R. Brunkhorst

Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement: a prospective, randomized study.

OBJECTIVE There is growing concern about the toxic side effects of daily oral cyclophosphamide (CYC) treatment. Intravenous (i.v.) pulse administration of CYC has been shown to be effective in patients with systemic lupus erythematosus, but contradictory results have been reported in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS The efficacy and toxicity of i.v. pulse administration of CYC (0.75 gm/m2) versus daily oral CYC treatment (2 mg/kg body weight) were investigated in a prospective, randomized, multicenter study in patients with ANCA-associated vasculitis and renal involvement. RESULTS The cumulative CYC dose was reduced by 57% in patients with i.v. pulse treatment (n = 22) compared with patients treated with daily oral therapy (n = 25). Patient survival, remission rate, time of remission, relapse rate, and outcome of renal function were not different between the 2 treatment groups. However, the rate of leukopenia (P < 0.01) and severe infections (P < 0.05 by 1-tailed test) was significantly reduced in the i.v. pulse group compared with the group receiving daily oral treatment. Moreover, gonadal toxicity was reduced in the i.v. pulse group, as indicated by significantly lower levels of follicle-stimulating hormone. CONCLUSION This randomized study shows that i.v. CYC administration is an effective therapeutic tool with low toxicity in patients with ANCA-associated vasculitis and renal involvement.

Usefulness of procalcitonin for differentiation between activity of systemic autoimmune disease (systemic lupus erythematosus/systemic antineutrophil cytoplasmic antibody‐associated vasculitis) and invasive bacterial infection

OBJECTIVE To investigate whether the determination of serum procalcitonin (PCT) in systemic autoimmune disease will help to discriminate invasive infection from highly active underlying disease. METHODS Three hundred ninety-seven serum samples, from 18 patients with systemic lupus erythematosus (SLE) and 35 patients with systemic antineutrophil cytoplasmic antibody-associated vasculitis (AAV), were analyzed. Clinical disease activity was assessed by the Systemic Lupus Activity Measure in SLE patients and by the Birmingham Vasculitis Activity Score in AAV patients. Procalcitonin concentrations were determined in parallel with concentrations of neopterin, interleukin-6 (IL-6), and C-reactive protein (CRP). Additionally, serum creatinine values were obtained. RESULTS In 321 of the 324 samples from the 42 patients with autoimmune disease but without systemic infection, serum PCT levels were within the normal range (i.e., <0.5 ng/ml), whereas the values for neopterin, IL-6, and CRP were elevated in patients with active underlying disease. All 16 systemic infections occurred in 11 patients with AAV, and were associated with PCT levels that were markedly elevated, to a mean +/- SD of 1.93 +/- 1.19 ng/ml. No correlation between the degree of renal impairment and PCT concentrations was seen. CONCLUSION PCT may serve as a useful marker for the detection of systemic bacterial infection in patients with systemic autoimmune disease.

Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients.

FTY720, a new and potent immunosuppressant, causes in animal models a rapid, reversible reduction of all subsets of peripheral blood lymphocytes, inducing their migration to secondary lymphoid organs. In this human phase I trial, the pharmacodynamics of single oral doses of FTY720 were evaluated. A randomized, double‐blind, placebo‐controlled, time‐lagged study of six different single ascending oral doses of FTY720 ranging from 0.25 to 3.5 mg was conducted in stable renal transplant patients receiving a cyclosporine‐based regimen. Absolute and subset lymphocyte counts, as well as absolute differential leukocyte counts, were determined by differential blood counts and flow cytometry at screening and multiple intervals thereafter. A pharmacodynamic model was established. Twenty‐four single doses of FTY720 that were administered caused a transient, reversible pan‐lymphopenia within 4 h. Lymphocyte subgroup analysis revealed that almost all subsets declined, with CD4‐ and CD45RA‐positive cells being affected the most. Natural killer cells, granulocytes and monocytes were not influenced by FTY720. The lymphocyte count returned to baseline within 72 h in all dosing cohorts except the highest. Pharmacokinetik/pharmacodynamic modelling revealed a nonlinear dose effect and resulted in a good fit with observed values. These data show that FTY720 is highly effective in humans, with single oral doses of FTY720 ranging from 0.25 to 3.5 mg causing a reversible selective panlymphopenia.

Attitude of patients toward transplantation of xenogeneic organs

Abstract Background: The prospect of xenotransplantation has stimulated considerable hopes as well as major concerns. The question of whether or not patients accept xenografts is influenced not only by scientific facts but also by psychological factors. It was the aim of this study to analyze the attitudes of patients toward transplantation of xenogeneic organs and evaluate factors influencing these attitudes. Methods: To this end, attitudes toward xenogeneic compared with allogeneic organ grafts were evaluated by means of detailed questionnaires in 1049 patients in Germany, who either had received transplants (n=722) or were on the waiting list for various organ grafts (n=327). Answers were correlated to demographic data as well as to the physical and mental conditions of the patients. Results: The survey indicates that 77% of patients would accept xenografts while 7% would refuse them if results of xenotransplantation were comparable with those of allotransplantation. If xenotransplantation were associated with increased risks due to more intensive medication 58% would still basically accept xenografts. Acceptance of xenografts was significantly higher in patients who had received transplants and among males. Age, religion, waiting time, and type of organ were not found to influence acceptance rates. Xenografts were thought to be associated with considerable or severe emotional stress by 23% of patients, versus 3% for allografts. The pig was the preferred donor animal, and gene therapeutic manipulation for improvement of results would be accepted by 84%. Inadequate graft function/increased risk of rejection and risk of disease transmission were the major concerns for 60% and 52% of patients, respectively; emotional concerns were the major concerns for 24% and animal-rights concerns for 15%. Conclusions: These findings show that the potential acceptance rate of xenografts would be quite high, with a more positive attitude in transplanted patients than in waiting-list patients; there was no major difference in acceptance rate for various types of organs. Major concerns about xenotransplantation currently are functional inferiority and transmission of diseases.

Procalcitonin for discrimination between activity of systemic autoimmune disease and systemic bacterial infection

ObjectiveTo investigate whether serum procalcitonin (PCT) levels could be useful to differentiate between systemic infection and the activity of the underlying disease in autoimmune disease.MethodsIn 18 patients with systemic lupus erythematodes (SLE) and 35 patients with systemic antineutrophil cytoplasmic antibody-associated vasculitis (AAV) clinical disease activity was assessed by score systems. Infection was defined by clinical and microbiological means. PCT was determined in parallel with concentrations of neopterin, interleukin-6 (IL-6), and C-reactive protein (CRP) in 397 serum samples.ResultsOnly in 3 of the 324 samples taken from patients with autoimmune disease but without concomitant infection, serum PCT levels were above the normal range (>0.5 ng/ml), whereas neopterin, CRP and IL-6 were elevated in patients with active underlying disease. All systemic infections (N=16 in AAV-patients) were associated with markedly elevated PCT-levels (mean±SD:1.93±1.19 ng/ml).ConclusionPCT may serve as a useful marker for the detection of systemic bacterial infection in patients with autoimmune disease.

Early identification of biliary pancreatitis with procalcitonin.

To the Editor: In acute pancreatitis, early detection of obstruction in the biliary tree is essential for urgent desobliteration (1). The endoscopic retrograde cholangiopancreaticography (ERCP) can identify ductal and gallbladder stones and allows immediate relief by endoscopic sphincterotomy (EPT). However, ERCP and EPT are not indicated in the majority of patients with nonbiliary pancreatitis and bear the risk of inducing pancreatitis itself. Several clinical and biochemical parameters have been proposed to differentiate between biliary and nonbiliary pancreatitis but lack specificity, whereas ultrasound (US) imaging is often not diagnostic because of technical limitations (bowel gas or ileus) (2). Increased serum concentrations of acute-phase proteins and cytokines have been emphasized to be of prognostic value, but to our knowledge they have not been used as differentiation markers between the types of pancreatitis. We tested whether the 116 amino-acid pep-tide procalcitonin (PCT), which is reported to be a sensitive and specific marker for bacterial inflammation (3, 4) allows early discrimination between biliary and nonbiliary pancreatitis.

Recurrence of Membranoproliferative Glomerulonephritis after Renal Transplantation in a Patient with Chronic Hepatitis C

Chronic hepatitis C (HCV) infection may be associated with membranoproliferative glomerulonephritis (MPGN) with or without concomitant cryoglobulinemia. We report on a patient with end-stage renal disease caused by MPGN I in association with replicative HCV infection. Two years after successful renal transplantation, this patient developed nephrotic syndrome caused by recurrence of MPGN I in the renal transplant. The recurrence of renal disease after transplantation in this patient with chronic replicative HCV further elucidates the role of the viral infection in the pathogenesis of MPGN and suggests anti-viral treatment as, e.g., with interferon.

High mortality from urothelial carcinoma despite regular tumor screening in patients with analgesic nephropathy after renal transplantation

Patients with end-stage renal failure due to analgesic nephropathy have an increased risk of developing a urothelial carcinoma. To determine the impact of renal transplantation on the frequency of urothelial carcinomas, we analyzed 2072 patients who underwent 2371 renal transplantations between 1968 and 1993, including 78 (3.8%) with clinically proven analgesic nephropathy. Before and after transplantation a regular tumor screening was performed in patients with analgesic nephropathy by urine cytology and abdominal sonography. In 11 of the 78 patients with analgesic nephropathy (14.1%; age 51–66 years, 40–108 months after initiation of dialysis treatment, 5–77 months after transplantation), a urothelial carcinoma of the native urinary tract, especially the kidneys, was diagnosed. Therapy comprised nephroureterectomy (n=6), transurethral resection (n=6) and/or cystectomy (n=2). Seven patients died due to tumor progression 16.3 (4–33) months postoperatively and one patient died due to a perioperative complication. Despite regular tumor screening after transplantation, the diagnosis of a urothelial carcinoma was made very late, leading to a high tumor-related mortality. As a consequence, we suggest that a bilateral nephroureterectomy should be performed prophylactically in patients with proven analgesic nephropathy. In addition, a cystoscopy with lavage cytology testing of the bladder should be performed twice a year.

INDIKATIONSSTELLUNG ZUR LEBERTRANSPLANTATION BEI SCHWERER KNOLLENBLATTERPILZVERGIFTUNG

Summary. The clinical course of 12 patients with mushroom poisoning was evaluated in order to define the parameters considered to be relevant to the indication for liver transplantation. Eight patients recovered under conservative therapy; one patient died due to pre-existing, concomitant cardiopulmonary disease. In three patients transplantations had to be performed because of severe liver failure. On admission, the transplanted patients had a decreased Quicks test score and factor V value (< 10 %). The peak of liver enzymes, serum bilirubin, serum creatinine, partial thromboplastin time and azotemia were not of any prognostic value. Main indications for liver transplantation were a very low initial Quicks test score and factor V value (both < 10 %) and their inadequate response under substitution therapy. The development of encephalopathy and renal failure were further parameters indicating poor prognosis.Zusammenfassung. Der Verlauf von 12 Patienten mit Knollenblätterpilzvergiftung wurde retrospektiv analysiert, um prognostische Kriterien für die Indikationsstellung zur Lebertransplantation herauszuarbeiten. Acht Patienten erholten sich unter konservativer Therapie, bei 3 Patienten war eine Lebertransplantation erforderlich; ein Patient starb bei Vorliegen schwerer Begleiterkrankungen unter konservativer Therapie. Die transplantierten Patienten wiesen initial einen Quick- und Faktor-V-Wert unter 10 % auf. Die Höhe der Transaminasen, des Serumbilirubins, des Serumkreatinins, eine Verlängerung der PTT sowie eine Azotämie hatten keinen sicheren prognostischen Wert. Für die Indikationsstellung zur Transplantation war der initiale Quick- und Faktor-V-Wert und deren inadäquater Anstieg unter Substitution entscheidend. Die Ausbildung einer Encephalopathie sowie ein progredientes Nierenversagen stellen zusätzliche prognostisch schlechte Parameter dar.Schlüsselwörter: Knollenblätterpilzvergiftung – Lebertransplantation – fulminantes Leberversagen.

Indications for liver transplantation in severe amanita phalloides mushroom poisoning

The clinical course of 12 patients with mushroom poisoning was evaluated in order to define the parameters considered to be relevant to the indication for liver transplantation. Eight patients recovered under conservative therapy; one patient died due to pre-existing, concomitant cardiopulmonary disease. In three patients transplantations had to be performed because of severe liver failure. On admission, the transplanted patients had a decreased Quicks test score and factor V value (< 10%). The peak of liver enzymes, serum bilirubin, serum creatinine, partial thromboplastin time and azotemia were not of any prognostic value. Main indications for liver transplantation were a very low initial Quicks test score and factor V value (both < 10%) and their inadequate response under substitution therapy. The development of encephalopathy and renal failure were further parameters indicating poor prognosis.Summary. The clinical course of 12 patients with mushroom poisoning was evaluated in order to define the parameters considered to be relevant to the indication for liver transplantation. Eight patients recovered under conservative therapy; one patient died due to pre-existing, concomitant cardiopulmonary disease. In three patients transplantations had to be performed because of severe liver failure. On admission, the transplanted patients had a decreased Quicks test score and factor V value (< 10 %). The peak of liver enzymes, serum bilirubin, serum creatinine, partial thromboplastin time and azotemia were not of any prognostic value. Main indications for liver transplantation were a very low initial Quicks test score and factor V value (both < 10 %) and their inadequate response under substitution therapy. The development of encephalopathy and renal failure were further parameters indicating poor prognosis.Zusammenfassung. Der Verlauf von 12 Patienten mit Knollenblätterpilzvergiftung wurde retrospektiv analysiert, um prognostische Kriterien für die Indikationsstellung zur Lebertransplantation herauszuarbeiten. Acht Patienten erholten sich unter konservativer Therapie, bei 3 Patienten war eine Lebertransplantation erforderlich; ein Patient starb bei Vorliegen schwerer Begleiterkrankungen unter konservativer Therapie. Die transplantierten Patienten wiesen initial einen Quick- und Faktor-V-Wert unter 10 % auf. Die Höhe der Transaminasen, des Serumbilirubins, des Serumkreatinins, eine Verlängerung der PTT sowie eine Azotämie hatten keinen sicheren prognostischen Wert. Für die Indikationsstellung zur Transplantation war der initiale Quick- und Faktor-V-Wert und deren inadäquater Anstieg unter Substitution entscheidend. Die Ausbildung einer Encephalopathie sowie ein progredientes Nierenversagen stellen zusätzliche prognostisch schlechte Parameter dar.Schlüsselwörter: Knollenblätterpilzvergiftung – Lebertransplantation – fulminantes Leberversagen.