Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders.

Various complement-mediated renal disorders are treated currently with the complement inhibitor eculizumab. By blocking the cleavage of C5, this monoclonal antibody prevents cell damage caused by complement-mediated inflammation. We included 23 patients with atypical haemolytic uraemic syndrome (aHUS, n = 12), C3 glomerulopathies (C3G, n = 9) and acute antibody-mediated renal graft rejection (AMR, n = 2), treated with eculizumab in 12 hospitals in Germany. We explored the course of complement activation biomarkers and the benefit of therapeutic drug monitoring of eculizumab. Complement activation was assessed by analysing the haemolytic complement function of the classical (CH50) and the alternative pathway (APH50), C3 and the activation products C3d, C5a and sC5b-9 prior to, 3 and 6 months after eculizumab treatment. Eculizumab concentrations were determined by a newly established specific enzyme-linked immunosorbent assay (ELISA). Serum eculizumab concentrations up to 1082 µg/ml point to drug accumulation, especially in paediatric patients. Loss of the therapeutic antibody via urine with concentrations up to 56 µg/ml correlated with proteinuria. In aHUS patients, effective complement inhibition was demonstrated by significant reductions of CH50, APH50, C3d and sC5b-9 levels, whereas C5a levels were only reduced significantly after 6 months' treatment. C3G patients presented increased C3d and consistently low C3 levels, reflecting ongoing complement activation and consumption at the C3 level, despite eculizumab treatment. A comprehensive complement analysis together with drug monitoring is required to distinguish mode of complement activation and efficacy of eculizumab treatment in distinct renal disorders. Accumulation of the anti-C5 antibody points to the need for a patient-orientated tailored therapy.

Extracorporeal photopheresis increases neutrophilic myeloid-derived suppressor cells in patients with GvHD.

Extracorporeal photopheresis (ECP) is beneficial in patients with T-cell-mediated disorders, including GvHD, but the underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells characterized by their capacity to suppress T-cell proliferation. We quantified MDSCs by flow cytometry in peripheral blood from patients after BMT with GvHD before and after ECP treatment, patients after BMT but without GvHD and age-matched healthy controls. MDSC functionality was analyzed using T-cell proliferation, cytokine release and arginase activity. GvHD patients showed increased baseline percentages of neutrophilic MDSCs (PMN-MDSCs) compared with healthy controls and patients after BMT without GvHD. ECP treatment in GvHD patients rapidly increased circulating percentages of PMN-MDSCs. Functionally, PMN-MDSCs efficiently dampened Th1 and Th17 responses and were paralleled by an increase of cellular and extracellular arginase activity. Following ECP longitudinally over 16 weeks, two GvHD responder subgroups were identified, with group one continuously increasing PMN-MDSCs and group two with stable or decreasing PMN-MDSCs over time. This study demonstrates for the first time that ECP increases T-cell-dampening PMN-MDSCs in GvHD patients, a finding that should be confirmed in larger series of GvHD patients.

[The treatment with levamisole of frequently recurring steroid-sensitive idiopathic nephrotic syndrome in children]. / Die Behandlung des häufig rezidivierenden steroidsensiblen idiopathischen nephrotischen Syndroms im Kindesalter mit Levamisol.

BACKGROUND AND OBJECTIVE: The treatment of frequently relapsing steroid-sensitive nephrotic syndrome in children with established immunosuppressive drugs (steroids, cyclophosphamide, cyclosporin A) sometimes presents problems because of the expected incidence of side effects. Stimulation of the immune system with the anthelminthic drug levamisole in this disease has been documented. Aim of this study was to assess in a prospective but uncontrolled series of observations its value and side effects. PATIENTS AND METHODS: 25 patients (15 boys, ten girls; median age 10 [3.5-22] years) were given levamisole, 2 mg/kg/48 h. Before this treatment was started eight of the children/adolescents (32%) had frequent relapses and 17 (68%) had become steroid-dependent. Treatment was started during steroid-induced remission and continued for 3-24 (median 6) month, while steroids were discontinued after four weeks. RESULTS: Relapse frequency per patient month was reduced from a mean of 0.5 (0.33-0.83) before to 0.31 (0-0.67) during levamisole administration (P < 0.001). In 12 patients (48%) no or considerably fewer relapses were observed. Patients with exclusively frequent relapses responded to levamisole better than those with steroid dependence (7/8 [87.5%] vs. 5/18 [27.7%], P = 0.01). Side effects were reversible leukopenia in two patients and nonspecific skin rash as well as epigastric pain in one patient. CONCLUSION: Levamisole is an efficacious addition or alternative, with a low incidence of side effects, in the treatment of frequently relapsing nephrotic syndrome, particularly so in yet steroid-dependent patients.

[Bilharziasis as the etiology in hematuria and proteinuria in childhood]. / Bilharziose als Ursache von Hämaturie und Proteinurie im Kindesalter.

Haematuria and proteinuria are important symptoms of primary and secondary nephropathies. We report three african children presenting to our center in whom infection with S. haematobium resulted in haematuria and proteinuria. The third patient concomitantly suffered from steroid-sensitive relapsing nephrotic syndrome with the histological features of focal and segmental glomerulo-sclerosis. The diagnosis was in all cases established by light microscopy and urinary symptoms improved after treatment with praziquantel. In the third patients long term remission of the nephrotic syndrome could be maintained after 4 doses of praziquantel for recurrent bladder symptoms. We conclude that bilharziosis must be considered in the differential diagnosis of children with haeamturia and proteinuria even in Europe. The diagnosis can be established easily by light microscopy and an effective and low-risk treatment (with Praziquantel) can be offered.

Increased need of erythropoietin during peritonitis in children on continuous peritoneal dialysis.

Ten continuous ambulatory peritoneal dialysis (CAPD) patients experienced 23 episodes of peritonitis and were treated with intraperitoneal (IP) antibiotics as per sensitivity report. Serum ferritin was measured before and after the treatment. In 6 patients, erythropoietin (EPO) was also measured before and after the treatment. There was a significant drop in the serum EPO levels after therapy compared to the levels before, whereas serum ferritin levels did not change.

[Value of lymphography, computer tomography and ultrasound in the diagnosis of infradiaphragmatic malignant lymphomas in children]. / Der Stellenwert von Lymphographie, Computertomographie und Ultraschall bei der Diagnostik infradiaphragmaler maligner Lymphome bei Kindern.

25 children with Hodgkin's disease and 6 children with Non-Hodgkin-lymphoma were reviewed in order to compare the diagnostic value of lymphography, CT and sonography. As compared with staging-laparotomy, sensitivity for the detection of lymph node involvement was 78% for lymphography, 33% for CT and 57% for the ultrasound examination. Specifity was 55%, 88%, and 83% respectively. Undetected involvement of splenic and liver hilar lymph nodes, unspecific lymphadenitis and fluid-filled bowl loops caused most of the false negative and false positive findings. In 10 children histological examination showed splenic involvement. No splenic lesion was seen by CT in 7 of these children. Splenic disease could be clearly identified by ultrasound in only one child. Although children with lymph node involvement had always splenic manifestations of malignant lymphomatous disease it is concluded that staging laparotomy is an indispensable tool in diagnosing malignant lymphoma. Lymphography should not be abandoned with children. It should be used in combination with either CT or ultrasound examination.

[Torsion of a wandering spleen]. / Torquierte Wandermilz.

The torsion of an ectopic (= wandering) spleen is a rare entity especially in children. Clinically it presents either with signs of an "acute abdomen" or as a fairly painful abdominal "tumor" of the chronic recurrent type. Ultrasonography, arteriography, and additional scintigraphy in special cases are of greatest value in the preoperative diagnostic management. Splenopexy, sometimes after resecting parts of a very enlarged organ, is the therapy of choice. The complete exstirpation of the ectopic spleen should be reserved only for exceptional cases. By presenting a case report, the etiologic factors, the clinical signs, the diagnostic steps, the differential diagnostic considerations as well as the mode of therapy for this rare disease are described and discussed.

[Results and specific problems in unrestricted indications for kidney transplantation in children]. / Ergebnisse und spezifische Probleme bei unbegrenzter Indikation zur Nierentransplantation im Kindesalter.

In Hamburg 22 children had 33 renal transplantations in the time from 1976 till 1982. 58% of all children in this area with end-stage renal disease have now a functioning graft compared to only 11% of the adult patients. This is the result of preferred transplantation in children whenever possible. Retransplantation was more frequent in children (32%) than in adults (19%). 5 years function rate of renal allografts is significantly worse in children than in adults. Growth and degree of rehabilitation are described in 12 pediatric renal allograft recipients who survived with a functioning graft for at least 3 years. Good rehabilitation as indicated by attendance of school and employment was reached in 83% of these patients. Different growth patterns occurred. Clinical factors associated with growth performance include graft function and age at the time of transplantation.