Anna Maria Dall'Omo

Angiotensin I-converting enzyme genotype significantly affects progression of IgA glomerulonephritis in an italian population.

To evaluate the role of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in the progression of immunoglobulin A glomerulonephritis (IgA-GN), genotype distribution in 81 biopsy-proven cases of IgA-GN was studied. A logistic regression model showed that the risk for homozygous DD was not significantly elevated in patients with IgA-GN compared with healthy subjects (odds ratio = 1.16; confidence interval [CI], 0.4 to 3.3). However, the 5-year (78% v 90%) and 10-year (52% v 82%) renal survival rates for 47 patients with serum creatine (Cr) levels of 1.5 mg/dL or less at biopsy was significantly less in DD patients (n = 18; chi2 = 5.41; P = 0.02). The hazard ratio (HR) for DD (multivariate analysis from Cox proportional model after adjustment for known factors of progression, such as hypertension [HPT] and proteinuria [PTO]) was 3.07 (CI, 1.1 to 9.4). The HR for heavy PTO was 6.1 (CI, 1.9 to 19). The association of DD genotype with progression was even more striking when patients with other risk factors (heavy proteinuria) were excluded, as shown by DD-related risk in the absence (HR = 3.6; CI, 1.1 to 12) and presence (HR = 2; CI, 0.4 to 10) of PTO. The risk ratio was further increased by the coexistence of DD + PTO (HR = 9.16; CI, 1.8 to 15.7). Furthermore, in a cross-sectional study among patients with IgA-GN, a logistic regression model showed that the risk for homozygous DD was greater, although not at a statistically significant level in the end-stage renal failure subgroup compared with the normal renal function subgroup (odds ratio = 3.16; CI, 0.7 to 13.7) after adjustment by sex, age at biopsy, HPT, PTO, and therapy. Last, DD was significantly more frequent in those patients who started hemodialysis at an earlier age (chi2 for trend = 6.81; P = 0.009). Our study further supports that ACE genotype is a risk factor not for the development, but for the worsening of IgA-GN clinical course. However, on the basis of current knowledge, we cannot exclude that I/D polymorphism may simply serve as a prognostic marker, eventually linked with other discrete loci involved in the progression of renal damage.

Genetic, Immunologic, and Environmental Heterogeneity of IDDM: Incidence and 12-Mo Follow-Up of an Italian Population

The 1-yr incidence of insulin-dependent diabetes mellitus (IDDM) in a population of the Piedmont and Aosta Valley area of Italy was recorded. Anti-virus antibodies (e.g., Coxsackie B1-6, mumps, cytomegalovirus), islet cell antibodies (ICAs), and H LA-A, -B, -C, and -DR were determined in 74 IDDM patients (38 males, 36 females) and in controls. Total IDDM incidence was 5.0/100,000, and the incidence for those <20 yr of age was 11.6/100,000. Anti-virus antibody frequency was not different in IDDM patients and controls. ICAs were present in 58% of IDDM patients at onset and in 30% after 12 mo, and complement-fixing ICAs were found in 39 and 17%, respectively. IDDM was significantly and positively associated with DR3/DR4 and negatively associated with DR2 and DR5. ICA frequency was significantly higher in DR3/DR4 heterozygote patients than in patients without DR3 and DR4. These results suggest that in this IDDM population 1) viral etiology is not evident, 2) ICAs offer only a partial pathogenetic explanation, and 3) genetic and immunologic heterogeneity is evident.

Immune Reconstitution and Early Infectious Complications Following Nonmyeloablative Hematopoietic Stem Cell Transplantation

Abstract Non-myeloablative stem cell transplantation (NMT) has been increasingly used in compromised patients who would otherwise have been unable to undergo allotransplant. There is little understanding of the kinetics of immune reconstitution and its influence on infective complications following NMT. The aim of present study was to evaluate lymphocyte subset reconstitution over the first 12 months post-transplant in 15 adult patients receiving NMT with comparison to that of 30 patients grafted with a conventional hemopoietic stem cell transplantation (HSCT). NMT recipients were conditioned with fludarabine-based conditioning regimens. Peripheral blood stem cell (PBSC) was the source of stem cells in 13 NMT recipients and in 24 conventional HSCT recipients. Absolute numbers of helper (CD4+) T cells, naive (CD4+ CD45RA+) and memory (CD4+ CD45RO+) T cells as well as suppressor (CD8+) T cells, CD19+ B cells and NK cells were comparable in the two groups at all time points after transplantation. A median value of 200 CD4+ T cells/μl was achieved at 2 months post-transplant by the NMT and HSCT recipients. The CD4:CD8 ratio remained severely depressed throughout the study period. Almost all CD4+ lymphocytes expressed CD45RO antigen in the both groups of patients B lymphocytes showed low counts throughout the entire study period in both groups. Bacteremia and CMV antigenemia occurred respectively in 13 and 36% of the patients in the NMT group and in 15 and 39% of the patients in the HSCT group. Our preliminary data indicate that patients receiving a NMT have a lymphocyte reconstitution similar to that observed in patients who received a conventional HSCT. The incidence of bacteremia and CMV infection were not significantly different between the groups. Nevertheless, due to the small sample size, these results should be considered suggestive rather than definitive.

Outcome of pregnancy after organ transplantation: a retrospective survey in Italy

The number of women who decide to have a child after organ transplantation has increased. We determined the outcomes of 67 pregnancies of women who had undergone kidney, liver or heart transplantation. All recipients had been maintained on immunosuppressive therapy before and during pregnancy. Pregnancy complications at term were observed in 17 out of 67 women (25%), hypertension being the most frequent complication (16.17%). Two transplant rejections were reported. Sixty-eight infants were delivered (including one pair of twins); five women had two pregnancies at term. Twenty-eight miscarriages (29.2%) were recorded. Of these 68 babies (including the pair of twins), 40 (58.8%) were born at term and 28 (41.2%) before term. The babies were followed-up for 2 months to 13 years. According to our previous experience, our study shows that patients who have undergone organ transplantation can give birth to healthy infants as long as they are monitored accurately during pregnancy.

Prognostic values of soluble CD30 and CD30 gene polymorphisms in heart transplantation.

Pretransplant soluble CD30 (sCD30) is a predictor of kidney graft outcome. Its status as a predictor of heart transplant (HT) outcome has not been established. We have studied this question by assessing sCD30 levels and the number of (CCAT)n repeats of the microsatellite in the CD30 promoter region, which is able alone to repress gene transcription, in the sera of 83 HT patients and 77 of their donors. sCD30 was non-significantly increased in the patients, whereas there were no differences in the CD30 microsatellite allele frequencies. A negative correlation between the number of (CCAT)n and sCD30 levels was evident in the donors. Patients with pretransplant sCD30≤30 U/ml displayed a significantly better survival. In conclusion, sCD30 levels are predictive of HT outcome.

Comparison of acute and subacute effects of deflazacort and prednisone on glucose metabolism in man

SummaryCorticosteroid treatment produces glucose intolerance with insulin resistance. Recent reports have indicated that deflazacort (DF) is significantly less diabetogenic than prednisone (PN). A euglycaemic hyperinsulinaemic (100 µU/ml) glucose clamp (EHGC) and 3H-glucose infusion for 240 min were performed in 6 healthy volunteers (HV) after administration of 15 mg PN or 18 mg DF, 12 h and 2 h before test. The glucose metabolic clearance rate (MCR) was significantly (p=0.02) higher after DF (4.75±0.58 ml/min·kg) than after PN (3.31±0.27 ml/min·kg). Basal hepatic glucose production (HGP) was significantly (p=0.003) lower after DF (3.58±0.33 mg/kg·min) than after PN (4.44±0.23 mg/kg·min). A similar pattern was obtained for glucose volume (GV) and glucose pool (GP). The kinetic parameters of insulin were not significantly different after the two drugs. After 7 day of PN 30 mg/day or DF 36 mg/day, EHGC and 3H-glucose infusion for 240 min were performed in 10 HV. Glucose MCR values were significantly (p=0.03) higher after DF (5.03±0.91 ml/min·kg) than after PN (2.80±0.26 ml/min·kg). HGP values did not different significantly after the two drugs. GV (p=0.001) and GP (p=0.002) were significantly lower after DF than after PN. Insulin kinetics were not significantly different after the two drugs. It is concluded that on acute and 7-day administration to healthy subjects DF, in an anti-inflammatory dose equivalent to PN, shows significantly less influence on glucose metabolism.

Chronic graft-versus-host disease after reduced-intensity stem cell transplantation versus conventional hematopoietic stem cell transplantation

Abstract The aim of this study was to retrospectively analyse clinical characteristics of chronic GVHD (cGVHD) and requirements for immunosuppressive treatment (IST) in patients receiving reduced-intensity stem cell transplantation (RIST). About 29 patients who underwent RIST between September 1999 and April 2003 were evaluable for cGVHD; they were compared to an age-matched cohort of 29 patients who received conventional stem cell transplantation (CST). A total of 26 patients in the RIST group and 24 in the CST group developed cGVHD, which was graded as limited disease in 15 (52%) and 12 (41%) cases, respectively, and as extensive disease in 11 (38%) and 12 (41%) cases, respectively. Kaplan–Meier estimates of the risk of cGVHD at 1 year after transplant were 96 and 82%, respectively (p=0.4). The median day of onset of cGVHD was 117 (range 93–220) in RIST group and 112 (range 77–225) in CST group. The skin was the most common target organ, involving 22 (84%) patients in the RIST group and 17 (71%) in the CST group. The probability of withdrawal from systemic IST at 3 years was 63 and 52% in the two groups, respectively, (p=0.7). By multivariate analysis, RIST was the only, independent, prognostic factor for the development of refractory cGVHD (?p=0.01). In conclusion, we did not find major differences between patients receiving RIST and CST respect to timing, clinical characteristics and incidence of cGVHD. Refractory disease was more frequently observed in patients receiving RIST, although the probability of withdrawal from systemic IST was not significantly different between the two groups.

HLA IN JUVENILE DERMATITIS HERPETIFORMIS: CLINICAL HETEROGENEITY CORRELATED WITH DNA AND SEROLOGICAL POLYMORPHISM

A group of 30 Italian children affected by Dermatitis Herpetiformis (DH) was analysed for HLA region polymorphisms with both serological and DNA methods. Serological typing was performed on HLA‐A, B, C, DR, DQ antigens and C4A, C4B, Bf polymorphisms. DNA RFLPs obtained with TaqI enzyme were investigated with cDNA probes specific for DR beta, DQ alpha and DQ beta genes. The results were correlated with intestinal involvement and age at onset of the disease. The following observations were made: (1) the intestinal biopsies revealed a direct correlation between degree of lesions and age at onset of DH; (2) a significantly increased relative risk (RR) was found for the following HLA antigens: A1 (RR = 2.2), B8 (RR = 6.2), Cw7 (RR = 3.9), C4AQO (RR = 7.4), DR3 (RR = 5.2), DR7 (RR = 4.4), DRw53 (RR = 4.7), DQw2 (RR = 6.0); (3) B8 and DR3 were significantly more frequent in patients with severe intestinal lesions; and (4) of the two DR3 subtypes revealed by RFLP typing, only 3.1 showed an increased frequency in DH patients (RR = 8.4). It is suggested that the susceptibility to Juvenile DH is determined by the same genes, within the HLA region, that are associated with Coeliac Disease.

The Italian quality control scheme for crossmatching procedures and HLA sera screening: the 2002 pilot study.

CONTEXT The first national quality control (QC) program of histocompatibility serum testing was performed in Italy in 2002. OBJECTIVE To monitor the performance of HLA typing laboratories while meeting the accreditation requirements of the European Federation for Immunogenetics (EFI), which require HLA typing laboratories to participate in external QC of their crossmatch and antibody analyses. DESIGN The Turin Transplant Immunology Service was asked to organize a QC survey of 17 HLA typing laboratories in Italy. Each laboratory received 12 serum specimens and 6 blood samples and was required to perform 36 crossmatches and 12 serum antibody specificity determinations. SETTINGS Data of participating centers were compared to establish whether EFI requirements were satisfied. RESULTS In crossmatch analysis, the results of 32 of 36 crossmatches reached the 75% consensus target, with all the participating laboratories meeting the standards of the EFI. In antibody analysis, only 7 of 17 laboratories met the EFI standards. CONCLUSION The first Italian QC program shows that the participating laboratories obtained consistent results in crossmatching, whereas the results were less satisfactory in the determination of serum antibody specificity, where consensus was reached only with monospecific sera and antibody-negative samples.

Persistent Negativity of ICAs During Preclinical Period and At Acute Onset in 2 Cases of IDDM

FIG. 1. Insulin response to intravenous glucose tolerance test (i.v.GTT) before onset and at 1st test. development of overt insulin-dependent diabetes mellitus (IDDM). We report two cases (women, aged 25 and 27 yr) of IDDM patients who had their clinical onset (ketoacidosis) during a 5-yr follow-up study on 74 siblings of IDDM patients. Both these cases were DR3/DR4 (1 HLA identical and 1 aploidentical with the proband), and their islet cell antibodies [ICAs; method of Bottazzo et al. (6)] and anti-virus antibodies, i.e., Coxsackie Bi_6, herpes simplex, cytomegalovirus, mumps (4-fold increase in titer), were persistently negative during the preclinical period (determined every 4 mo) and at clinical onset. Both cases began to show a low first-phase insulin response and a decreased early phase of insulin secretion (Fig. 1) during the intravenous glucose tolerance test (performed every 4 mo) 30 and 33 mo before clinical onset. Plasma glucose values were normal during the intravenous glucose tolerance test, except for the last test ~60 days before the clinical onset in one of the two cases. Anti-virus antibodies and ICAs were persistently negative also in the other 72 siblings (16 HLA identical, 43 aploidentical with the proband, and 11 DR3/DR4). The ICA negativity could be the result of an underestimation of the positivity due to our criteria of immunofluorescence evaluation. Nevertheless, during a previous cross-sectional study on ICA prevalence in IDDM patients at their clinical onset, we obtained a positivity of 66% (7), which is comparable with other reported results in different populations (6). The high prevalence of the onset of IDDM among ICAnegative siblings during a 5-yr longitudinal study (2 of 74, or 2.7%) and among DR3/DR4 siblings (2 of 13, or 15.4%) and the absence of anti-virus antibodies are remarkable. The progressive decrease of insulin response to the intravenous glucose tolerance test represents the only predictive marker of overt clinical onset of IDDM.