Kurt Derfler

Immunoadsorption in severe C4d-positive acute kidney allograft rejection: a randomized controlled trial.

Antibody‐mediated rejection (AMR) frequently causes refractory graft dysfunction. This randomized controlled trial was designed to evaluate whether immunoadsorption (IA) is effective in the treatment of severe C4d‐positive AMR. Ten out of 756 kidney allograft recipients were included. Patients were randomly assigned to IA with protein A (N = 5) or no such treatment (N = 5) with the option of IA rescue after 3 weeks. Enrolled recipients were subjected to tacrolimus conversion and, if indicated, ‘anti‐cellular’ treatment. All IA‐treated patients responded to treatment. One death unrelated to IA occurred after successful reversal of rejection. Four control subjects remained dialysis‐dependent. With the exception of one patient who developed graft necrosis, non‐responders were subjected to rescue IA, however, without success. Because of a high graft loss rate in the control group the study was terminated after a first interim analysis. Even though limited by small patient numbers, this trial suggests efficiency of IA in reversing severe AMR.

Flow cytometry based detection of HLA alloantibody mediated classical complement activation

Complement-dependent cytotoxicity (CDC) panel reactive antibody (PRA) testing is used to assess recipient presensitization and post-transplant alloantibody formation in transplant recipients. However, CDC test results can be affected by false-positive reactions brought about by autoantibodies or antilymphocyte reagents. As an alternative to the CDC-PRA assay, detection of HLA alloantibodies using HLA antigen-coated microbeads (FlowPRA test) was recently established. FlowPRA testing, however, does not distinguish between (presumably more harmful) complement-fixing and noncomplement-fixing alloantibodies. In this study, we established a novel assay allowing flow cytometric detection of HLA alloantibody dependent classical complement activation using the FlowPRA test. For the detection of complement activation, FlowPRA beads were incubated with sera from highly sensitized dialysis patients (CDC-PRA reactivity >60%) and then stained for C4 (C4d, C4c) and C3 (C3d, C3c) fragments, as well as C1q deposition using indirect immunofluorescence. We demonstrate alloantibody induced induction of C4 fragment, and in parallel C1q deposition to HLA class I or class II beads. As shown by immunoblotting, C4 staining was not due to the presence of preformed C4 fragment-IgG/M complexes. Indeed, C4 fragment deposition in our in vitro system was demonstrated to result from de novo complement activation. First, inactivation of C4 by treatment of sera with methylamine, which inhibits cleavage of the internal thioester, completely abolished C4 fragment deposition. Second, C4 fragment deposition was not observed in the evaluation of C4-free immunoadsorption eluates obtained from highly sensitized dialysis patients. After supplementation with complement, however, eluates induced C4 deposition. Deposition of C4 split products and C1q was temperature-dependent with maximum binding after incubation at 4 degrees C for 60 min. In contrast, maximum C3 fragment deposition was found at 37 degrees C. At this temperature, C3 deposition occurred in an alloantibody and C4-independent fashion, presumably as a result of alternative complement activation. In summary, we describe a novel cell-independent and easy-to-perform PRA test that permits flow cytometry based detection of alloantibody induced classical complement activation. Future studies will have to evaluate its possible relevance as an alternative to CDC-PRA testing in clinical transplantation.

Recommendations for the use of immunoapheresis in the treatment of autoimmune bullous diseases

Despite the use of high‐dose systemic corticosteroids in combination with other immunosuppressants, in some patients with autoimmune bullous diseases only insufficient improvement is achieved. In these cases and in acute severe disease, adjuvant immunoapheresis has been increasingly used. A consensus meeting was held in mid‐2005 in Hamburg, aiming at developing guidelines for the use of immunoapheresis in the treatment of autoimmune bullous diseases.This paper summarizes the experts‘ recommendations.

Rapid decrease of serum cholesterol concentration and postpartum depression.

On the basis of studies of pharmacological reduction of serum lipid concentrations, it has been suggested that reduction in serum cholesterol and triglyceride is associated with occurrence of depressive symptoms, suicides, and violent deaths.1 2 3 Pregnancy induces a physiological rise in both serum cholesterol and triglyceride concentrations, with peak concentrations at term and a rapid decrease within a few days after delivery. Maternity blues is a common complication of the puerperium independent of obstetric variables.4 We postulated that the sudden fall in blood lipids after delivery could serve as a “natural” model to test the suggested association between serum lipids and mood. We studied 20 healthy primiparous women (mean age 25.3, SD 3.7, range 19-34 years) without substantial marital, health, or socioeconomic problems and without a history of psychiatric disorders who registered consecutively for obstetric …

Increased serum activity of interleukin-2 in patients with pre-eclampsia.

Pre-eclampsia is a severe complication in pregnancy, manifested by hypertension, proteinuria and oedema, and in the most severe cases leading to fetal death. Immunological mechanisms are generally assumed to be of major importance in the genesis of the disease. Foidart showed anti-laminin antibodies to be involved in preeclampsia. [ 11. Circulating immune complexes [2] and complement activation [3] as well as alterations in T-cell subsets [4] and suppressor activity [5] have also been observed, but still there remains much uncertainty about the pathophysiological mechanisms involved. IL-2 is an important cytokine in the T-cell pathway [6] as it is released by antigenstimulated T cells and enhances alloantigen reactivity by augmentation of cellular cytytoxic function. The question of whether increased cytokine release can be used as a diagnostic marker for an ongoing alteration of maternofetal immune response prompted us to study the serum activity of IL-2 in pregnant women suffering from pre-eclampsia.

Extracorporeal lipid elimination for treatment of gestational hyperlipidemic pancreatitis

Gestational hyperlipidemia complicated by pancreatitis during the 24th week of gestation has been successfully managed by long-term extracorporeal elimination of triglyceride-rich lipoproteins. Three modes of treatment (plasma exchange, immunospecific apheresis, and a combination of both treatments) were compared for efficacy as therapy for metabolic derangements, altered blood rheology, and the loss of immunoglobulins. Treatments were performed by means of a peripheral venovenous approach. A combination plasma exchange/apheresis technique was highly effective; the loss of immunoglobulins remained acceptable. Clinical symptoms of pancreatitis subsided within 24 hours of the first treatment. A relapse during the 32nd week of gestation necessitated treatments more frequently than once a week. At the 36th week of gestation, after confirming lung maturity as indicated by a lecithin-sphingomyelin ratio of > 2.0, a cesarean section was performed. A healthy boy was delivered (2470 g; Apgar score, 9/10). This is the first report to show that long-term extracorporeal elimination of lipoproteins is a highly effective treatment of hyperlipidemic gestational pancreatitis.

Effects of combined low-density lipoprotein apheresis and aggressive statin therapy on coronary calcified plaque as measured by computed tomography

Eight patients with heterozygous familial hypercholesterolemia who received combined long-term low-density lipoprotein apheresis and high-dose statin therapy showed a significant decrease in volume of coronary calcium over a period of 29 months as measured by, computed tomography. This suggests that the effects of aggressive lipid-lowering therapy can be assessed non-invasively and may be used as surrogate end points when testing new therapies.

Immunoadsorption and plasma exchange in pregnancy.

Background: During pregnancy, familial hyperlipidemia or systemic lupus erythematosus (SLE) can exacerbate having devastating consequences for both mother and fetus. Immunoadsorption is established for removal of pathogenic proteins lipoproteins or autoantibodies, but this procedure has only rarely been used in pregnancy. Methods: We evaluated retrospectively 126 extracorporeal treatments during six pregnancies. Forty low-density lipoprotein immunoadsorptions, 6 sole plasma exchanges and 36 combined procedures (plasma exchange followed by immunoadsorption) were performed for severe hypertriglyceridemia, complicated by acute pancreatitis. Forty-four IgG immunoadsorptions were executed in 2 pregnant women suffering from SLE with a disastrous course during prior pregnancies. Results: In hyperlipidemic pregnant women, mean triglyceride levels prior to treatment were 3,841 ± 2,076 mg/dl (mean ± SD) and total cholesterol was 617 ± 354 mg/dl. Until delivery, a 27% reduction of triglycerides could be achieved. Clinical and serological signs of pancreatitis disappeared after initiation of extracorporeal therapy. Four healthy babies were delivered (birthweights between 2,250 and 3,360 g). In 1 woman suffering from SLE, intrauterine fetal death occurred in the 22nd week of gestation despite a reduction of cardiolipin antibodies by 69%. The second case (a twin pregnancy) was complicated by steroid-resistant antibody-mediated anemia. Due to frequent immunoadsorptions, red blood cell count improved (reduction of antierythrocyte antibodies by 66.6%) and 2 healthy babies (birthweights 2,120 and 2,350 g) were delivered by cesarean section. Conclusion: Long-term antibody-based immunoadsorption has been demonstrated to be safe and well tolerated in pregnant women and enables normal intrauterine/fetal development. Although rarely indicated during pregnancy, this treatment modality might be a promising new technique for removal of autoantibodies and lipoproteins in patients with serious gestational complications without sufficient response to conventional therapy.

Renal Replacement Therapy in Type 2 Diabetic Patients: 10 Years' Experience

The objective of this study was to determine the impact of renal transplantation and hemodialysis treatment on outcome of elderly diabetic patients with end-stage renal disease (ESRD) among other factors related to survival. Results of treatment of ESRD in 78 patients with non-insulin-dependent diabetes mellitus (type 2) showed a survival rate of 58% at 1 year and 14% at 5 years, independent of treatment modality. Patients who received a renal allograft had a higher survival rate as compared with patients on hemodialysis treatment (5-year survival, 59% v 2%; P < 0.005). Diabetic patients with a history of myocardial infarction, stroke, or peripheral gangrene before onset of renal replacement therapy had a worse prognosis in comparison to patients without vascular complications (5-year survival, 2% v 21%; P < 0.05). Analysis of patients who survived less than 6 months and more than 24 months was performed. Long-term survivors were slightly younger, had diabetes for a shorter period, and showed a better metabolic control of diabetes mellitus. Sixteen long-term survivors received a renal allograft. In contrast, only three short-term survivors were transplanted. Furthermore, short-term survivors also had a greater than 70% incidence of severe vascular complications before renal replacement therapy. A history of myocardial infarction, stroke, or peripheral gangrene is an independent predictor of decreased survival, irrespective of whether the patients were transplanted or maintained on chronic hemodialysis treatment. In contrast, renal transplantation improved survival of elderly diabetic patients without vascular complications and should be the treatment of choice in this specific group of patients.

Lupus nephritis: prolonged immunoadsorption (IAS) reduces proteinuria and stabilizes global disease activity

BACKGROUND Systemic lupus erythematosus (SLE) is characterized by pathogenic autoantibodies, which can be removed by extracorporeal procedures. While previous studies have shown short-term efficacy of immunoadsorption (IAS) in SLE, no information on long-term benefit and safety is available. METHODS IAS was offered to patients with highly active renal disease when conventional therapy had failed. Eleven patients entered the prolonged IAS programme and were followed for up to 10 years (mean 6.4 ± 3.5). Efficacy of IAS was determined by reduction in proteinuria (primary outcome), global disease activity [SLE Disease Activity Index (SLEDAI)] and anti-double-stranded DNA (anti-dsDNA) levels (secondary outcomes). Full/partial remission was defined as ≤ 0.5/≤ 1.0 g/day for proteinuria, ≤ 5/≤ 8 for SLEDAI and ≤ 25/≤ 50 IU/mL for anti-dsDNA levels. We further assessed flares, infections, malignancies and procedure-related adverse events. RESULTS Short-term IAS (≤ 1 year) resulted in a significant reduction of proteinuria (9.2 ± 3.7 to 2.3 ± 2.4, P = 0.0001), disease activity (SLEDAI 19 ± 8 to 4 ± 2, P = 0.0004) and dsDNA levels (168 ± 205 to 45 ± 34, P = 0.001). In patients without remission after 1 year (n = 5), prolonged IAS decreased proteinuria from 4.3 ± 2.4 to 0.5 ± 0.4 g/day, P = 0.02. At the end of observation, complete remission in proteinuria was achieved in seven patients (64%) and partial remission in two (18%) additional patients. One patient flared and was discontinued; in all other patients, disease activity and anti-dsDNA stabilized at remission levels. Flares (0.28 ± 0.30) and infections (0.66 ± 0.70 per patient/year) were relatively uncommon; no malignancies, anaphylactic or orthostatic adverse events were observed. CONCLUSION IAS is effective in short-term use but prolonged IAS can provide additional therapeutic benefit while showing an acceptable safety profile. The vast majority of initially therapy-refractory patients met the remission criteria at the end of observation.