Relationship of hepatitis B or C virus prevalences, risk factors, and outcomes in renal transplant recipients: analysis of German data.

BACKGROUND: Chronic liver disease resulting from hepatitis B (HBV) and hepatitis C (HCV) virus infections is still a major concern in kidney recipients. Our aim was to evaluate the prevalences, risk factors, and impact of HBV and HCV infections in adult renal transplant recipients in Germany. MATERIALS AND METHODS: Data were collected on 1633 kidney recipients transplanted between 1989 and 2002 at the 21 German renal transplant centers participating in MOST, the prospective Multinational Observational Study in Transplantation. Subgroup analyses compared HBV- and HCV-positive patients vs those with HBV/HCV-negative serology at the time of transplantation. RESULTS: The prevalences of 4.4% (n = 72) for HBV and 5.8% (n = 94) for HCV showed a marked decline over the last 15 years. Retransplantations were significantly more common among HBV+ (29%) and HCV+ (36%) than HBV-/HCV- patients (12%). HCV+ patients experienced significantly longer dialysis times and received significantly more pretransplantation blood transfusions. Between all groups, no significant differences were observed in acute rejection rate at 12 months or in renal graft function up to 5 years posttransplantation (mean glomerular filtration rate: HBV+, 57.3 mL/min; HCV+, 58.5 mL/min; HBV-/HCV-, 59 mL/min). No progressive elevations in liver enzymes and bilirubin were noted during the 5-year observation period. CONCLUSIONS: HBV and HCV infections currently have a low prevalence among German kidney graft recipients. Long dialysis times, blood transfusions, and retransplantations were identified as risk factors for hepatitis infections. At 5 years posttransplantation, kidney and liver functions did not differ significantly between HBV+ and HCV+ vs HBV-/HCV- renal transplant recipients.

Cyclosporine-based immunosuppressive strategies for kidney recipients: interim analysis of German data from the Multinational Observational Study (MOST).

INTRODUCTION: We collected data from kidney recipients with a functioning graft at German kidney transplant centers in order to analyze the efficacy of various cyclosporine (CsA)-based immunosuppressive strategies, the effects of different perioperative and maintenance regimens, and the impact of donor source on clinical outcome. METHODS: As part of the ongoing prospective Multinational Observational Study in Transplantation (MOST), data for both prospective and retrospective analysis were collected from kidney recipients over 18 years bearing a functioning graft that was transplanted at 21 German kidney transplant centers between 1987 and 2002. RESULTS: Data from 1223 renal graft recipients, including their CsA-based immunosuppressive regimens, were stratified as: 402 de novo patients (median 6.8 months posttransplant) and 821 patients on maintenance therapy (median 71 months posttransplant). Triple regimens with CsA + mycophenolate mofetil (MMF) + steroids (Ste) currently comprise the major perioperative immunosuppressive strategies in Germany (de novo 65%). IL-2 receptor antagonist (IL-2Ra) use is increasing (de novo 18%, maintenance 4%), while mono and dual regimen use de novo is declining (de novo 4%, maintenance 20%). Among 689 patients transplanted between 1987 and 2002 with outcome data, the mean incidence of acute rejection during the first posttransplant year was 21.6%. Rejection rates on initial therapy with CsA + MMF + Ste +/- antibodies (n = 517) averaged 17.8%. CONCLUSIONS: Between 1987 and 2002, CsA-based immunosuppression combined with MMF and Ste became the most commonly used strategy for both initial and maintenance therapy after kidney transplantation in Germany, yielding the low acute rejection rates particularly when combined with IL-2Ra.

Ciclosporin in psoriasis clinical practice: an international consensus statement.

The main recommendations for the use of ciclosporin in the management of psoriasis are: (i) intermittent short courses (average of 12 weeks duration) of ciclosporin are preferable; (ii) ciclosporin should be given in the dose range 2.5-5.0 mg kg(-1) day(-1) (doses greater than 5.0 mg kg(-1) day(-1) should only be given in exceptional circumstances); (iii) treatment regimens should be tailored to the needs of each patient; (iv) selection of patients should take into account psychosocial disability, as well as clinical extent of disease and failure of previous treatment; (v) each patient's renal function (as measured by serum creatinine) should be thoroughly assessed before and during treatment; (vi) each patient's blood pressure should be carefully monitored before and during treatment; (vii) adherence to treatment guidelines substantially reduces the risk of adverse events; (viii) long-term continuous ciclosporin therapy may be appropriate in a subgroup of patients; however, duration of treatment should be kept below 2 years whenever possible; and (ix) when long-term continuous ciclosporin therapy is necessary, annual evaluation of glomerular filtration rate may be useful to accurately monitor renal function.

Entry-into-human study with the novel immunosuppressant SDZ RAD in stable renal transplant recipients.

AIMS: To evaluate the tolerability of single oral SDZ RAD doses in stable renal transplant recipients and the pharmacokinetics of ascending SDZ RAD doses when coadministered with steady-state cyclosporin A microemulsion (Neoral). METHODS: This randomized, double-blind, placebo-controlled, sequential study involved 54 patients in six treatment groups; a different SDZ RAD dose (0.25, 0. 75, 2.5, 7.5, 15, 25 mg) was assessed in each group. Patients received a single oral dose of SDZ RAD (n=6) or placebo (n=3) with their usual Neoral dose. SDZ RAD and cyclosporin A pharmacokinetic parameters were determined. RESULTS: All SDZ RAD doses were well tolerated, with no discontinuations due to adverse events, serious adverse events, or deaths. Similar proportions of patients receiving SDZ RAD and placebo had at least one adverse event (44% and 50%, respectively). Mean changes in laboratory variables (baseline to endpoint) showed no clinically meaningful differences between SDZ RAD and placebo groups. SDZ RAD was absorbed rapidly and showed dose-proportional pharmacokinetics (dose: 2.5-25 mg), based on systemic exposure. Multiple postabsorptive phases in the pharmacokinetic profile indicate tissue distribution. The elimination half-life ranged from 24 to 35 h across the five highest dose groups. Pharmacokinetics were similar in men and women. Co-administration of escalating single oral SDZ RAD doses did not affect steady-state cyclosporin A pharmacokinetics. CONCLUSIONS: SDZ RAD was well tolerated; safety profiles of SDZ RAD and placebo were similar. SDZ RAD pharmacokinetics were dose-proportional across the range 2.5-25 mg in conjunction with cyclosporin A-based therapy, according to systemic exposure. Cyclosporin A pharmacokinetics were not affected by coadministration of single oral doses of 0.25-25 mg SDZ RAD.

[Myocardial infarct and rhabdomyolysis after a high-voltage accident with successful resuscitation]. / Myokardinfarkt und Rhabdomyolyse nach einem Hochspannungsunfall mit erfolgreicher Reanimation.

HISTORY AND CLINICAL FINDINGS: A 25-year-old man working as varnisher near a power transmission line sustained a 110,000 V shock. Immediately cardiopulmonary resuscitation (CPR) of the pulseless and unconscious man by lay personnel was continued after 5 minutes by an emergency physician. Normal cardiac rhythm was established after 25 electrical defibrillating shocks and 25 minutes of CPR. He was then taken to hospital by helicopter. On admission the intubated and ventilated patient was precariously stable on high doses of catecholamines. His blood pressure was 100/60 mm Hg, the heart rate 110/min. There were current marks on both hands and the left foot; part of the right pectoral muscle was contracted bulge-like. Creatine kinase activity in serum was raised to 2070 U/l (MB fraction 174 U/l). The ECG showed significant ST-elevations in V2-V4. TREATMENT AND COURSE: At first most attention was paid to stabilising cardiac function. The activity of serum creatine kinase rose to a maximum of 13,881 U/l during the first 6 hours. To prevent renal failure caused by the marked rhabdomyolysis large fluid volumes were administered while intracardiac pressures were monitored via a right-heart catheter and urinary alkalization obtained. The precordial leads of the ECG showed an evolution of changes as in an anteroseptal infarction, the latter confirmed echocardiographically by hypo- and akinesia of the anterior wall. The patient was successfully extubated after 32 hours and was symptom-free without cerebral impairment after 13 days. As subsequent coronary angiography was normal the previous signs of myocardial infarction were most likely caused by current-induced vasospasms. CONCLUSIONS: Immediate resuscitation measures after high-voltage shock can prevent physical and mental damage. The rare diagnosis of acute myocardial infarction requires careful consideration because the usual diagnostic criteria of enzyme abnormalities and symptoms cannot be used.

[Urinary tract infections--causes, differential diagnosis and treatment]. / Harnwegsinfektionen--Ursachen, Differentialdiagnose und Behandlung.

Infections of the urinary tract occur quite frequently in patients of both sex in the practice as well as in the hospital. They are caused mainly by bacteria. However, virus- and significant fungus-infections of the kidney and the urinary tract are observed due to acquired immuno-suppression or induced by the physician. The current knowledge about this problem is still insufficient. Obtaining a careful history, the physical examination and biochemical analysis are still of great value for a successful treatment. Besides the drug therapy, the physiological immunological mechanisms should be activated by unspecific procedures. If they are the only risk factor, urinary tract infections including chronic courses never lead to kidney failure necessitating a dialysis.

Concentration-guided strategies in drug development: experience with a cyclosporine analog in transplantation.

A concentration-guided study was designed to maintain adequate immunosuppression and avoid excessive drug exposure while determining steady-state relative bioavailability of two cyclosporine G (CyG) oral formulations in stable renal transplant patients. In period I (week 1), 26 patients taking cyclosporine A (CyA)-based immunosuppressive regimens entered the study. Doses were titrated to maintain trough concentrations within a predefined range, as measured by fluorescence polarization immunoassay (FPIA). Patients were given an oral solution of CyG in period II (weeks 2-3), and a microemulsion capsule formulation of CyG in period III (weeks 4-5), with dose titration as necessary to achieve trough concentrations in a predefined range, as measured by FPIA. Full pharmacokinetic profiles were obtained on the last day of each study period. Treatment with CyA was reinitiated in period IV (week 6) at the same doses as at study entry. All blood samples were analyzed at the conclusion of the study using CyG- and CyA-specific high-performance liquid chromatography (HPLC). When changing from oral solution to capsule for CyG, an average 19% dose reduction was necessary to compensate for the elevated trough concentrations resulting from the increased bioavailability of the capsule formulation. The concentration-guided strategy was successful in avoiding over-exposure, and resulted in comparable values for area under the concentration-time curve (AUC) for both formulations of CyG. Dose normalization of the pharmacokinetic parameters subsequently allowed calculation of the relative bioavailability. Specifically, a faster rate and greater extent of CyG absorption from the capsule than the oral solution were manifested as a slightly earlier time to peak concentration (tmax), an average 44% increase in the maximum concentration (Cmax), and an average 29% increase in AUC. This experience demonstrated that a concentration-guided trial design allowed a drug development question for a compound with a narrow therapeutic index to be addressed safely and directly in the target patient population.

[The HLA system. An introduction]. / Das HLA-System. Eine Einführung.

The cellular identity is determined by the cell surface antigens. The recognition of self and non-self in vertebrates is mainly controlled by antigens and coded for by the major histocompatibility complex (MHC). Upon recognition of a foreign antigen, the immune system does not only initiate a reaction with the help of cytotoxic T-cells, phagocytes and humoral antibodies; memory cells are also generated, enabling a very swift and powerful response after repeated exposure to the same foreign antigens. These characteristics, although essential for the survival of the organism in a hostile environment, can markedly limit the life of useful and potentially lifesaving organ transplants.

[Automatic ultrasound-guided fine needle biopsy of the transplanted kidney. Risks and uses]. / Automatische ultraschallgesteuerte Feinnadelbiopsie der Transplantatniere. Risko und Nutzen.

Renal allograft biopsy is very valuable in the assessment of graft dysfunction, but complications are frequent and graft loss has even been described. Between 1991 and 1993, a total of 133 graft biopsies were done. We used an automated biopsy gun with a fine-caliber core needle (diameter 1.2 mm) under ultrasound guidance. Histological diagnosis was possible in 95.5% of the biopsies. On average 5.5 glomerula per specimen were obtained. This method proved to be safe, surgical intervention becoming necessary in 2 cases (1.5%).

Cyclosporine pharmacokinetics and variability from a microemulsion formulation--a multicenter investigation in kidney transplant patients.

The steady-state pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine (Sandimmune Neoral) were compared with the commercial formulation (Sandimmune) in 55 clinically stable renal allograft recipients. In study period I (2 weeks' duration), patients entered the study on a stable, individualized twice-daily dosage regimen of the commercial formulation. In period II (2 weeks), they were changed over to the microemulsion formulation at the same dose as at study entry. In period III (2 weeks), dose titration was subsequently allowed if necessary to provide comparable steady-state trough concentrations as at study entry. The commercial formulation was reinstituted during period IV (2 weeks). Safety and tolerability were assessed at weekly clinic visits, and the steady-state pharmacokinetics of cyclosporine in whole blood were characterized at the end of each study period. A milligram-to-milligram dose conversion was adequate when making the initial change between formulations in order to maintain steady-state trough concentrations in the target therapeutic range. Concomitant with this conversion, the steady-state peak concentration and area under the curve increased on average by 59% and 30%, respectively, due to absorption-related differences between the formulations. These increases were not associated with an increase in adverse experiences or changes in blood pressure or clinical laboratory parameters over the first four weeks after the change-over. Trough concentrations were more stable and were more strongly correlated with systemic exposure (area under the curve) during treatment with the microemulsion formulation. Intraindividual coefficients of variation in steady-state peak concentration, time to attain the peak, area under the curve, and percent peak-trough fluctuation ranged from 18% to 74% from the commercial formulation. Variability from the microemulsion formulation was significantly less, ranging from 10% to 22%.

Pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine in renal allograft recipients--a concentration-controlled comparison with the commercial formulation.

The steady-state pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine (Sandimmune Neoral) were compared with Sandimmune in 18 clinically stable renal allograft recipients. In study period I (2 weeks duration), patients entered the study on a stable, individualized twice-daily dosage regimen of Sandimmune. Two approaches were assessed for changing patients over from Sandimmune to Sandimmune Neoral. In period II (2 weeks), doses were converted based on the area under the curve ratio derived from a relative bioavailability study comparing the two formulations in healthy volunteers. In period III (2 weeks), doses were titrated to provide comparable steady-state trough concentrations as at study entry. Sandimmune was reinstituted during period IV (2 weeks). Safety and tolerability were assessed at weekly clinic visits and the steady-state pharmacokinetics of cyclosporine in whole blood were characterized at the end of each study period. Dose conversion in period II based on the AUC ratio derived from healthy volunteers was inadequate for achieving comparable cyclosporine exposure as assessed by steady-state AUC and troughs. The concentration-controlled approach (period III) indicated that maintaining the same cyclosporine dose when changing between formulations yields comparable steady-state trough concentrations. Concomitant with this conversion, steady-state peak concentration and AUC increased on average by 39% and 15%, respectively, due to absorption-related differences between the formulations. These increases were not associated with adverse events or changes in blood pressure or clinical laboratory parameters. Furthermore, they were not detrimental to the transplanted kidney as monitored by ultrasound examination. The pharmacokinetic profiles from Sandimmune Neoral exhibited less variability and yielded a stronger correlation between trough concentration and systemic exposure (AUC) compared with Sandimmune.

Safety and steady-state pharmacokinetics of a new oral formulation of cyclosporin A in renal transplant patients.

The steady-state pharmacokinetics of a new oral formulation of cyclosporin A (Sandimmun Neoral, NOF, a microemulsion) was compared with those of the market formulation (Sandimmun, SIM) in stable renal transplant patients. Both formulations were administered as soft gelatin capsules every 12 h with doses adjusted to provide comparable trough concentrations (CminSS). Whole blood samples were obtained over a steady-state dosing interval (tau), and the cyclosporin A level was determined by a specific monoclonal RIA. Both formulations were well tolerated. The mean doses were 139 +/- 27 mg (SIM) vs. 120 +/- 19 mg (NOF), indicating a milligram dose-conversion factor of approximately 1:1 to yield comparable troughs. NOF exhibited a stronger correlation between AUCtauSS and CminSS (r2 = 0.821) compared with SIM (r2 = 0.288), due in part to less variability in the NOF profiles. Average increases of 39% in CmaxSS and 15% in AUCtauSS during treatment with NOF were not associated with any safety concerns over the 4-week exposure to Sandimmun Neoral, as evidenced by the absence of changes in blood pressure, hematologic and biochemical parameters (including serum creatinine and blood urea nitrogen, BUN) and ultrasound of the transplanted kidney.

[Long-term results following kidney transplantation. An empirical analysis of 467 allogeneic kidney transplants concerning the effect of clinical and immunological variables on graft function]. / Langzeitergebnisse nach Nierentransplantation. Eine empirische Analyse von 467 allogenen Nierentransplantationen über den Einfluss klinischer und immunologischer Variablen auf die Transplantatfunktion.

In a homogeneous group of 467 cadaver kidney transplants performed within one single center between 1979 and 1987, we analysed the influence of main risk factors on long-term survival up to 72 months. Calculating survival rates by Kaplan-Meier actuarial methods the overall graft survival exceeded 71%. The corresponding patient survival was higher than 90%. A good HLA-A-B and DR match was of significant positive influence. Patients who received cyclosporine had a significant better outcome compared to conventional immunosuppressive therapy. A marked advantage was demonstrated for such variables as number of pretransplant blood transfusions, number of rejection episodes, preservation time and renal function as measured by plasma creatinine. Independently age was a main risk factor for curtailed graft survival. Although immunological factors accounted for more than 45% of transplant loss we found a surprisingly high percentage of infections (36%). Vascular problems or technical failure were below 10%. We conclude that a profound clinical examination in the pretransplant period is of high value and remains necessary to identify high risk patients in the long range.

[Cyclosporine-induced gingival hyperplasia in renal transplant patients]. / Ciclosporin-induzierte Gingivahyperplasie bei Patienten mit Nierentransplantaten.

Cyclosporine-induced gingival hyperplasia was investigated in a clinical study of 80 renal transplant patients. 34% of the patients exhibited at least mild gingival hyperplasia in the anterior, and 9% presented this finding also in the posterior region. No direct correlation was found between the oral dose or the whole blood concentration of cyclosporine and the presence of gingival overgrowth. Young and female patients were at a significantly greater risk of developing cyclosporine-induced gingival hyperplasia than the other patients. The presence of dental plaque or gingival inflammation was not found to be related to the incidence of gingival hyperplasia.

Hemofiltration in myoglobinuric acute renal failure.

The frequency of myoglobinuric renal failure is estimated between 8 and 20%. Despite early onset of therapy often the use of renal substitution by hemodialysis or hemofiltration is required. This study of the clinical course of nine patients with myoglobinuric acute renal failure reveals continuous arterio-venous hemofiltration (CAVH) to have an effective clearance for myoglobin. Thus, the time until recovery of renal function as well as the frequency of secondary complications in rhabdomyolysis induced acute renal failure can be distinctly reduced.

Results of a long-term administration of omega-3 fatty acids in haemodialysis patients with dyslipoproteinaemia.

In this study we evaluated the effect of a daily administration of 1 g salmon-oil concentrate containing 0.2 g eicosapentaenoic acid (EPA) on the blood pressure, serum cholesterol, HDL and LDL cholesterol, triglycerides and magnesium of ten patients on chronic haemodialysis. Systolic and diastolic blood pressure values decreased significantly from 156 +/- 27.7/84 +/- 14.3 to 140 +/- 22.8/75.6 +/- 8.21 mmHg. Concordantly, mean arterial pressure (MAP) decreased significantly from 108 to 96 mmHg. Total serum cholesterol decreased significantly by 64%, HDL cholesterol increased by 47% (P less than 0.001). Serum triglyceride values decreased significantly to 48%. There was a distinct decline of magnesium from 1.42 +/- 0.27 to 1.28 +/- 0.13 mg/dl (P less than 0.001). According to these results, the administration of omega-3 fatty acids may be considered as a reasonable approach in the treatment of dyslipoproteinaemia in patients on continuous haemodialysis.

Automatic microdisc electrophoresis for urinary protein analysis: a comparison with standard analysis.

Molecular weight related urinary protein analysis is a very valuable diagnostic tool in modern nephrology. However, until recently urine had to be prepared for analysis by several procedures including concentration. Using a new micro-method it was demonstrated that the clinical significance of urinary disc-electrophoresis is much higher than with former systems. Thus, the use of microdisc electrophoresis (Phast system) is recommended for urinary protein analysis in the future.

Early detection of renal dysfunction: practical recommendations.

Test programmes for early detection of renal dysfunction are urgently needed. They should be adapted to the population under investigation, whether the general population or an occupationally or medically exposed population. At present, there is no clinically relevant definition of renal dysfunction on the basis of pathological test results. Due to the complex function and structure of the kidney, measurement of a single parameter is not sufficient for early detection of renal dysfunction. However, any prophylactic and prospective protocol should take into account the sensitivity and specificity of the applied tests, the amount of work involved and the possible positive effects for the population at risk.

[Comparison of automated micro-disc electrophoresis for the analysis of urine proteins with a conventional system]. / Vergleich der automatisierten Mikro-Disc-Elektrophorese zur Harnproteinanalyse mit einem herkömmlichen System.

Recently a new system for analyzing urinary proteins due to their molecular weight distribution has been introduced. The whole system is automatically driven and uses a silver staining. Due to the small amount of protein necessary for analysis native urine samples can be used. The data presented here show that the automatic micro-disc-electrophoresis (Phast-system) is very useful for any routine testing due to the quick (2 hours) and easily obtainable results with a very high reproducibility. The clinical relevance of urinary protein analysis seems to be much higher using this system.