Diletta Domenica Torres

Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy

BACKGROUND Immunoglobulin A nephropathy (IgAN) is the most common cause of chronic renal failure among primary glomerulonephritis patients. The best treatment for IgAN remains poorly defined. We planned a long-term, prospective, open-label, multicentre, centrally randomized controlled trial to assess whether the combination of prednisone and ramipril was more effective than ramipril alone in patients with proteinuric IgAN. METHODS Ninety-seven biopsy-proven IgAN patients with moderate histologic lesions, 24-h proteinuria > or =1.0 g and estimated glomerular filtration rate (eGFR) > or = 50 ml/min/ 1.73 m(2) were randomly allocated to receive a 6-month course of oral prednisone plus ramipril (combination therapy group) or ramipril alone (monotherapy group) for the total duration of follow-up. The primary outcome was the progression of renal disease defined as the combination of doubling of baseline serum creatinine or end-stage kidney disease (ESKD). The secondary outcomes were the rate of renal function decline defined as the eGFR slope over time, and the reduction of 24-h proteinuria. RESULTS After a follow-up of up to 96 months, 13/49 (26.5%) patients in the monotherapy group reached the primary outcome compared with 2/48 (4.2%) in the combination therapy group. The Kaplan-Meier analysis showed a significantly higher probability of not reaching the combined outcome in the combination therapy group than in the monotherapy group (85.2% versus 52.1%; log-rank test P = 0.003). In the multivariate analysis, baseline serum creatinine and 24-h proteinuria were independent predictors of the risk of primary outcome; treatment with prednisone plus ramipril significantly reduced the risk of renal disease progression (hazard ratio 0.13; 95% confidence interval 0.03-0.61; P = 0.01). The mean rate of eGFR decline was higher in the monotherapy group than in the combination therapy group (-6.17 +/- 13.3 versus -0.56 +/- 7.62 ml/min/ 1.73 m(2)/year; P = 0.013). Moreover, the combined treatment reduced 24-h proteinuria more than ramipril alone during the first 2 years. CONCLUSIONS Our results suggest that the combination of corticosteroids and ramipril may provide additional benefits compared with ramipril alone in preventing the progression of renal disease in proteinuric IgAN patients in the long-term follow-up.

Desmopressin Acetate in Percutaneous Ultrasound-Guided Kidney Biopsy: A Randomized Controlled Trial

BACKGROUND Bleeding complications occur in one-third of percutaneous kidney biopsies and increase costs of the hospital stay. The aim of the study was to evaluate the effect of prebiopsy administration of desmopressin acetate versus placebo in the incidence of postbiopsy bleeding complications. STUDY DESIGN Double-blind randomized controlled clinical trial. SETTING & PARTICIPANTS We enrolled all patients with serum creatinine level ≤1.5 mg/dL and/or estimated glomerular filtration rate ≥60 mL/min/1.73 m(2) and normal coagulation parameters undergoing ultrasound-guided biopsy of the native kidney in our unit from August 2008 to December 2009. INTERVENTION We examined prebiopsy subcutaneous administration of desmopressin acetate, 0.3 μg/kg, compared with placebo. OUTCOMES & MEASUREMENTS The primary outcome was incidence of bleeding complications. Secondary outcomes were hematoma size, postbiopsy hemoglobin level, coagulation parameters, glomerular filtration rate, blood pressure, and length of hospital stay. RESULTS 162 adult patients (88 men and 74 women) were enrolled; 80 were allocated to desmopressin treatment, and 82, to the placebo group. Desmopressin compared with placebo significantly decreased the risk of postbiopsy bleeding (11 of 80 [13.7%] vs 25 of 82 [30.5%]; relative risk, 0.45; 95% CI, 0.24-0.85; P = 0.01), hematoma size (median, 208 [25th-75th percentile, 120-300] vs 380 [25th-75th percentile, 270-570] mm(2); P = 0.006] in the 36 patients who experienced bleeding, and mean hospital stay (4.9 ± 1.1 vs 5.9 ± 1.7 days; P = 0.004); postbiopsy hemoglobin levels were not affected significantly in either group. LIMITATION Single-center design of the study. CONCLUSIONS Prebiopsy desmopressin administration decreases the risk of bleeding and hematoma size in patients undergoing percutaneous kidney biopsy without a cost increase.

Role of interferon- γ gene polymorphisms in susceptibility to IgA nephropathy: a family-based association study

T helper (h) lymphocytes in pathogenic immune response at mucosal effector site play a key role in IgA nephropathy (IgAN). We evaluated the impact of some Th1/Th2/Th3/TR-type, and of monocyte/macrophage cytokines on IgAN susceptibility with a family-based association study including 53 patients, 45 complete trios, 4 incomplete trios and 36 discordant siblings. Cytokine gene polymorphisms with a potential regulatory role on their production were investigated using the family-based association test (FBAT): IFNγ intron-1 CA repeat at position 1349–1373; IL-13 −1055C/T; TGFβ +915G/C; IL-10 5′-proximal and distal microsatellites; TNFα −308G/A, −238G/A. The FBAT multi-allelic analysis showed an association between IFNγ polymorphism and susceptibility to IgAN (P=0.03). The bi-allelic analysis evidenced that the 13-CA repeat allele was preferentially transmitted to the affected individuals (P=0.006; Bonferroni P-value=0.04). The direct sequencing of IFNγ amplicons showed a strict association between the 13-CA repeat allele and the A variant of the +874T/A single nucleotide polymorphism (SNP rs2430561) directly adjacent to the 5′ end of the microsatellite. The in vitro production of IFNγ evaluated in peripheral blood mononuclear cells from 10 genotyped patients demonstrated a correlation between the +874A allele and a lower production of IFNγ (P=0.028 Mann–Whitney test). This SNP affects IFNγ production lying within a binding site for the transcription factor NF-κB. No significant difference was observed in the 15 years renal survival between IgAN patients carrying different IFNγ gene polymorphisms. This first family-based association study demonstrates that the +874A allele, strictly associated with IFNγ 13-CA repeat allele, confers susceptibility to IgAN, without influencing renal survival.

Altered modulation of WNT-beta-catenin and PI3K/Akt pathways in IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. The basic defect lies within the IgA immune system and in peripheral blood leukocytes, rather than local kidney abnormalities. To define the intracellular mechanisms leading to the disease, we conducted a microarray study to identify genes and pathways differentially modulated in peripheral blood leukocytes isolated from 12 IgAN patients and 8 healthy controls. The genes whose expression discriminated between the IgAN patients and controls were primarily involved in canonical WNT-beta-catenin and PI3K/Akt pathways. We also tested peripheral blood mononuclear cells and their subpopulations isolated from an independent group of IgAN patients and healthy controls. There were low protein levels of inversin and PTEN, key regulators of WNT-beta-catenin and PI3K/Akt, in IgAN patients, suggesting hyperactivation of these pathways. Also, there were increased phospho-Akt protein levels and nuclear beta-catenin accumulation with an enhanced peripheral blood mononuclear cell proliferation rate. Subpopulation analysis uncovered a major irregularity of WNT signaling in monocytes. Hence, hyperactivation of these pathways may provide insight into mechanisms contributing to the pathogenesis of IgAN.

Pregnancy and progression of IgA nephropathy: results of an Italian multicenter study.

BACKGROUND Whether pregnancy impacts on the long-term outcome of immunoglobulin A (IgA) nephropathy is unknown. This study aims to compare the long-term outcome of kidney disease in women with IgA nephropathy and preserved kidney function who did and did not become pregnant. STUDY DESIGN Multicenter longitudinal cohort study. SETTING & PARTICIPANTS Women of childbearing age with biopsy-proven IgA nephropathy, serum creatinine level<or=1.2 mg/dL at diagnosis, and minimum follow-up of 5 years after biopsy recruited from 35 nephrology centers participating in a national collaborative study group of pregnancy and kidney disease sponsored by the Italian Society of Nephrology. PREDICTORS Pregnancy, treated as a time-dependent variable; baseline proteinuria; hypertension; and kidney biopsy histologic characteristics. OUTCOME & MEASURES Rate of change in estimated creatinine clearance, change in proteinuria, and new-onset hypertension. RESULTS 245 patients were enrolled. Of these, 223 women (136 and 87 in the pregnancy and nonpregnancy groups, respectively) had serum creatinine levels<or=1.2 mg/dL at diagnosis. Baseline data (including age, estimated creatinine clearance, prevalence of hypertension, and histologic grade of kidney damage) were similar between groups with the exception of proteinuria (protein excretion, 1.33 vs 0.95 g/d in the pregnancy vs nonpregnancy groups, respectively; P=0.03). Kidney function decreased 1.31 mL/min/y (95% CI, 0.99-1.63) during a median follow-up of 10 years (range, 5-31 years) and did not differ between groups. Baseline proteinuria predicted a faster decrease, but did not modify the effect of pregnancy. Pregnancy did not affect changes in proteinuria over time or risk of new-onset hypertension. LIMITATIONS Unrecognized or unmeasured factors associated with the decision of becoming pregnant might have influenced results. CONCLUSIONS Pregnancy does not seem to affect the long-term outcome of kidney disease in women with IgA nephropathy and preserved kidney function.

Altered modulation of WNT–β-catenin and PI3K/Akt pathways in IgA nephropathy

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. The basic defect lies within the IgA immune system and in peripheral blood leukocytes, rather than local kidney abnormalities. To define the intracellular mechanisms leading to the disease, we conducted a microarray study to identify genes and pathways differentially modulated in peripheral blood leukocytes isolated from 12 IgAN patients and 8 healthy controls. The genes whose expression discriminated between the IgAN patients and controls were primarily involved in canonical WNT-beta-catenin and PI3K/Akt pathways. We also tested peripheral blood mononuclear cells and their subpopulations isolated from an independent group of IgAN patients and healthy controls. There were low protein levels of inversin and PTEN, key regulators of WNT-beta-catenin and PI3K/Akt, in IgAN patients, suggesting hyperactivation of these pathways. Also, there were increased phospho-Akt protein levels and nuclear beta-catenin accumulation with an enhanced peripheral blood mononuclear cell proliferation rate. Subpopulation analysis uncovered a major irregularity of WNT signaling in monocytes. Hence, hyperactivation of these pathways may provide insight into mechanisms contributing to the pathogenesis of IgAN.

Searching for IgA nephropathy candidate genes: genetic studies combined with high throughput innovative investigations.

Idiopathic IgA Nephropathy (IgAN) is the most common biopsy-proven glomerulonephritis worldwide. All races with the exception of Blacks and Indians are involved. Families with two or more relatives affected by IgAN may be observed in 15-20% of pedigrees of IgAN patients. Genome wide linkage study has been considered the most promising approach to identify IgAN susceptibility genes. Therefore, some European investigators constituted the European IgAN Consortium which was initially funded by the European Union. Data from linkage analysis studies, family association studies and case-control association studies are reported. To date, the Consortium has identified two loci (located on chromosomes 4q26-31 and 17q12-22), in addition to the previous study which described the first IgAN locus on chromosome 6q22-23. The functional mapping of genes involved in the disease proceeds from the identification of susceptibility loci identified by linkage analysis (step 1) to the isolation of candidate genes within gene disease-susceptibility loci, after obtaining information by microarray analysis carried out on peripheral leukocytes and renal tissue samples (step 2). Then, the process will proceed from the design of RNA interferenceagents against selected genes (step 3) to the application of systematically tested effect of RNA agents on functional cellular assay (step 4). The above combined high-throughput technologies will give information on the pathogenic mechanisms of IgAN. In addition, these data may indicate potential targets for screening, prevention and early diagnosis of the disease and more appropriate and effective treatment.

A pediatric neurologic assessment score may drive the eculizumab-based treatment of Escherichia coli-related hemolytic uremic syndrome with neurological involvement

BackgroundThrombotic microangiopathy (TMA) is a clinical syndrome encompassing a large group of rare but severe disorders including thrombotic thrombocytopenic purpura (TTP) and both typical and atypical forms of hemolytic uremic syndrome (HUS). The key role of the complement system is well known in TTP and atypical HUS, but recent reports describe its involvement in the pathogenesis of HUS secondary to gastrointestinal infections due to Shiga toxin-producing Escherichia coli (STEC).MethodsTMA mainly affects the kidney, but extra-renal complications are frequently described. The involvement of the central nervous system (CNS) represents often a life-threatening condition and it can result in serious long-term disability in HUS patients who overcome the acute phase of illness. In the present study, we retrospectively analyzed a pediatric cohort of a single tertiary pediatric hospital in Southern Italy, in which this complication occurred in 12/54 children (22% of cases), of whom five with severe neurological involvement had been successfully treated with eculizumab.ResultsThe great clinical variability of brain injury in our cohort has led us to retrospectively build a “neurological score” useful to assess the clinical severity of neurologic involvement. Subjects with higher neurologic score due to the most severe CNS involvement resulted in the group of patients early treated with eculizumab, obtaining a good clinical response (four out five patients). In conclusion, the early treatment with eculizumab in children with severe neurological involvement during STEC-HUS was associated with complete regression of both acute kidney injury (AKI) and neurological lesions observed at magnetic resonance imaging (MRI).ConclusionsA “neurological score” may be a useful tool to drive the early treatment of CNS complications in STEC-HUS with eculizumab, although future perspective controlled studies are urgently needed to validate this therapeutic approach.

Altered modulation of WNT|[ndash]||[beta]|-catenin and PI3K|[sol]|Akt pathways in IgA nephropathy

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. The basic defect lies within the IgA immune system and in peripheral blood leukocytes, rather than local kidney abnormalities. To define the intracellular mechanisms leading to the disease, we conducted a microarray study to identify genes and pathways differentially modulated in peripheral blood leukocytes isolated from 12 IgAN patients and 8 healthy controls. The genes whose expression discriminated between the IgAN patients and controls were primarily involved in canonical WNT-beta-catenin and PI3K/Akt pathways. We also tested peripheral blood mononuclear cells and their subpopulations isolated from an independent group of IgAN patients and healthy controls. There were low protein levels of inversin and PTEN, key regulators of WNT-beta-catenin and PI3K/Akt, in IgAN patients, suggesting hyperactivation of these pathways. Also, there were increased phospho-Akt protein levels and nuclear beta-catenin accumulation with an enhanced peripheral blood mononuclear cell proliferation rate. Subpopulation analysis uncovered a major irregularity of WNT signaling in monocytes. Hence, hyperactivation of these pathways may provide insight into mechanisms contributing to the pathogenesis of IgAN.

Altered modulation of WNT–β-catenin and PI3KsAkt pathways in IgA nephropathy

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. The basic defect lies within the IgA immune system and in peripheral blood leukocytes, rather than local kidney abnormalities. To define the intracellular mechanisms leading to the disease, we conducted a microarray study to identify genes and pathways differentially modulated in peripheral blood leukocytes isolated from 12 IgAN patients and 8 healthy controls. The genes whose expression discriminated between the IgAN patients and controls were primarily involved in canonical WNT-beta-catenin and PI3K/Akt pathways. We also tested peripheral blood mononuclear cells and their subpopulations isolated from an independent group of IgAN patients and healthy controls. There were low protein levels of inversin and PTEN, key regulators of WNT-beta-catenin and PI3K/Akt, in IgAN patients, suggesting hyperactivation of these pathways. Also, there were increased phospho-Akt protein levels and nuclear beta-catenin accumulation with an enhanced peripheral blood mononuclear cell proliferation rate. Subpopulation analysis uncovered a major irregularity of WNT signaling in monocytes. Hence, hyperactivation of these pathways may provide insight into mechanisms contributing to the pathogenesis of IgAN.