Changes in immunological parameters after conversion from cyclosporine A to azathioprine in renal transplant recipients.

Long term CsA therapy did not interfere with the basal levels of natural killer (NK) activity in stable cadaveric renal transplant recipients. However, 3 months after changing immunosuppressive therapy from CsA to AZA, NK activity was significantly decreased (36 +/- 25% vs 19 +/- 15%, P less than 0.01). Following in vitro exposure to IFN-gamma an increase in NK activity from 36 to 44% (P less than 0.05) could be induced during CsA therapy but this was no longer observed after conversion to AZA (19 to 22%, N.S.). A prominent decline in the number of NK cells expressing the surface receptor for the Fc portion of IgG was also found postconversion. The IFN-gamma production capacity after mitogen stimulation of unprimed lymphocytes was more depressed during CsA than during AZA therapy (median 25 vs 80 U/ml 10(6) cells, P less than 0.05), suggesting a reversible inhibition of CsA on lymphokine production. Despite the better IFN-gamma production capacity, both the activity, inducibility and number of NK cells were significantly lower under AZA therapy than under CsA therapy. These findings indicate that CsA exerts its immunosuppressive action without an important interference with NK activity. Monitoring mononuclear cells showed a decrease in absolute numbers of all phenotypically distinct cells studied after conversion. The prominent decrease in CD 8 cells resulted in an increase of CD 4/CD 8 ratio.

Mononuclear cells infiltrating kidney allografts in the absence of rejection. Effect of conversion from cyclosporin to azathioprine therapy.

Focal small mononuclear cell infiltrates were found in renal allograft biopsies of 13/14 transplant recipients with a stable function after long-term cyclosporin A (CsA) therapy. Phenotypical analysis of the infiltrating cells using monoclonal antibodies showed a slight preponderance of T cells (56% +/- 8%), with only small percentages of B cells (5% +/- 2%), NK cells (2% +/- 1%), and monocytes (2% +/- 1%). Within the T-cell population the median calculated CD4/CD8 ratio was 1:3. Thirty-five percent of the infiltrating mononuclear cells remained unidentified with the monoclonal antibody panel used (silent cells). Three months after immunosuppressive therapy had been changed from CsA to azathioprine (AZA), the size of the infiltrates was significantly increased and there was a marked invasion of mononuclear cells between tubular epithelium despite a significant improvement in creatinine clearance (P less than 0.01). the phenotypical composition of these infiltrates was dominated by T cells (84% +/- 3%), with a median CD4/CD8 ratio of 2:7 due to an increase in CD4+ cells and a decrease in CD8+ after conversion (P less than 0.05). The percentages of B cells, NK cells, and monocytes showed no significant changes after conversion. During AZA therapy nearly all infiltrating mononuclear cells were stained with the monoclonals used, leaving no silent cells postconversion.

Histological lesions associated with cyclosporin: incidence and reversibility in one year old kidney transplants.

To determine the type and reversibility of the long term effects of cyclosporin A, biopsy specimens were taken from 20 recipients of kidney allografts, twelve months after transplantation, and three months later, during which time azathioprine was substituted for cyclosporin A. Arteriolar IgM and complement deposits and tubular isometric vacuolisation associated with cyclosporin A treatment significantly regressed after stopping this drug one year after transplantation. Conversion to azathioprine was accompanied by an increase in mononuclear cell infiltrates and tubulitis despite an evident improvement in renal function. Nephrotoxicity as a result of cyclosporin A is common but can be reversed--at least partially.

Intact humoral immune response in patients on continuous ambulatory peritoneal dialysis.

After influenza vaccination no statistically significant difference in antibody response was observed between patients on continuous ambulatory peritoneal dialysis (CAPD) and healthy volunteers while a large group of hemodialysis (HD) patients was found to have a significantly lower response rate. This difference remained statistically significant when CAPD patients were compared to a matched HD group. As the antibody formation after influenza vaccination is a T cell-dependent phenomenon, the normal immune response to vaccination suggests an intact humoral and cellular immunity in CAPD patients.

Who should be converted from cyclosporine to conventional immunosuppression in kidney transplantation, and why.

Twenty-three cadaveric renal allograft recipients with stable but compromised kidney function were electively converted from cyclosporine to azathioprine one year after transplantation. Within a few weeks glomerular filtration rate (GFR) rose by 40% and serum creatinine fell from 171 +/- 12 (mean +/- SEM) to 129 +/- 7 mumol/L. The increase in GFR was due to an increase in effective renal plasma flow of 21%. This suggests that one year of continuous cyclosporine (CsA) therapy does not result in irreversible structural renal damage. Although antihypertensive treatment was not changed, blood pressure fell from 142 +/- 4/90 +/- 3 to 123 +/- 3/77 +/- 2 mmHg. In addition a significant drop in serum cholesterol and triglycerides and an improvement in glucose tolerance were found. The beneficial effects on renal function, blood pressure, and metabolic indices were, however, outweighed by a high incidence of postconversion rejection in recipients of a second allograft. For these patients conversion from CsA to azathioprine seems therefore contraindicated. Recipients of a first kidney allograft can be converted safely, as long-term CsA administration in these patients induced a solid engraftment. The sequelae of the mode of treatment--impaired renal function, hypertension, and metabolic disturbances--are reversible even after late conversion.

Trivalent influenza vaccine in patients on haemodialysis: impaired seroresponse with differences for A-H3N2 and A-H1N1 vaccine components.

One hundred and one patients on haemodialysis, 21 patients on peritoneal dialysis and 30 healthy controls received a trivalent split vaccine containing 15 micrograms haemagglutinin of a recent influenza A-H3N2, influenza A-H1N1 and influenza B strain, respectively. Antibody production after four weeks was determined by the haemagglutination-inhibition test and expressed as response rate, protection rate and overall mean fold increase. The patients on haemodialysis revealed a diminished seroresponse, as compared to patients on peritoneal dialysis and controls. For influenza A-H3N2, this was less distinct than for the other two antigens. In patients on haemodialysis the protection rate was 66% against the A-H3N2 vaccine component (versus 85% in controls, not significant), but only 25% against A-H1N1 and 27% against B (versus 84 and 77% in controls, p less than 0.001). Duration of haemodialysis up to eight years did not affect seroresponse. Patients on haemodialysis who were primed for influenza A-H1N1 in the period 1947-1957, reacted markedly better to the A-H1N1 vaccine component than subjects of other priming periods. A booster injection of the same vaccine dosage four weeks after the first immunization, performed in 98 patients on haemodialysis, was of little value: it had virtually no effect with regard to influenza A-H1N1 and influenza B, and showed, though significantly better, still poor results for A-H3N2. The differences in seroresponse between the A-H3N2 and A-H1N1 vaccine component suggest a major defect of primary, and a minor defect of secondary humoral response in patients on haemodialysis. The consequences for vaccine policy in these patients are discussed.

Impairment of the immune response to influenza vaccination in renal transplant recipients by cyclosporine, but not azathioprine.

Influenza vaccination has been strongly recommended for immunosuppressed renal transplant recipients. However, immunosuppression may lead to impaired antibody responses. We studied the antibody response to an inactivated trivalent influenza vaccine in 59 renal transplant recipients with life-sustaining kidney function: 21 were on cyclosporine and prednisone, 38 on azathioprine and prednisone. Healthy volunteers (n = 29) and patients on hemodialysis (n = 28) served as controls. Despite comparable renal allograft function, cyclosporine-treated patients had a significantly lower immune response against influenza A viruses than azathioprine-treated patients, whether mean antibody levels, fourfold titer rise, or seroconversion to protective titers was analyzed. No significant differences in antibody responses were found between healthy controls and patients on azathioprine. The patients on hemodialysis showed an impaired response to vaccination. However, in contrast to the cyclosporine-treated patients, booster immunization proved valuable in this group.