CC-chemokine receptor five gene polymorphism in primary IgA nephropathy: the 32 bp deletion allele is associated with late progression to end-stage renal failure with dialysis.

The chemokine (CK) receptor 5 (CCR5) is necessary for two adjacent cysteines (CC)-CKs such as Regulated upon Activation Normal T cell Expressed and Secreted, a/o Macrophage Inflammatory Protein 1alpha/beta to mediate their inflammatory properties. The CCR5 gene polymorphism with 32-basepair deletion (d32) leads to receptor inactivation/dysfunction in homo/heterozygous individuals. We have evaluated its role in both initiation and/or progression of primary immunoglobulin A (IgA) nephropathy (IGAN) in a case-control study involving a prospective cohort of 318 IGAN patients and a matched group of 294 controls. Genotyping was performed by a two-specific primers single polymerase chain reaction technique: normal allele (nl) vs d32 allele. The d32 allele frequency was not different in patients (11.0%) vs controls (8.3%), indicating no significant influence on IGAN initiation. Genotype to clinical phenotype correlation demonstrated that progression to renal/patient death was associated with the d32 allele: 18.2% (12 out of 66 with d32) vs 8.3% (21 out of 252); chi(2)=6.73; P=0.017. The Kaplan-Meier survival without renal/patient death was worse in d32-positive patients (log-rank test; P=0.002). The Cox regression analyses confirmed that the nl/nl genotype was a significant and independent protective factor for progression to end-stage renal failure (ESRF)/dialysis: beta/standard error (s.e.)=-3.1; chi(2)=9.5; relative risk=0.31 (95% confidence interval 0.15-0.65); P=0.002. The d32-CCR5 polymorphism played a significant role in the progression of primary IGAN, with the nl/nl genotype being an independent protective factor for late progression towards ESRF/dialysis. These data raise question about the usefulness of systematic CCR5 genotyping in IGAN patients.

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.

Transplantation Report. 2: Pre-emptive renal transplantation in adults aged over 15 years. The EDTA-ERA Registry. European Dialysis and Transplant Association-European Renal Association.

Between 1985 to 1992, 2545 renal transplantation (RTx) were performed as pre-emptive grafts in adults. This procedure represented 7.2% of first RTx for patients starting first renal replacement therapy (RRT) during this period, 6.1% of RTx performed in 1992 and 5.6% of all RTx ever performed and reported to the EDTA Registry. The procedure is more frequent in cases of live donor grafts, representing one third of pre-emptive RTx. Both 5 year patient and graft survivals are unaffected by dialysis duration prior to the first RTx: none in pre-emptive, < 1 years, 1-5 years or > 5 years. In our personal view, this procedure should be developed.

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.

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.

[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.

[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.

[Immunopathology of glomerulonephritis with mesangial IgA deposits]. / Immunopathologie de la glomérulonéphrite à dépôts mésangiaux d'IgA.

IgA nephropathy is the most frequent type of glomerulonephritis in France. Its definition is on renal pathology. Mesangial IgA deposits are dimeric or polymeric and probably from secretory origin. Circulating IgA molecules correspond to immune complexes with unknown antigens. The IgA subclass remains still controversial: exclusive IgA1 versus IgA1 and IgA2. The pathogenesis of the disease is based on an immune defect specific of the secretory IgA system and eventually of the serum IgA system. The human disease can be experimentally reproduced. Nevertheless, numerous unknown explanations persist in this disease.