seroconversion could be found when CAPD and HD patients were analyzed separately. Only minor side effects have been observed. According to these preliminary data i.d. hepatitis B vaccination in patients with ESRD may be equivalent to i.m. administration of the vaccine. Given equivalency i.d. vaccination may be a cost-saving alternative to i.m. vaccination (only a quarter of the dose of i.m. administered vaccine is needed) with a good practicability (vaccination can be performed during HD) and a low rate of side effects.

Uraemic pruritus and exposure to di(2-ethylhexyl)phthalate (DEHP) in haemodialysis patients

Uraemic pruritus is a frequent and disabling symptom in patients on dialysis. The pathogenesis of uraemic pruritus is nevertheless still obscure. We investigated whether di(2-ethylhexyl)phthalate (DEHP), the most commonly used plasticizer in polyvinylchloride (PVC) haemodialysis tubings, is a possible pathogenetic factor in uraemic pruritus. Serum concentrations of DEHP and its major derivatives mono-(2-ethylhexyl)phthalate (MEHP), 2-ethylhexanol (2-EH) and phthalic acid (PA) were determined in uraemic patients before and after a haemodialysis session and compared with the occurrence and intensity of pruritus in these patients. Twenty-one patients on regular haemodialysis for at least 6 months were examined. The severity of uraemic pruritus was assessed using a standard questionnaire (pruritus score). The quantitative analysis of DEHP and its derivatives was carried out by GC/selected ion monitoring mass spectrometry. Fourteen out of 21 patients (66%) complained about uraemic pruritus to a variable degree. The post-dialysis serum concentrations of DEHP, MEHP and 2-EH were significantly higher than the corresponding pre-dialysis values, whereas the post-dialysis concentrations of PA (0.122 +/- 0.078 microgram/microliter) were significantly lower than pre-dialysis levels (0.194 +/- 0.101 microgram/microliter, P = 0.00068). Neither pre- nor post-dialysis serum concentrations of DEHP, MEHP, PA or 2-EH were correlated with the severity of uraemic pruritus. Additionally, serum concentrations of DEHP and its metabolites did not differ significantly in patients with and without pruritus. These findings suggest that patients on haemodialysis are regularly exposed to considerable amounts of DEHP and metabolites. Phthalic acid, one of the presumed end products of DEHP metabolism, might be eliminated at least in part by haemodialysis. The exposition to DEHP and metabolites during haemodialysis, as assessed by measuring serum concentrations, bears no immediate relation to the occurrence or intensity of uraemic pruritus.

How do nephrologists in haemodialysis units consider the symptom of itch? Results of a survey in Germany

BACKGROUND Despite advances in dialysis treatment of end-stage renal disease, pruritus remains a widespread and distressing concomitant of chronic renal failure. The prevalence of uraemic pruritus (UP) across countries ranges from 10 to 77%. Data from the DOPPS study showed that moderate to severe UP occurs in >40% of patients on haemodialysis. We aimed to provide data on how common and how serious a problem pruritus is as perceived by nephrologists in daily haemodialysis practice. Method. A national cross-sectional survey in 1420 nephrologists assessed information on the number of dialysed patients, gender distribution, perceived prevalence of UP, time-related aspects of UP, characteristics of UP and its association with dialysis and therapy of UP. RESULTS Most respondents reported UP to be prevalent in 1-30% of their patients, and 30% reported an association between UP and dialysis. Seventy-five percent reported an undulating pattern. Nearly half the sample suggested a relationship between quality of dialysis and UP. No substantial differences in recognition and management of UP as a function of organizational affiliation were detected. CONCLUSIONS The prevalence of UP may be underestimated by nephrologists. Large variation in the reported prevalence of UP and the undulating pattern of UP after dialysis may impede the recognition of UP.

A new lactate-based, plasticizer-free, neutral peritoneal dialysis fluid provided in a two-compartment system: effect on peripheral leukocyte function.

Background: A new neutral peritoneal dialysis fluid (PDF; Balance®) provided in a two-compartment bag (pH 7.4, no plasticizers, minimal glucose degradation products – GDP) was investigated in comparison with a neutral control (Hanks’ balanced salt solution with gelatin 0.1%) and other PDFs with standard properties and plasticizers (Andy plus®, pH 5.2, GDP), plasticizer free (stay safe®, pH 5.2, GDP), and in addition plasticizer free after sterile filtration instead of heat sterilization (pH 5.2) regarding the function of peripheral blood leukocytes. Methods: Blood was drawn from 12 volunteers, and blood monocytes (MN) and polymorphonuclear leukocytes (PMNL) were collected. The cells were incubated for 30 min in control medium and the PDFs: glucose 1.5% (83 mmol/l) and 4.25% (238 mmol/l). Respiratory burst of cells was evaluated by chemiluminescence and superoxide (SO) generation after stimulation with phorbol myristate acetate. Results: In comparison with the control medium, incubation of MN in the two-compartment PDF showed preservation of respiratory burst. In contrast, the incubation of MN in standard PDF and plasticizer-free PDF showed impaired functions. The same was found for PMNL. SO anion measurement in MN and PMNL after incubation in the new two-compartment PDF also showed preservation of cell function in comparison with the control medium. The incubation of PMNL in standard PDF and plasticizer-free PDF with a high glucose content showed depressed SO anion generation. Conclusions: These in vitro data demonstrate a better preservation of in vitro phagocyte function with adaptation of pH and reduction of glucose, GDP, and plasticizers in PDFs. The best results are achieved with the two-compartment, lactate-based neutral PDF.

Effects of L-carnitine on leukocyte function and viability in hemodialysis patients: A double-blind randomized trial

Excess morbidity and mortality among long-term hemodialysis patients because of infectious complications is partly caused by an impairment of cellular immune defense. We hypothesized this impairment is related to an abnormal carnitine metabolism also present in these patients. In a double-blind, randomized, placebo-controlled trial, we investigated the effect of L-carnitine on phagocytic function and viability of blood leukocytes in 17 patients undergoing maintenance hemodialysis. After an observation period of 1 month, the patients received either 10 mg/kg of L-carnitine or placebo intravenously at the end of each hemodialysis session over a period of 4 months. Leukocyte oxidative metabolism was measured by means of luminol-enhanced chemiluminescence and superoxide generation after stimulation with Staphylococcus aureus or phorbol myristate acetate. Killing capacity and phagocytosis of radiolabeled staphylococci were determined. A lactate dehydrogenase (LDH) release test was applied to assess cell viability. We were unable to show an effect of L-carnitine on phagocytic function and viability in vivo. Several clinical parameters were observed during the trial. No statistically significant differences concerning dialysis-related morbidity, anemia, or reduction of blood urea nitrogen and creatinine levels were detected. Additionally, we tested the effect of L-carnitine on phagocytic function after in vitro incubation of blood leukocytes, which also showed no changes. LDH release was decreased, indicating an improved viability of these cells. The latter results were found after in vitro incubation of cells, but could not be confirmed in vivo. In summary, we could not show beneficial effects of L-carnitine administration in hemodialysis patients for the dosage and duration of treatment stated, either on phagocytic function and viability or on the clinical and biochemical parameters observed.

Chronic Pruritus in the Absence of Skin Disease: Pathophysiology, Diagnosis and Treatment.

Chronic pruritus arises not only from dermatoses, but also, in up to half of cases, from extracutaneous origins. A multitude of systemic, neurological, psychiatric, and somatoform conditions are associated with pruritus in the absence of skin disease. Moreover, pruritus is a frequently observed side effect of many drugs. It is therefore difficult for physicians to make a correct diagnosis. Chronic pruritus patients frequently present to the dermatologist with skin lesions secondary to a long-lasting scratching behavior, such as lichenification and prurigo nodularis. A structured clinical history and physical examination are essential in order to evaluate the pruritus, along with systematic, medical history-adapted laboratory and radiological tests carried out according to the differential diagnosis. For therapeutic reasons, a symptomatic therapy should be promptly initiated parallel to the diagnostic procedures. Once the underlying factor(s) leading to the pruritus are identified, a targeted therapy should be implemented. Importantly, the treatment of accompanying disorders such as sleep disturbances or mental symptoms should be taken into consideration. Even after successful treatment of the underlying cause, pruritus may persist, likely due to chronicity processes including peripheral and central sensitization or impaired inhibition at spinal level. A vast arsenal of topical and systemic agents targeting these pathophysiological mechanisms has been used to deter further chronicity. The therapeutic options currently available are, however, still insufficient for many patients. Thus, future studies aiming to unveil the complex mechanisms underlying chronic pruritus and develop new therapeutic agents are urgently needed.

S2k Guidelines for the diagnosis and treatment of chronic pruritus - update - short version: Guidelines for pruritus

Associated with a host of different diseases, pruritus is a cardinal symptom that poses an interdisciplinary diagnostic and therapeutic challenge. Over time, that symptom may progress independently of the initial cause, thus losing its function as a warning sign and turning into a clinically relevant disease of its own. In Germany, approximately 13.5 % of the general population are affected by chronic pruritus, with an incidence of 7 %. All forms of chronic pruritus require targeted treatment consisting of (a) diagnosis and management of the underlying disease, (b) dermatological treatment of primary or secondary (for example, dry skin, scratch lesions) symptoms, (c) symptomatic antipruritic treatment, and (d) psychological/psychotherapeutic treatment in case of an underlying or associated psychological or psychosomatic condition. Medical care of patients with chronic pruritus should therefore include an interdisciplinary approach, in particular with respect to diagnosis and therapy of the underlying disease as well as in terms of the management of treatment and adverse events. The objective of the present interdisciplinary guidelines is to define and standardize diagnostic and therapeutic procedures in patients with chronic pruritus. This is a short version of the current S2 guidelines on chronic pruritus. The long version may be found at www.awmf.org.

Epidermal Langerhans cells in uremic patients on hemodialysis or continuous ambulatory peritoneal dialysis.

Skin biopsies of 33 uremic patients-13 patients on continuous ambulatory peritoneal dialysis (CAPD), 12 on hemodialysis (HD), 8 patients with end-stage renal disease (ESRD) before initiation of dialysis treatment-and 10 healthy volunteers were investigated to determine the number of Langerhans cells (LC) by light microscopy after staining for S-100 protein. The epidermal LC count was significantly lower in patients on CAPD (mean: 62.9 LC/mm2; p = 0.027) and patients on HD (mean: 30.4 LC/mm2; p = 0.0015) compared to controls (mean: 110.1 LC/mm2) and uremic patients before initiation of dialysis treatment (mean: 122.6 LC/mm2). The difference between LC counts of CAPD and HD patients did not reach statistical significance (p = 0.057). There was no relation between LC count and age (p = 0.057) or epidermal width (p = 0.26). No statistically significant correlation could be demonstrated between duration of dialysis and LC count (r = -0.33, p = 0.10). LC counts of CAPD patients with diabetes mellitus (n = 7) were not significantly different from those of nondiabetics (n = 6; p = 0.77). LC counts seem to be normal in uremic patients before dialysis treatment. The reduction in LC density in the skin of dialysis patients may contribute to immunodeficiency of uremic patients on regular dialysis treatment.

Measurement of 12(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid and its metabolite 12-oxo-5Z,8E,10E-heptadecatrienoic acid in human plasma by gas chromatography/negative ion chemical ionization mass spectrometry

Thromboxane A2, the predominant product of arachidonic acid metabolism in the blood platelet, is a potent vasoconstrictor and platelet agonist. During its biosynthesis from cyclic endoperoxide, 12(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid (HHT) is formed in equal amounts. The further metabolism of HHT, catalyzed by 15-hydroxyprostaglandin dehydrogenase, leads to 12-oxo-5Z,8E,10E-heptadecatrienoic acid (Oxo-HT). Sample workup procedures are described which allow for the sensitive and reproducible determination of these two arachidonic acid metabolites in human plasma by gas chromatography-mass spectrometry in the presence of deuterated analogues as internal standards. HHT is derivatized to the pentafluorobenzyl ester tert-butyldimethylsilyl ether. In order to enable quantification of low concentrations of about 10 pg/ml in nonstimulated human plasma, the samples have to be purified by HPLC. Oxo-HT is derivatized to the pentafluorobenzyl ester, which is purified by HPLC, and then derivatized to the trimethylsilyloxime. The method allows quantification of Oxo-HT in concentrations down to 10 pg/ml plasma. The reported methods have been used to measure HHT and Oxo-HT in stimulated platelet rich plasma and to quantify HHT in nonstimulated plasma. Determination of endogenous levels of these two arachidonic acid metabolites may give new insights into the overall biosynthesis of thromboxane A2 in man.

Lacking evidence for calcium-binding protein fetuin-A to be linked with chronic kidney disease-related pruritus (CKD-rP)

Sir, Uraemic pruritus, now better known as chronic kidney disease-related pruritus (CKD-rP), is still a commonly experienced, tormenting and challenging symptom in patients with chronic kidney diseases [1]. There has been an ongoing discussion whether pruritus in chronic kidney disease is brought about by the common disturbance of calcium/phosphate homeostasis [2]. Recently it has been proposed that a vicious circle of metabolic derangements (malnourishment, inflammation, arteriosclerosis) may explain the exaggerated morbidity and mortality in a subset of haemodialysis patients [3]. Inflammation might be the most deleterious factor in this respect which, besides other factors, is related to the occurrence of CKD-rP and down-regulation of fetuin-A, an important calcium-binding circulating protein favouring tissue-calcifications in these patients [4]. Thus, we were interested in whether patients with CKD-rP display lower levels of serum fetuin-A. Ten patients in a hospital-based haemodialysis centre complaining about CKD-rP were compared to another 12 patients who did not report to have suffered from CKD-rP at least 6 months prior to the interview. Patients with CKD-rP were asked to score the intensity of current pruritus using a visual analogue scale (VAS) ranging from 0 to 10. In both groups, 10 ml of blood was taken immediately after puncture of the arterio-venous fistula, and fetuin-A, 25-hydroxyvitamin D3 (25[OH]D3), total protein, albumin, calcium (corrected for serum albumin), phosphate, and high-sensitivity CRP (hsCRP) were measured. Independent t-tests (continuous variables) and a χ2-test (gender) evaluated whether there were significant (P < 0.05) differences between patients with and without CKD-rP. The mean pruritus intensity of patients with CKD-rP was 5.9 ± 1.9. After identifying one univariate outlier (hsCKP = 35.6) in the group of patients without CKD-rP, CRP was significantly higher in patients with CKD-rP. We failed, however, to find significant differences in serum-calcium, phosphate, fetuin A and 25-OH-Vitamin D3 between the two groups (Table ​(Table1).1). Additionally, there was no relationship between the intensity of CKD-rP and the metabolic factors measured (including CRP) in patients suffering from pruritus. Table 1 Patient and clinical characteristics between the two groups. PTH (intact parathyreoid hormone), hsCRP (high-sensitivity C-reactive protein), 25(OH)D3 (25-hydroxyvitamin D3) Although our study approach has methodological limitations (small number of patients, no matched pairs) the results suggest that neither calcium-binding protein fetuin-A levels nor 25(OH)D3 values were noticeably different in patients with CKD-rP compared to patients without CKD-rP. On the other hand, the marker for inflammation, CRP, was found to be significantly higher in patients with CKD-rP as shown before [5]. We hence believe that other inflammation-driven processes need to be studied in the future in order to understand the pathomechanisms of CKD-rP. Conflict of interest statement. None declared.