Patients' representations of their end-stage renal disease: relation with mortality.

BACKGROUND: Self-regulation theory explains how patients' illness perceptions influence self-management behaviour (e.g. via adherence to treatment). Following these assumptions, we explored whether illness perceptions of ESRD-patients are related to mortality rates. METHODS: Illness perceptions of 182 patients participating in the NECOSAD-2 study in the period between December 2004 and June 2005 were assessed. Cox proportional hazard models were used to estimate whether subsequent all-cause mortality could be attributed to illness perception dimensions. RESULTS: One-third of the participants had died at the end of the follow-up. Mortality rates were higher among patients who believed that their treatment was less effective in controlling their disease (perceived treatment control; RR = 0.71, P = 0.028). This effect remained stable after adjusting for sociodemographic and clinical variables (RR = 0.65, P = 0.015). CONCLUSIONS: If we consider risk factors for mortality, we tend to rely on clinical parameters rather than on patients' representations of their illness. Nevertheless, results from the current exploration may suggest that addressing patients' personal beliefs regarding the effectiveness of treatment can provide a powerful tool for predicting and perhaps even enhancing survival.

Activation of coagulation and fibrinolysis following OKT3 administration to renal transplant recipients: association with distinct mediators.

Treatment with OKT3 induces cytokine release and activates the complement system. Since both phenomena may affect coagulation and fibrinolysis we studied these systems in 8 renal transplant recipients during OKT3 treatment. In 8 of 9 patients a similar pattern was observed: plasma thrombin-antithrombin-III-complex, tissue-type plasminogen-activator and plasmin-alpha 2-antiplasmin-complex levels were increased as compared to pretreatment levels (p less than 0.05) at 15 min after the first OKT3 dose and reached peak values at 1 h. No significant changes were observed upon subsequent OKT3 administrations or in a control group of 8 patients. In one patient upon the first OKT3 administration only complement activation, and no cytokine release was observed, whereas plasma thrombin-antithrombin-III-complex, tissue-type plasminogen-activator and plasmin-alpha 2-antiplasmin-complex levels increased only at 15 min. In conclusion, we demonstrate a biphasic activation of coagulation and fibrinolysis upon the first OKT3 dose; the initial phase seems to be associated with complement activation, the later phase with cytokine release.

Guidelines for the optimal use of muromonab CD3 in transplantation.

Muromonab CD3 (OKT3), the murine anti-CD3 monoclonal antibody (mAb) of the IgG-2a class, directed against the CD3 molecule on the surface of human T cells, has proven to be a powerful immunosuppressive agent in solid organ transplantation and has been shown to be superior to high-dose steroids as first-line treatment of acute allograft rejection. It is comparable to antithymocyte globulin (ATG) in treating steroid-resistant rejection and it is also effective as rescue treatment in ATG-resistant rejection. However, OKT3 treatment is followed by a substantial percentage of re-rejections, most of which respond well to steroids. In the early post-transplant period, a prophylactic course of OKT3 can delay the onset of acute rejection, in particular in immunologically high-risk patients. First-dose-related adverse effects (pyrexia, dyspnoea, headache, nausea, vomiting and diarrhoea) of OKT3 are severe, but usually transient and seldom life-threatening, provided overhydration has been corrected and steroids have been given before the first administration. These adverse effects are partly attributed to the release of cytokines as a result of mononuclear cell activation. In addition, complement activation and subsequent activation of neutrophils may play a role in their pathogenesis. After exposure of patients to OKT3 an increased incidence of infections and malignancies has been reported. However, most likely this merely reflects the total burden of immunosuppression. Xenosensitisation represents an important limitation to OKT3 treatment, although a second or third course can still be effective in patients with low antibody titres. In practice, the initiation of OKT3 treatment should be preceded by correction of overhydration, if necessary by means of dialysis or ultrafiltration. According to the instructions from the manufacturer the first dose of OKT3 is preceded by paracetamol (acetaminophen), an antihistamine and intravenous (IV) corticosteroids, in an attempt to mitigate the first dose-related symptoms. A regimen consisting of administration of 2 IV doses of 250mg methylprednisolone, given 6 hours and 1 hour before the first OKT3 injection, followed by a 2-hour infusion of OKT3, is most effective in diminishing OKT3-induced adverse effects.

[Eye paralysis and confusion]. / Blikparese en verwardheid.

Two patients, women of 85 and 76 years, presented with horizontal ocular paresis. The first patient had a palliative ileocecal resection for adenocarcinoma with metastases and developed the ocular paresis only after intravenous glucose infusion. The second had chronic haemolytic anaemia and weight loss due to malnutrition. The two women were also confused. In both patients acute Wernicke's encephalopathy was diagnosed, caused by thiamine deficiency. The disorder could easily have been missed because of confounding clinical problems. Early treatment of Wernicke's encephalopathy (thiamine 100 mg/day intramuscularly for 3 days) is of major importance in preventing permanent neurological damage or even death.

[A patient with alveolar echinococcosis (Echinococcus multilocularis infection]. / Een patiënt met alveolaire echinokokkose (infectie met Echinococcus multilocularis).

In a 45-year-old Swiss male, who had been living in the Netherlands for 20 years, alveolar echinococcosis was diagnosed. He had probably been infected during his youth in Switzerland. His illness became symptomatic more than 20 years later. The diagnosis was reached by microscopic examination of material obtained from a necrotic mass in the liver. Imaging revealed that the disease had spread diffusely throughout the liver, spleen and abdomen. Curative resection was impossible. Percutaneous drainage of the hepatic necrotic mass was complicated by a bacterial infection for which he was treated with antibiotics. Treatment with high doses of albendazole resulted in considerable improvement. The patient represents the first case of Echinococcus multilocularis infection diagnosed in the Netherlands.

CAPD peritonitis after colonoscopy: follow the guidelines.

We present two cases of peritonitis shortly after endoscopic examination of the large bowel with polypectomy in patients on continuous ambulant peritoneal dialysis (CAPD) despite the standard preventive measure to drain the dialysate from the abdomen prior to the procedure. We have reviewed the current literature on this topic. These cases demonstrate that the administration of prophylactic broad-spectrum antibiotics next to the drainage of the abdomen prior to colonoscopy in CAPD patients should be considered as recommended in the International Society for Peritoneal Dialysis (IS PD) guidelines 2005.

T gamma/delta lymphocytes in renal transplant recipients.

T gamma/delta lymphocytes are able to perform allospecific cytotoxicity and natural killer cytotoxicity in vitro. However, very little is known about their function in vivo. To investigate the possible involvement of T gamma/delta lymphocytes in the immune response to renal allografts, fine-needle aspiration biopsies and peripheral blood of 15 renal transplant recipients were studied during the first 4 weeks after transplantation. In addition peripheral blood of patients before transplantation, half a year and one year after transplantation was studied. No increase in the percentage of T gamma/delta lymphocytes in the fine-needle aspiration biopsies, including those taken during acute rejection episodes, was found. A significant decrease in the percentage of T gamma/delta lymphocytes was observed in peripheral blood after transplantation. We conclude that T gamma/delta lymphocytes seem to play no major role in the immune response to renal allografts.

Low-dose OKT3 induction therapy following renal transplantation: a controlled study.

In a prospective clinical study we tested the immunosuppressive properties and toxicity of low-dose OKT3 induction therapy in renal transplant recipients. 50 consecutive renal transplant recipients were alternatingly assigned to low-dose OKT3 induction or prednisolone/cyclosporin. Low-dose OKT3 induction treatment consisted of 0.5 mg OKT3 twice daily for 10 days, initially combined with azathioprine and prednisolone maintenance immunosuppression that was converted to prednisolone/cyclosporin at the end of the course. During a 15-29-month follow-up period, low-dose OKT3 induction therapy was found to reduce significantly the incidence of acute rejections, as compared to the usual prednisolone/cyclosporin maintenance immunosuppression (21 versus 52%, P = 0.02). There also was a tendency towards an improved graft function after low-dose OKT3, although no significance was reached. Furthermore, compared to a historical control group of renal transplant patients in whom acute rejection was treated with 5 mg OKT3 daily, low-dose OKT3 appeared to cause fewer side-effects. We conclude that low-dose OKT3 induction therapy is superior to prednisolone/cyclosporin in preventing acute rejection after renal transplantation and that it is better tolerated than conventional OKT3 treatment.

Local production of interleukin-6 during acute rejection in human renal allografts.

Interleukin-6 is involved in T-cell activation and possibly plays a role in the pathogenesis of acute rejection of transplanted organs. This is indicated by elevated levels of interleukin-6 in serum and urine of renal allograft recipients, and elevated amounts of mRNA for interleukin-6 in all different cell types of the renal allograft during acute rejection episodes. However, transplant recipients receive immunosuppressive drug therapy which may inhibit production of interleukin-6 at the post-transcriptional level. Therefore, the aim of the present study was to detect interleukin-6 in biopsies taken during acute renal allograft rejection by immunohistochemical staining. In addition, serial sections were stained with cellular markers to identify interleukin-6-producing cells. In biopsies taken during acute rejection (n = 7), interleukin-6 could be detected in tubular cells (7/7) mesangial cells (3/7) and monocytes/macrophages (4/7), but not in vascular endothelium or lymphocytes. In control biopsies weak interleukin-6 staining of tubular cells only was present or there was no staining at all. We conclude that interleukin-6 is actually produced in the renal allograft during acute rejection, and that elevated urinary interleukin-6 levels during acute rejection seem to originate mainly from synthesis of interleukin-6 by renal tubular cells.

Serum neopterin/creatinine values correlate with severity of symptoms caused by cytomegalovirus infection in renal transplant recipients.

Serum neopterin/creatinine ratios were longitudinally measured in 86 renal transplant recipients from the day before transplantation until 4 months after transplantation, and the relationship to the clinical symptoms of cytomegalovirus (CMV) infection was studied. Infection with cytomegalovirus occurred in 23 patients, 11 cases of which were due to primary infection. Symptoms caused by CMV infection were more severe in male patients, in patients who had received prior antirejection treatment, and in patients with primary CMV infection. The measurement of serum neopterin/creatinine ratios proved to be a marker for the severity of symptoms caused by CMV infection, as peak values were significantly higher in eight patients with CMV disease than in patients with no or only mild symptoms of CMV infection (P < 0.05). Moreover, in seven out of eight cases of CMV disease, serum neopterin/creatinine ratios started to rise up to 2 weeks before CMV infection was proven by serology.

Interleukin-6 and neopterin in renal transplant recipients: a longitudinal study.

Serum and urine interleukin-6 (IL-6) levels and serum neopterin/creatinine ratios were longitudinally studied in 86 renal transplant recipients until 4 months after transplantation. During acute rejection and acute tubular necrosis (ATN), serum and urine IL-6 levels were elevated compared to during stable transplant function (P < 0.001). During acute rejection, serum IL-6 levels increased at least 2 days before plasma creatinine started to rise (P < 0.05), indicating its early involvement in the rejection process. During cytomegalovirus (CMV) disease, serum, but not urine, IL-6 levels were higher (P < 0.01), and serum neopterin/creatinine values were higher than during stable transplant function, ATN, or acute rejection (P < 0.01). No significant differences with stable transplant function occurred during cyclosporin A toxicity. Measurement of serum IL-6 provided a sensitivity of 84% and a specificity of 85% for the diagnosis of acute rejection episodes not coinciding with ATN. All cases of CMV disease could be diagnosed by measurement of serum neopterin/creatinine, which provided a specificity of 73%.

Interleukin-6 concentrations in the serum of patients with AIDS-associated Kaposi's sarcoma during treatment with interferon-alpha.

Interleukin-6 (IL-6) levels were determined in the serum of 14 HIV-1-infected patients with Kaposi's sarcoma, 10 HIV-1-infected patients without symptoms, and 10 healthy male subjects. IL-6 levels were also determined in the serum of the 14 patients with Kaposi's sarcoma during treatment with high-dose human recombinant interferon-alpha (IFN alpha). Serum IL-6 levels were significantly higher in the patients with Kaposi's sarcoma than in the HIV-infected patients without symptoms and the controls. There was no consistent pattern of changes of IL-6 levels during IFN alpha treatment. These results support the view that IL-6 is a cytokine involved in the pathogenesis of AIDS-associated Kaposi's sarcoma, but appear to argue against an effect of IFN alpha on the production or release of IL-6 as an important mechanism of action of IFN alpha.

Effects of anti-CD3 monoclonal antibodies on functional activity of lymphocytes: studies in vivo and in vitro.

Lymphocyte functional activity was tested in 38 renal transplant recipients receiving induction treatment with various anti-CD3 MoAbs, i.e. OKT3, T3.G2a (an IgG2a anti-CD3 MoAb) or T3.A (an IgA anti-CD3 MoAb of the same idiotype). During treatment with OKT3 and T3.G2a, lymphocyte response to phytohaemagglutinin-P (PHA), as determined with the use of a whole-blood lymphocyte culture technique, decreased significantly. However, during treatment with T3.A PHA response was not affected. Using a conventional lymphocyte culture technique, PHA response was unchanged during treatment with all three MoAbs, indicating that the immunosuppressive effect of OKT3 and T3.G2a is probably dependent upon the presence of MoAb in culture medium and is reversible. In addition, we tested in vitro inhibition of aspecific mitogen- or antigen-induced lymphocyte stimulation by OKT3, T3.A and T3.G2a. It appeared that at low concentrations (< 25 ng/ml) T3.G2a and OKT3 exerted a stronger immunosuppressive effect than T3.A. However, at higher concentrations T3.A, OKT3 and T3.G2a were equally immunosuppressive. We conclude that the immunosuppressive effect of T3.A is caused by blindfolding. At low concentrations T3.G2a exerts its immunosuppressive effect mainly through modulation of the CD3 and/or T cell receptor complex, as a result of interaction with Fc receptors on monocytes. At higher concentrations blindfolding of the CD3/T cell receptor complex may contribute to immunosuppression.

Complement activation during OKT3 treatment: a possible explanation for respiratory side effects.

Respiratory side effects that sometimes occur during treatment with anti-CD3 MAb OKT3 might result from pulmonary sequestration of activated neutrophils. Therefore, we studied complement activation in relation to activation and pulmonary sequestration of neutrophils during antirejection treatment with OKT3. In each of nine patients studied, plasma C3a-desarg and C4b/c levels increased compared with pretreatment values already in the first sample taken 15 minutes after the first dose of OKT3 (P < 0.05), with peak values at 15 and 30 minutes, respectively. Levels of neutrophil degranulation product elastase (complexed to alpha 1-antitrypsin) also increased already at 15 minutes after the first dose of OKT3 (P < 0.05), which is before elevated levels of the cytokines TNF alpha, IL-6 or IL-8 were detectable. In contrast, upon subsequent OKT3 administrations or in the control group treated with methylprednisolone, neither complement activation, cytokine release nor neutrophil degranulation occurred. In five studied patients treated with OKT3, pulmonary sequestration of radiolabeled granulocytes was observed from 3 until 15 minutes after the first dose of OKT3, together with peripheral blood granulocytopenia, which lasted at least 30 minutes. In conclusion, we demonstrate a simultaneous activation of complement and pulmonary sequestration of activated granulocytes immediately following the first dose of OKT3. These phenomena may be involved in the development of respiratory side effects complicating this therapy.