The influence of prophylactic immunosuppressive regimens on natural killer and lymphokine-activated killer cells in renal transplant recipients.

We investigated natural-killer cells in 81 renal transplant recipients (RTR) in order to define what kind of in vivo prophylactic immunosuppression could be responsible of the impairment of these NK cells. Cell-surface phenotyping was performed by direct immunofluorescence with Leu7 (CD57), Leu11 (CD16), and Leu19 (CD56) antibodies, in one- and two-color stainings. Functional properties were analyzed with freshly isolated nonadherent mononuclear cells (NK activity) and after in vitro activation with r-IL-2 (LAK activity), in cytotoxicity assays using K562 and Daudi tumor lines as specific targets. A flow cytometry technique using carboxy-Fluorodiacetate was applied to monitor the cytotoxicity of NK cells. Our data emphasize the already known deficiency of NK cells: both NK subsets (CD16+ and/or CD56+) and NK activity were decreased in RTR. Moreover, we demonstrated that the in vitro IL-2-induced LAK cytotoxicity was also diminished in RTR. NK cells and functions were normal in RTR treated with cyclosporine only, decreased in RTR treated with both cyclosporine and azathioprine, and at the lowest level in RTR treated with azathioprine without cyclosporine. A multivariate statistical analysis found a negative linear regression between the doses of azathioprine and the number of functions of NK cells, confirming that azathioprine was responsible for the deficiency of NK cells in our RTR.

Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients.

INTRODUCTION: A previous trial in renal transplantation comparing sirolimus (rapamycin) to cyclosporine (CsA) in a triple-drug therapy regimen with azathioprine and corticosteroids found that the incidence of acute rejection was similar (approximately 40%) with a trend for better renal function with sirolimus. METHODS: In 14 European centers, first cadaveric renal allograft recipients were randomized to receive sirolimus (n = 40) or CsA (n = 38) in an open-label design. All patients received corticosteroids and mycophenolate mofetil 2 g/day. Sirolimus and CsA were concentration controlled; trough levels of mycophenolic acid and prednisolone were also measured. RESULTS: At 12 months, graft survival (92.5% sirolimus vs. 89.5% CsA), patient survival (97.5% sirolimus vs. 94.7% CsA), and the incidence of biopsy-proven acute rejection (27.5% sirolimus vs. 18.4% CsA) were not statistically different. The use of antibodies to treat suspected rejection episodes was also similar (7.5% sirolimus vs. 5.3% CsA). More sirolimus patients received bolus steroid therapy (20 vs. 11, P = 0.068). From month 2 onward, the calculated glomerular filtration rate was consistently higher in sirolimus-treated patients. The adverse events reported more frequently with sirolimus were thrombocytopenia (45% vs. 8%) and diarrhea (38% vs. 11%). In the CsA group, increased creatinine (18% vs. 39%), hyperuricemia (3% vs. 18%), cytomegalovirus infection (5% vs. 21%), and tremor (5% vs. 21%) were observed significantly more often. DISCUSSION: Patient and graft survival and the incidence of biopsy-proven acute rejection at 12 months were comparable between sirolimus and CsA, whereas safety profiles were different. These data suggest that sirolimus may be used as primary therapy for the prevention of acute rejection.

Comparison of pathological lesions on repeated renal biopsies in 73 patients with primary IgA glomerulonephritis: value of quantitative scoring and approach to final prognosis.

In order to improve our possibility of establishing a long-term prognosis in IgA nephritis, 73 patients out of a cohort of 282, followed over a mean period of 12 years at the same institution for an IgA nephritis, had a prospective second renal biopsy 5 years later. For all biopsies (RB1 and RB2), we developed a quantitative scoring for all elementary lesions with a glomerular, an interstitial, a tubular and a vascular index. The sum of these 4 indexes gave a global optical score (GOS). Pathological improvement on light microscopy (delta GOS less than or equal to -2) was noticed only in 3 patients (4%), stability (-2 less than delta GOS less than +2) in 30 patients (41%), mild deterioration (+2 less than or equal to GOS less than 5) in 23 patients (32%) and major progression (delta GOS greater than or equal to 5) in 17 patients (23%). We observed no pathological remission, even in the 14 patients with complete clinical remission. The pathological progression was characterized by an increase in all elementary lesions, mainly the tubulo-interstitial and vascular ones. By immunofluorescence mesangial IgA deposits remained stable with no disappearance; however, the number and intensity of vascular C3 deposits were significantly greater on RB2. Chronic renal failure (serum creatinine greater than 1.5 mg/dl) correlated best with major pathological progression and mainly with the progression of extraglomerular lesions. IgA nephritis is a slowly progressive disease with no pathological remission, and its evolution is characterized by progression of extraglomerular lesions, mainly vascular, which might play a major role in the ultimate development of chronic renal failure.

Mesangial IgA glomerulonephritis in HLA-identical brothers.

Two HLA identical brothers with mesangial IgA glomerulonephritis are reported. Patient 1 developed gross hematuria at age 12 and required chronic hemodialysis at age 20. Patient 2 presented at age 21 with gross hematuria and normal renal function, the follow up period is only 9 months. Neither of these patients had nerve deafness, ocular defects or complement abnormalities. The family history did not support a diagnosis of classical hereditary nephritis, but a genetic linkage is strongly suggested by the identical HLA phenotypes of these brothers (A10 - A32 - B13 - B35). The B35 antigen has previously been suspected to be linked to this disease. These observations strongly support the hypothesis of an aberrant, genetically controlled, immune response, in patients with mesangial IgA glomerulonephritis.

Live poliovirus vaccine in patients with chronic glomerulonephritis: effects on renal function and specific antibody response.

Twenty-one patients with chronic glomerulonephritis (GN) (5 with renal failure) received three doses of live trivalent poliovirus vaccine administered orally. The effect of the polio vaccination on the renal function and the titers of antibodies to poliovirus were studied. No significant consequence was observed in renal disease. Before vaccination, titers of poliovirus type 1 and 3 antibodies were significantly decreased as compared to healthy adult subjects. After vaccination, the patients exhibited a significant rise in poliovirus antibody titers for the three serotypes, although some of them failed to develop a fourfold or greater antibody rise to at least one of the three serotypes, especially in the group of patients with renal failure. These results indicate that live poliovirus vaccination is not deleterious in patients with GN and can provide a good protection.

Immunogenetics and immunopathology of human primary membranous glomerulonephritis: HLA-A, B, DR antigens; functional activity of splenic macrophage Fc-receptors and peripheral blood T-lymphocyte subpopulations.

In most of our patients with idiopathic membranous nephritis (MGN), we have studied the HLA-A, B, DR phenotype, the clearance of anti Rhesus D coated-51 Cr-labeled-autologous erythrocytes, and the peripheral blood T-lymphocyte subpopulations as ascertained by monoclonal antibodies (OKT3, OKT4, OKT8). The frequency of HLA-B8 antigen is 57.14% in 28 primary MGN versus 14.4% in 104 local controls (Pc less than 0.00018). The frequency of HLA-DR3 antigen is 65.38% in 26 primary MGN patients versus 20.27% in 74 local control individuals (Pc less than 0.00008). The half-life of sensitized erythrocytes is 37.30 +/- 9.55 min in 10 controls, 1963 min and 1601 min in 2 splenectomized controls, 12 min in a patient with hypersplenism, and 67.05 +/- 69.64 min in 18 idiopathic MGN patients respectively. The half-life is significantly prolonged in 6 out of 18 MGN patients. This prolongation correlates with exacerbation of the disease while normal values are obtained with remission. The OKT3 positive subpopulation (total T-lymphocytes) is 63.77 +/- 10.37% in 31 controls versus 53.74 +/- 13.81% in 22 MGN (P less than 0.002). The OKT4 positive subpopulation (helper T-cells) is 37.90 +/- 8.21% in controls versus 32.79 +/- 10.89% in MGN (P less than 0.03). The OKT8 positive subpopulation (suppressor T-cells) is 21.60 +/- 5.28% versus 20.03 +/- 5.76% respectively. The OKT4/OKT8 ratio is 1.85 +/- 0.58 in controls versus 1.74 +/- 0.69 in MGN. During exacerbation, the T-lymphocyte subset fractions are normal, whereas OKT3 and OKT4 are decreased during remission. MGN is a strongly HLA-linked disease.(ABSTRACT TRUNCATED AT 250 WORDS)

[Monitoring of renal grafts. Value of the determination of serum neopterin and neopterin versus creatinine ratio]. / Surveillance des greffes rénales. Intérêt du dosage de la néoptérine sérique et du rapport sérique néoptérine sur créatinine.

In a longitudinal study, 53 renal allograft recipients were investigated for changes in serum creatinine and neopterin levels and in the neopterin/creatinine (N/C) ratio which makes it possible to disregard the glomerular filtration level. The patients were divided into 5 groups according to their clinical situation: stability, acute renal failure due to acute tubular necrosis, acute graft rejection, bacterial or viral infection and cyclosporin overdosage. Only N/C discriminated between these situations, being normal (less than 200.10(-6) in groups 1 and 2, significantly elevated in groups 3 and 4 and low in group 5. The highest N/C value was observed in patients with primary cytomegalovirus infection. It is concluded that the N/C ratio is a good biochemical parameter to be used in the follow-up of renal allograft recipients.

[Immunogenetics of primary membranous glomerulonephritis]. / Immunogénétique des glomérulonéphrites extramembraneuses primitives.

In 65 patients with a biopsy-proven diagnosis of membranous glomerulonephritis, the association with HLA class I, class II and class III antigens was studied using classical techniques. We found a highly significant association with the HLA-DR3 (Pc = 8 x 10(-5)) antigen and with the HLA-B8 (Pc = 2 x 10(-4)) antigen in linkage disequilibrium with the former. In addition, there was an excess of null C4 allotypes (C4 AQo or C4 BQo) in patients and a significant decrease of BfS allele. Finally, the most commonly observed phenotype was A1 B8 DR3 BfS C4AQoB1. These results confirm a strong association between major histocompatibility complex and primary membranous glomerulonephritis, raising the possibility of a susceptibility gene being necessary for the development of that disease.