Down-regulation of interferon-gamma parallels clinical response to selective leukocyte apheresis in patients with inflammatory bowel disease: a 12-month follow-up study.

BACKGROUND & AIMS: Pilot studies have indicated a therapeutic role for an apheresis device (Adacolumn) that selectively adsorbs leukocytes in patients with inflammatory bowel diseases. It may also exert immunoregulatory effects contributing to its clinical efficacy. This study aimed to correlate the clinical response to leukocyte apheresis with the expression of key cytokines in mucosal tissue, in peripheral leukocytes, and in plasma. METHODS: Ten patients (seven with Crohn's disease and three with ulcerative colitis, median age: 31 years) with mild to moderately chronic activity were recruited to an open study. Patients were refractory to or had a relapse despite conventional treatment including azathioprine. Leukocyte apheresis was performed once a week for five consecutive weeks. Clinical efficacy was assessed on week 7 and after 12 months. Colonoscopy with multiple biopsies was performed at the start of the study and after 7 weeks for semiquantitative immunohistochemical analyses of cytokines. Cytokine levels in blood and the proportion of cytokine producing CD4+ and CD8+ lymphocytes were determined. RESULTS: The apheresis procedures were well tolerated and no major adverse events were encountered. The median clinical activity score decreased from 12 to 7 on week 7 (P=0.031, n=9) and to 4 after 12 months (P=0.004, n=9). Five patients were in clinical remission at the 12th month. Tissue interferon (IFN)-gamma-positive T-cells decreased in clinical responders (P=0.027) after apheresis. In parallel, significantly lower levels of IFN-gamma-producing lymphocytes were detected in peripheral blood. IFN-gamma-positive cells in pretreatment biopsies completely disappeared or decreased in posttreatment biopsies sampled on week 7 in responders (P=0.027) and appeared to predict the maintenance of long-term remission or response after 12 months. CONCLUSIONS: Leukocyte apheresis is a novel and safe nonpharmacological adjunct therapy that may prove useful in steroid refractory or dependent patients when conventional drugs have failed. Down-regulation of IFN-gamma in mucosal biopsies and in peripheral leukocytes may be a predictive marker for sustained, long-term response.

ABO-incompatible kidney transplantation and rituximab.

We have designed a protocol for ABO-incompatible kidney transplantations based on antigen-specific immunoadsorption rather than plasmapheresis to remove anti-A or anti-B antibodies and with a Prograf/Cellcept/prednisolone protocol using rituximab rather than splenectomy to prevent rebound antibodies. Twelve patients have successfully received transplants with this protocol. The ABO-antibodies were readily removed by the antigen-specific immunoadsorption and maintained at a low-level posttransplantation. There were no side effects. All patients have normal renal transplant function with a follow-up of 1 to 34 months.

Plasma exchange or immunoadsorption in patients with rapidly progressive crescentic glomerulonephritis. A Swedish multi-center study.

A therapeutic removal of antibodies may be achieved by immunoadsorption (IA) or by plasma exchange (PE). The aim of this prospective randomised study was to compare the efficacy of these different techniques with regard to treatment of patients with rapidly progressive glomerulonephritis (RPG) having at least 50% crescents. Forty-four patients with a RPG were included for treatment either by IA or PE (with albumin as substitution for removed plasma). All patients were additionally treated with immunosuppression. A median of 6 sessions of PEs were performed in 23 patients compared with 6 IAs in 21 patients. Goodpasture's syndrome (GP) was present in 6 patients (PE 3, IA 3). All of them started and ended in dialysis, two died. Among the remaining 38 patients (26 men, 12 women) 87% had antibodies to ANCA. Creatinine clearance for PE versus IA were at a median at start 17.1 and 19.8 ml/min, and at 6 months 49 and 49 ml/min, respectively. At 6 months 7 of 10 patients did not need dialysis (remaining: IA 0/5 and PE 2/5, n.s.). The extent of improvement did not differ between the groups. Three patients died during the observation period of 6 months (IA 2; PE 1, on HD). Although no difference was found between the IA or the PE group this study shows that the protocol used was associated with an improved renal function in most patients (except for Goodpasture's syndrome) whereas 70% of them could leave the dialysis program.

Long-term effects on lymphocytotoxic antibodies and immune reactivity in hemodialysis patients treated with recombinant human erythropoietin.

Twenty-six hemodialysis patients were given human recombinant erythropoietin to correct anemia. Eighteen patients had previously received multiple transfusions and 18 had been transfused within the preceding six months. Ten patients had lymphocytotoxic antibodies (panel reactive antibodies, PRA), measured as percent positive reactions against a panel of lymphocytes from 22 lymphocyte donors before the start of erythropoietin treatment. There was a significant decrease in mean PRA activity from 60% to 35% (p less than 0.05) during 6-18 months of treatment. Three of 26 patients received blood transfusions after the start of erythropoietin treatment, because of intercurrent disease or blood loss. Kidney transplantation was performed in four of the PRA-positive patients and in eight of the PRA-negative patients. Nine kidney transplants are currently functioning. The three graft losses were due to rejections. The lymphocyte immune reactivity measured after stimulation in MLC (mixed lymphocyte culture) against pooled lymphocytes and after PHA (phytohemagglutinin) and Con A (Concanavalin A) stimulation, was significantly lower in the hemodialysis patients than in the healthy controls (p less than 0.05). The responses did not change after correction of anemia. The number of OKM1 (Ortho's monoclonal antibody against M1 cells [monocytes])-positive cells among peripheral blood lymphocytes were significantly higher (p less than 0.001) in uremic patients than in healthy controls. After 12-18 months of treatment with erythropoietin this difference disappeared.(ABSTRACT TRUNCATED AT 250 WORDS)

Living donor nephrectomy. Complication rates in 490 consecutive cases.

490 living donor nephrectomies were performed during a 25-year period, all through a retroperitoneal approach. In this report, short-term complications and donor renal function are analysed. There was no mortality. The major complication rate was 1.4%. There were 5 cases of postoperative haemorrhage requiring reoperation, one of which developed non-A-non-B hepatitis. There was one case each of septicemia and pulmonary embolism. All these patients recovered. Minor complications were noted in 13.6% of the cases, mostly bacteriuria or minor pulmonary infiltrates. There were 5 cases of reversible heart disorders and 6 cases of mental disorders. After 6-12 months, all donors had satisfactory function of the remaining kidney, which had increased its GFR by 32-38%. We conclude that the short-term consequences of donor nephrectomy are acceptable. From previous reports, from this unit and from others, it is evident that the procedure does not carry any definite long-term health risks. With a permanent shortage of cadaveric organs and with continued superiority in the outcome of living donor transplantations, this important resource should not be disregarded.

Impaired glucose tolerance in cyclosporine-prednisolone-treated renal graft recipients.

In 33 renal transplant patients, an intravenous glucose tolerance test (IVGTT) was performed, and fasting plasma C-peptide concentrations analyzed. Nineteen of the patients were on treatment with cyclosporine-prednisolone (CsA-Po), and 14 were treated with azathioprine-prednisolone (Aza-Po). In the Aza-Po group, the K-values at IVGTT were normal in 13/14, but in the CsA-Po group they were only normal in 9/19 (P = 0.02). The fasting C-peptide levels were significantly higher in the CsA-Po group (P less than 0.001). within this group, there was no correlation between C-peptide level and serum-creatinine concentration, i.e. retention of C-peptide due to decreased renal function as judged by serum creatinine level was not suspected. Intrinsic prednisolone clearance was determined in the CsA-Po patients and was found to be lower than that previously described in Aza-Po patients. However, between those CsA-Po-treated patients with a pathologic K-value at IVGTT and those with a normal K-value there was no difference in prednisolone clearance, fasting C-peptide levels, CsA dose, or serum-creatinine concentrations. The pathophysiology of the cyclosporine-induced glucose intolerance is uncertain, and increased insulin resistance is possible.