The effects of vitamin E-coated membrane dialyzer compared to simvastatin in patients on chronic hemodialysis.

BACKGROUND: We investigated the effects of the use of vitamin E-coated membrane (VEM) dialyzer in comparison to simvastatin on markers of chronic inflammation, oxidative stress, and endothelial cell apoptosis in ten patients on chronic hemodialysis (HD), aiming at distinguishing the different treatment effects and their time sequence on these pathogenetic routes. METHODS: Ten HD patients were sequentially submitted to a 6-month treatment with the use of VEM and 10 mg of simvastatin daily, interrupted by a 3-month washout period. At baseline, at 3, and 6 months of each trial, serum C-reactive protein (CRP), apolipoprotein (Apo) A1 and B, lipoprotein-a [Lp(a)], high-sensitivity interleukin-6 (hsIL-6), monocyte chemoattractant protein-1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), soluble Fas (sFas), soluble Fas ligand (sFasL), and plasma oxidized low-density lipoproteins (oxLDL) levels were determined. RESULTS: VEM treatment resulted in a significant decrease in CRP, IL-6, sICAM-1 at 3 months, and oxLDL at 6 months, compared to baseline. Simvastatin resulted in a significant decrease in CRP, which correlated with decreases in both total (r = 0.87, p < 0.05) and low-density lipoprotein cholesterol, IL-6, sICAM-1, sVCAM-1, oxLDL, and sFas at 6 months, compared to baseline. Simvastatin effects on sVCAM-1 (mean difference = 652 ng/mL; 95% CI = 294 to 2686; p < 0.05) and sFas (mean difference = 1284 pg/mL; 95% CI = 510 to 1910; p < 0.05) differed significantly from the corresponding VEM effects. CONCLUSIONS: The 6-month use of VEM resulted in more direct and immediate anti-inflammatory effects compared with those caused by the 6-month treatment with simvastatin. Simvastatin caused a more intense decrease in the markers of inflammation, which was in part correlated with its lipid-lowering effects.

Steroids and azathioprine in the treatment of IgA nephropathy.

AIM: IgA nephropathy (IgAN) is a very common glomerulonephritis among young adults, but the best therapeutic approach has not been fully elucidated. This study evaluated the effect of two different treatment regimes in IgAN, steroids alone or in combination with azathioprine. METHODS: Among 122 patients with primary IgA nephropathy diagnosed in the 2000-2007 period, 22 fulfilled the inclusion criteria for the study: estimated glomerular filtration rate (eGRF) ≥30 ml/min/1.73 m(2), urine protein (Upr) ≥1 g/24 h, blood pressure (BP) <130/80 mmHg, and previous treatment with renin-angiotensin system inhibitors (RAASi) and polyunsaturated fatty acids (PFA) for at least 6 months. Patients were randomized to receive either methylprednisolone alone (MP group) or MP in combination with azathioprine (MP + Aza group) for 12 months, while treatment with RAASi + PFA continued unchanged in both groups. RESULTS: At the completion of the trial, renal function in the MP group remained stable, eGFR from 52 ± 26.7 to 53.6 ± 27.3 ml/min/1.73 m(2), p = NS, and Upr decreased from 2.4 ± 0.9 to 0.8 ± 0.5 g/24 h, p < 0.001. In the MP + Aza group, eGFR slightly increased from 57.4 ± 28.7 to 66 ± 31 ml/min/1.73 m(2), p = NS, and Upr decreased from 2.4 ± 1 to 0.7 ± 0.7 g/24 h, p < 0.001. Four patients from the MP group with partial remission at the end of the trial had a complete response when converted to Aza. Eleven patients (5 from the MP and 6 from the MP + Aza group) relapsed after stopping treatment and were restarted on lower doses. CONCLUSIONS: Both, steroid treatment alone and steroids in combination with azathioprine seem to be effective in reducing the severity of proteinuria and stabilizing renal function in IgAN. Patients who do not respond to steroids may have a better response with the combination of steroids and azathioprine.

Is presence of ANCA in crescentic IgA nephropathy a coincidence or novel clinical entity? A case series.

BACKGROUND: There are few anecdotal reports of circulating antineutrophil cytoplasmic autoantibodies (ANCAs) in patients with immunoglobulin A (IgA) nephropathy. STUDY DESIGN: Retrospective case series. SETTING & PARTICIPANTS: We studied 8 patients with crescentic IgA nephropathy associated with ANCAs against myeloperoxidase (n = 5) and proteinase 3 (n = 3) followed up for 2.4 +/- 1.7 years. They were compared with 26 patients with IgA nephropathy with > 10% crescentic glomeruli, but negative for ANCAs. OUTCOMES: We analyzed clinical and histologic features of patients and their response to treatment. MEASUREMENTS: Screening for ANCAs was performed using indirect immunofluorescence, and positive results were verified using enzyme-linked immunosorbent assay. RESULTS: All patients with crescentic IgA nephropathy and positive for ANCAs, compared with only one-third of ANCA-negative patients, presented with the clinical syndrome of rapid progressive glomerulonephritis. ANCA-positive patients reached a higher peak serum creatinine level within the first 3 months (4.2 +/- 2.2 vs 2.5 +/- 1.9 mg/dL; estimated glomerular filtration rate, 19.3 +/- 10.2 vs 45.9 +/- 30.1 mL/min/1.73 m(2)). ANCA-positive patients with IgA nephropathy had a higher percentage of crescentic glomeruli (54.3% +/- 18%) compared with ANCA-negative patients with crescentic IgA nephropathy (34.5% +/- 26%). ANCA-positive patients were treated using cyclophosphamide and corticosteroids. Kidney function improved in all these patients: serum creatinine level decreased from the peak of 4.2 +/- 2.2 to 1.7 +/- 0.7 mg/dL at the end of follow up (estimated glomerular filtration rate, 19.3 +/- 10.2 to 44.6 +/- 11.1 mL/min/1.73 m(2)). In contrast, no significant improvement was achieved in ANCA-negative patients. CONCLUSION: Patients with IgA nephropathy, crescents, and positive for ANCAs represent a clinical entity with a diverse more exaggerated clinical and histologic picture. However, disease in these patients responded well to aggressive immunosuppressive therapy.

Urinary levels of epidermal growth factor, interleukin-6 and monocyte chemoattractant protein-1 may act as predictor markers of renal function outcome in immunoglobulin A nephropathy.

AIM: Urinary cytokine excretion may reflect histological changes in immunoglobulin A nephropathy (IgAN), and their measurement can give information about disease outcome. METHODS: Thirty-three IgAN patients were prospectively followed for 5.6 +/- 3.1 years. Urinary levels of monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6 and epidermal growth factor (EGF) were measured at diagnosis and repeated 1 year later for IL-6 and EGF. RESULTS: Urinary MCP-1 and IL-6 levels were increased significantly, while EGF excretion reduced in IgAN patients, compared to controls. IL-6 urinary levels showed significant positive correlation with chronic histological lesions. Patients were classified into five groups, according to the Haas classification system. MCP-1 and IL-6 urinary levels were increased, whereas EGF levels were reduced in the progression of staging. EGF urinary excretion was a strong predictor factor of disease outcome, significantly correlated with creatinine clearance at time of diagnosis (r = 0.5, P = 0.005), and at the end of follow up (r = 0.6, P = 0.001). Urinary EGF levels measured a year later could predict long-term outcome better, and a cut of 0.05 pg/mg urine creatinine levels could distinguish between progressors and non-progressors. CONCLUSION: Urinary MCP-1, IL-6 and EGF levels may represent histology in IgAN. EGF excretion can be a predictive marker and its serial measurements may give information about disease outcome and the effect of treatment.

Carotid atherosclerosis and endothelial cell adhesion molecules as predictors of long-term outcome in chronic hemodialysis patients.

BACKGROUND/AIMS: Cardiovascular disease (CVD) remains the leading cause of increased morbidity and mortality for hemodialysis (HD) patients. The aim of this study was to investigate the predictive values of carotid artery atherosclerotic lesions and endothelial adhesion molecule levels for long-term outcome in non-diabetic HD patients. METHODS: 112 HD patients (60 male, mean age 59 years) consecutively entered the study. Atherosclerotic disease was assessed by measuring the mean and maximum intima-media thickness (IMT and IMTmax respectively) of the common carotid arteries using an ultrasound scanner. Circulating intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels were measured by ELISA. Patients were followed for the next 5 years and primary end points on follow-up were all-cause death, death from CVD causes and incidence of a CVD event. RESULTS: Kaplan-Meier analysis showed that survival curves for all-cause mortality, CVD mortality and morbidity differed significantly between the upper and lower tertiles of baseline IMT (p = 0.002, p = 0.01 and p = 0.001 respectively) and IMTmax values (p = 0.0007, p = 0.006 and p = 0.0003 respectively), as well as ICAM-1 (p = 0.008, p = 0.003 and p = 0.02 respectively) and VCAM-1 levels (p = 0.004, p = 0.012 and p = 0.025 respectively). In non-adjusted analysis all-cause mortality and CVD mortality and morbidity were significantly associated with IMT (p = 0.003, p = 0.01 and p = 0.001 respectively) and IMTmax values (p = 0.001, p = 0.007 and p = 0.0007 respectively). After adjusting for other significant covariates, IMT values remained associated only with CVD morbidity (p = 0.03), while IMTmax were associated with both CVD mortality and morbidity (p = 0.03 and p = 0.01 respectively). All-cause mortality and CVD mortality and morbidity were also significantly associated with serum ICAM-1 (p = 0.004, p = 0.005 and p = 0.01 respectively) and VCAM-1 levels (p = 0.008, p = 0.02 and p = 0.03 respectively). After adjusting for the same covariates, the associations between ICAM-1 and all-cause mortality and CVD mortality and morbidity remained significant (p = 0.02, p = 0.01 and p = 0.02 respectively), while serum VCAM-1 levels were independently associated only with all-cause mortality (p = 0.02). CONCLUSIONS: In non-diabetic HD patients, carotid atherosclerosis and adhesion molecule levels are independent predictors of long-term clinical outcomes and may be useful surrogate markers for risk stratification in these patients.

COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy.

Mutations in the COL4A3/COL4A4 genes of type IV collagen have been found in approximately 40% of cases of thin basement membrane nephropathy, which is characterized by microscopic hematuria and is classically thought to cause proteinuria and chronic renal failure rarely. Here we report our observations of 116 subjects from 13 Cypriot families clinically affected with thin basement membrane nephropathy. These families first came to our attention because they segregated microscopic hematuria, mild proteinuria, and variable degrees of renal impairment, but a dual diagnosis of focal segmental glomerulosclerosis (FSGS) and thin basement membrane nephropathy was made in 20 biopsied cases. Molecular studies identified founder mutations in both COL4A3 and COL4A4 genes in 10 families. None of 82 heterozygous patients had any extrarenal manifestations, supporting the diagnosis of thin basement membrane nephropathy. During follow-up of up to three decades, 31 of these 82 patients (37.8%) developed chronic renal failure and 16 (19.5%) reached end-stage renal disease. Mutations G1334E and G871C were detected in seven and three families, respectively, and were probably introduced by founders. We conclude that these particular COL4A3/COL4A4 mutations either predispose some patients to FSGS and chronic renal failure, or that thin basement membrane nephropathy sometimes coexists with another genetic modifier that is responsible for FSGS and progressive renal failure. The findings presented here do not justify the labelling of thin basement membrane nephropathy as a benign condition with excellent prognosis.

Fibrotic mechanisms in idiopathic rapidly progressive glomerulonephritis: the role of TGF-beta1 and C5b-9.

BACKGROUND: Idiopathic IRPGN is a form of renal vasculitis in which a high chronicity index is present despite minimal impairment of renal function. The present study investigated the mechanisms underlining the relatively early appearance of fibrosis. METHODS: In all, 34 patients (17 males) with biopsy proven idiopathic RPGN were included. On light microscopy, the percentage and evolution stage of crescents, the presence of glomerular necrosis, the degree or severity of arteriosclerosis, as well as the extent of tubulointerstitial (TIN) infiltration, interstial fibrosis, and tubular atrophy were assessed. Monoclonal antibodies were used to identify infiltrating macrophages, HLA-DR (+), alpha-SMA (+), and PCNA (+) cells, the expression of the adhesion molecule ICAM-1, the growth factor TGF-beta1, and the terminal complement component C5b-9. RESULTS: The presence of glomerular necrosis correlated positively with the number of SMA (+) cells in TIN (p = 0.036). Glomerular TGF-beta1 expression had positive correlation with tubular C5b-9 expression. The tubulointerstitial TGF-beta1 expression correlated with tubular C5b-9 expression (p = 0.001) and TGF-beta1 expression (p = 0.009). Independent factors predicting the severity of renal function impairment were the CRP levels (p = 0.002) and the degree of arteriosclerosis (p = 0.01). CRP levels correlated with the severity of interstitial infiltration and fibrosis (p = 0.02), the expression of TGF-beta1 in the glomeruli (p = 0.009) and the interstitial space (p = 0.001), and the intensity of tubular ICAM-1 and C5b-9 expression (p = 0.023, p = 0.002, respectively). The severity of proteinuria showed a significant correlation with the expression of TGF-beta1 in the glomeruli (p = 0.033) and the tubulointerstitium (p = 0.019). CONCLUSIONS: The activation of interstitial fibroblasts seems to be an early phenomenon that is related to the extent of glomerular necrosis. Glomerular TGF-beta1 may induce tubular expression of C5b-9. Increased tubular C5b-9 expression may result in interstitial fibrosis through increased TGF-beta1 production.

Role of interferon-gamma 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/T(R)-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): IFNgamma intron-1 CA repeat at position 1349-1373; IL-13 -1055C/T; TGFbeta +915G/C; IL-10 5'-proximal and distal microsatellites; TNFalpha -308G/A, -238G/A. The FBAT multi-allelic analysis showed an association between IFNgamma 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 IFNgamma 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 IFNgamma evaluated in peripheral blood mononuclear cells from 10 genotyped patients demonstrated a correlation between the +874A allele and a lower production of IFNgamma (P=0.028 Mann-Whitney test). This SNP affects IFNgamma production lying within a binding site for the transcription factor NF-kappaB. No significant difference was observed in the 15 years renal survival between IgAN patients carrying different IFNgamma gene polymorphisms. This first family-based association study demonstrates that the +874A allele, strictly associated with IFNgamma 13-CA repeat allele, confers susceptibility to IgAN, without influencing renal survival.

Predictors of outcome in idiopathic rapidly progressive glomerulonephritis (IRPGN).

BACKGROUND: Small vessel vasculitides are known to follow a devastating course towards end-stage renal disease, unless treated with immunosuppressive regiments. We investigated the value of clinical, histological and immunohistochemical parameters as predictors of outcome at diagnosis in patients with pauci immune necrotizing glomerulonephritis. METHODS: In 34 patients the percentage and evolution stage of crescents, the presence of glomerular necrosis, the degree or severity of arteriosclerosis, as well as the extent of tubulointerstitial infiltration, interstial fibrosis and tubular atrophy were assessed. Monoclonal antibodies were used to identify infiltrating macrophages, alpha-SMA(+) and PCNA(+) cells, the expression of integrins alpha3beta1 and LFA-1beta, the adhesion molecule ICAM-1, the growth factor TGF-beta1 and the terminal complement component C5b-9. RESULTS: 24 pts (70.6%) showed a complete or partial response to the treatment. The follow-up period was 20 +/- 22 months. At multivariate analysis, serum CRP (p = 0.024), the intensity of tubular expression of C5b-9 (p < 0.0001) as well as the extent of glomerular and tubular expression of alpha3beta1 integrin (p = 0.001 and 0.008 respectively) independently predicted the response to treatment. The response rate was better in ANCA(+) pts (p = 0.008). The extent of interstitial infiltrate (p < 0.0001), the severity of tubulointerstitial fibrosis (p < 0.0001) and the severity of tubular TGF-beta1 expression (p < 0.0001) were independent predictors of long term outcome of renal function. CONCLUSION: Patients with ANCA-associated renal vasculitis seem to respond better to the treatment. Acute phase reactants, such as CRP, implying a more intense parenchymal inflammatory reaction, as well as the intensity of the de novo expression of C5b-9 and the glomerular and tubular expression of alpha3beta1 integrin predict the response to therapy. The severity of TIN lesions and of the tubulo-interstitial TGF-beta1 and C5b-9 expression predict an unfavourable outcome.

The IgA nephropathy Biobank. An important starting point for the genetic dissection of a complex trait.

BACKGROUND: IgA nephropathy (IgAN) or Berger's disease, is the most common glomerulonephritis in the world diagnosed in renal biopsied patients. The involvement of genetic factors in the pathogenesis of the IgAN is evidenced by ethnic and geographic variations in prevalence, familial clustering in isolated populations, familial aggregation and by the identification of a genetic linkage to locus IGAN1 mapped on 6q22-23. This study seems to imply a single major locus, but the hypothesis of multiple interacting loci or genetic heterogeneity cannot be ruled out. The organization of a multi-centre Biobank for the collection of biological samples and clinical data from IgAN patients and relatives is an important starting point for the identification of the disease susceptibility genes. DESCRIPTION: The IgAN Consortium organized a Biobank, recruiting IgAN patients and relatives following a common protocol. A website was constructed to allow scientific information to be shared between partners and to divulge obtained data (URL: http://www.igan.net). The electronic database, the core of the website includes data concerning the subjects enrolled. A search page gives open access to the database and allows groups of patients to be selected according to their clinical characteristics. DNA samples of IgAN patients and relatives belonging to 72 multiplex extended pedigrees were collected. Moreover, 159 trios (sons/daughters affected and healthy parents), 1068 patients with biopsy-proven IgAN and 1040 healthy subjects were included in the IgAN Consortium Biobank. Some valuable and statistically productive genetic studies have been launched within the 5th Framework Programme 1998-2002 of the European project No. QLG1-2000-00464 and preliminary data have been published in "Technology Marketplace" website: http://www.cordis.lu/marketplace. CONCLUSION: The first world IgAN Biobank with a readily accessible database has been constituted. The knowledge gained from the study of Mendelian diseases has shown that the genetic dissection of a complex trait is more powerful when combined linkage-based, association-based, and sequence-based approaches are performed. This Biobank continuously expanded contains a sample size of adequately matched IgAN patients and healthy subjects, extended multiplex pedigrees, parent-child trios, thus permitting the combined genetic approaches with collaborative studies.

Effects of simvastatin on markers of inflammation, oxidative stress and endothelial cell apoptosis in patients on chronic hemodialysis.

AIM: We investigated the effects of simvastatin on markers of inflammation, oxidative stress and endothelial cell apoptosis in hyperlipidemic endstage renal disease patients on chronic hemodialysis (HD). METHODS: In 25 hyperlipidemic HD patients who received 10 mg of simvastatin for 6 months and another 25 controls, the extended lipid profile and serum hsIL-6, MCP-1, sICAM-1, sVCAM-1, and sE-selectin, plasma oxLDL, and serum sFas and sFasL levels were determined at baseline, 3 months and 6 months. In 18 patients of the simvastatin group, the expression of CD14, CD16, CD62L and CD64 on monocyfes was determined with flow cytometry. RESULT: Simvastatin treatment resulted in significant reductions in serum lipid levels at 3 months and beyond, compared to at baseline. Moreover, at 6 months, simvastatin caused a significant reduction in CRP (p < 0.001), which correlated to the decrease in total and LDL cholesterol levels, as well as a significant reduction in IL-6 (p=0.001), sICAM-1 (p < 0.001), sVCAM-1 (p < 0.001), oxLDL (p=0.001), sFas (p=0.02) and CD14 expression (p < 0.001), compared to baseline values. No significant changes in the controls were noticed during the study. CONCLUSION: In conclusion, in hyperlipidemic HD patients, simvastatin treatment resulted in a significant reduction in markers of endothelial dysfunction, inflammation, oxidative stress, endothelial cell apoptosis and peripheral blood monocyte stimulation. The reduction in CRP appears to be related to the lipid-lowering effects of simvastatin.

C5b-9 glomerular deposition and tubular alpha3beta1-integrin expression are implicated in the development of chronic lesions and predict renal function outcome in immunoglobulin A nephropathy.

OBJECTIVE: Tubular atrophy is one of the factors predicting poor outcome of renal function in primary immunoglobulin A nephropathy (IgAN). However, the development of tubular atrophy is a late phenomenon during the disease progression. It would be useful to identify early factors that potentially result in renal damage and could be used as early predictors of renal outcome. MATERIAL AND METHODS: Forty-eight patients with IgAN were examined retrospectively. All patients had a renal biopsy at the beginning of the study. Histological parameters were reviewed and immunohistochemistry was performed on cryostat sections. Monoclonal antibodies used were against C5b-9, alpha3beta1-integrin, transforming growth factor-beta1 (TGF-beta1) and alpha-smooth muscle actin (alpha-SMA), and the results were correlated with histological data and long-term outcome of renal function. RESULTS: In the glomeruli the extent of C5b-9 deposition had significant positive correlations with the degree of focal glomerulosclerosis (p=0.005), tubular atrophy (p=0.003), interstitial inflammation (p=0.005) and tubular expression of alpha3beta1 (p=0.0001). alpha3beta1 tubular expression correlated positively with the severity of proteinuria (p=0.01), number of glomerular and tubulointerstitial myofibroblasts, and the degree of tubular atrophy (p=0.0001) and interstitial monocyte infiltration (p =0.005). Tubular alpha3beta1 expression and the degree of tubular atrophy had significant implications in the development of renal failure at the beginning and at the end of follow-up, respectively. CONCLUSIONS: Glomerular deposition of C5b-9 may participate in the development of glomerulosclerosis in IgAN. Furthermore, its positive correlation with the intensity of tubular alpha3beta1-integrin suggests a possible implication in the development of tubulointerstitial fibrosis.

Induction and long-term treatment with cyclosporine in membranous nephropathy with the nephrotic syndrome.

BACKGROUND: Cyclosporine A (CyA) has been shown to be effective in membranous nephropathy (MN). However, the optimal dose and the duration of treatment remain controversial issues. We evaluated the efficacy of low-dose CyA alone or combined with corticosteroids as induction and long-term treatment for nephrotic patients with MN. METHODS: In the first part of the study, 51 nephrotic patients with MN were treated either with CyA and prednisolone (n=31) or CyA alone (n=20) for 12 months. Patients who responded with complete remission (CR) or partial remission (PR) were placed on long-term treatment with lower doses of CyA and prednisolone or CyA alone. The mean follow-up of the second part of the study was 26+/-16 months and 18+/-7 months, respectively. RESULTS: After 12 months of treatment, 26 patients in the combination group and 17 patients in the monotherapy group had a CR or PR of proteinuria (P=NS). Renal function was unchanged in the two groups. During long-term treatment relapses were more frequent in the monotherapy group (47 vs 15%, P<0.05). Daily CyA dose was higher in non-relapsers in both groups (combination 1.4+/-0.5 vs 1.0+/-0.3 mg/kg, P<0.001, monotherapy 1.5+/-0.4 vs 1.1+/-0.2 mg/kg, P<0.003). Relapsers in both groups had lower CyA trough levels (72+/-48 ng/ml) compared with non-relapsers (194+/-80 ng/ml) (P<0.03). Renal function and proteinuria remained stable during the follow-up. CONCLUSION: This study suggests that 12-month therapy with CyA (+/-prednisolone) is effective in inducing remission in most nephrotic patients with MN and well-preserved renal function. Longer treatment with lower doses is a useful approach to maintain remission. Relapses occur more frequently in the monotherapy group and usually are associated with CyA trough levels<100 ng/ml.

Genetic heterogeneity in Italian families with IgA nephropathy: suggestive linkage for two novel IgA nephropathy loci.

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, but its etiologic mechanisms are still poorly understood. Different prevalences among ethnic groups and familial aggregation, together with an increased familial risk, suggest important genetic influences on its pathogenesis. A locus for familial IgAN, called "IGAN1," on chromosome 6q22-23 has been described, without the identification of any responsible gene. The partners of the European IgAN Consortium organized a second genomewide scan in 22 new informative Italian multiplex families. A total of 186 subjects (59 affected and 127 unaffected) were genotyped and were included in a two-stage genomewide linkage analysis. The regions 4q26-31 and 17q12-22 exhibited the strongest evidence of linkage by nonparametric analysis (best P=.0025 and .0045, respectively). These localizations were also supported by multipoint parametric analysis, in which peak LOD scores of 1.83 ( alpha =0.50) and 2.56 ( alpha =0.65) were obtained using the affected-only dominant model, and by allowance for the presence of genetic heterogeneity. Our results provide further evidence for genetic heterogeneity among families with IgAN. Evidence of linkage to multiple chromosomal regions is consistent with both an oligo/polygenic and a multiple-susceptibility-gene model for familial IgAN, with small or moderate effects in determining the pathological phenotype. Although we identified new candidate regions, replication studies are required to confirm the genetic contribution to familial IgAN.

C5b-9 and adhesion molecules in human idiopathic membranous nephropathy.

BACKGROUND: Cellular immune responses and C5b-9 seem to play an important role in the pathogenesis and progression of idiopathic membranous nephropathy (IMN). The aim of the study was to investigate the role of C5b-9 and adhesion molecules in the pathogenesis of the disease. METHODS: The clinical and pathological data of 35 patients with biopsy-proven IMN were correlated with immunohistochemical findings using monoclonal antibodies against T lymphocytes, monocytes/macrophages (MM), HLA-DR antigens, C5b-9, and adhesion molecules such as alpha3beta1, LFA-1beta, and ICAM-1. RESULTS: In the glomeruli, C5b-9 deposits showed a significant correlation with the intensity of IgG and C3 deposition. The stage of the disease had a significant negative relationship with the glomerular alpha3beta1 expression. In the tubulointerstitium (TIN), the number of HLA-DR(+) cells was highly correlated with the numbers of total T lymphocytes, MM, and LFA-1beta(+) cells, as well as with the percentage of tubules with C5b-9 deposits. The extent of ICAM-1 expression in the TIN was significantly correlated with the numbers of interstitial MM, HLA-DR(+), and LFA-1beta(+) cells, as well as with the extent of tubular C5b-9 deposition. The severity of tubular atrophy and interstitial fibrosis had a relationship with the numbers of total T lymphocytes, MM, HLA-DR(+), and LFA-1beta(+) cells and with the extent of tubular C5b-9 deposition and ICAM-1 expression in the TIN. Serum creatinine (Scr) was highly correlated with the numbers of interstitial total T lymphocytes, MM, HLA-DR(+), and LFA-1beta(+) cells. Moreover, Scr had a significant relationship with the severity of tubular atrophy and interstitial fibrosis, as well as with the extent of tubular C5b-9 deposition and ICAM-1 expression in the TIN. Proteinuria was significantly correlated with the extent of tubular alpha3beta1 expression. CONCLUSIONS: In IMN, C5b-9 formation may be secondary to IgG and C3 deposition. Proteinuria may contribute to the TIN damage by altering the expression of alpha3beta1 integrins in tubular cells. De novo ICAM-1 and C5b-9 expression within the TIN as well as the activated interstitial cells may be important factors leading to renal damage and renal function impairment.

Focal segmental glomerulosclerosis in a patient with large bilateral asymptomatic adrenal myelolipomas.

Adrenal myelolipomas are rare benign tumors, usually discovered by chance in patients with hypertension, obesity or various endocrine disorders. Focal segmental glomerulosclerosis (FSGS) can occur as a primary disease or in a variety of secondary settings. So far, no association between the two conditions has been described. We report a case of a woman admitted for nephrotic syndrome, in which a coexistence of FSGS and bilateral large adrenal myelolipomas was revealed.

Treatment of severe IgA nephropathy with omega-3 fatty acids: the effect of a "very low dose" regimen.

BACKGROUND: The effect of a "very low dose" of purified omega-3 fatty acids (PFA) in the progression of severe IgA nephropathy (IgAN) was tested, in a randomized, prospective, controlled trial. METHODS: Fourteen patients were assigned to receive a "very low dose" of PFA (0.85 g EPA and 0.57 g PHA) and 14 patients were treated symptomatically and used as controls. Both groups were similar in terms of serum creatinine (Scr) and glomerular filtration rate (GFR) at baseline. Patients were treated for 4 years. The primary end-points were an increase of 50% or more in Scr or a decrease of 50% or more in GFR at the end of the study. RESULTS: During treatment, 1 patient (7%) in the PFA group and 6 (43%) in the control group had an increase of 50% or more in their Scr (p<0.01). Also, 1 patient (7%) in the PFA group and 7 (50%) in the control group had a decrease of 50% or more in GFR (p<0.007). The mean annual change in Scr was 0.2 mg/dL in the PFA group and 1.0 mg/dL in the control group (p<0.01). The mean annual change in GFR was -1.4 mL/min in the PFA group and -3.0 mL/min in the control group (p <0.001). One patient in the PFA group (7%) and 6 patients in the control group (43%) (p<0.01) developed end-stage renal disease during the period of observation. CONCLUSIONS: A "very low dose" of PFA is also effective in slowing renal progression in high-risk patients with IgAN and particularly those with advanced renal disease.

Carotid atherosclerosis is associated with inflammation and endothelial cell adhesion molecules in chronic haemodialysis patients.

BACKGROUND: Recently emerging evidence suggests that endothelial adhesion molecules may participate in atherogenesis. The aim of the present report was to investigate the probable association of circulating ICAM-1, VCAM-1 and E-selectin with atherosclerotic disease in chronic haemodialysis (HD) patients. METHODS: One hundred and twelve HD patients and 50 age- and sex-matched healthy normotensive controls participated in the study. Atherosclerotic disease in both groups was assessed by measuring intima-media thickness (IMT) and plaque score of the common carotid arteries using an ultrasound scanner. In addition, in a follow-up study, the survival of 81 patients after a mean period of 26 months was analysed in relation to ICAM-1 and VCAM-1 levels. RESULTS: IMT and plaque score were significantly higher in HD patients compared with control subjects (P < 0.001 and P < 0.0001, respectively). The above ultrasonographic indices were correlated with age both in controls (P = 0.0001 and P = 0.002, respectively) and HD patients (P = 0.0001 and P = 0.0001, respectively). A significant relationship was observed between IMT and systolic blood pressure (BP) both in controls and in HD patients (P = 0.002 and P = 0.01, respectively). In HD patients, plaque score was also correlated with systolic BP (P = 0.02). In HD patients, IMT and plaque score were correlated significantly with log CRP values (P = 0.01 and P = 0.01, respectively). Multivariate analysis showed that log CRP values were a strong independent contributor to plaque score (P = 0.01). IMT was significantly correlated with ICAM-1 and VCAM-1 concentrations (P = 0.0001 and P = 0.003, respectively). Multivariate analysis showed that ICAM-1 concentrations were a strong independent correlate of IMT (P = 0.001). E-selectin concentrations did not show any relation with IMT or plaque score. During the follow-up period, 13 of the 81 patients died. Survival analyses showed that patients with increased ICAM-1 had a shorter survival than patients with normal ICAM-1 values and that serum ICAM-1 levels were a strong predictor of death. CONCLUSIONS: In HD patients, carotid atherosclerosis is associated with inflammation and circulating levels of soluble adhesion molecules ICAM-1 and VCAM-1. The correlations between serum ICAM-1 and IMT and ICAM-1 and survival may indicate that this molecule could be a marker of a process that contributes to the high mortality of HD patients.

Circulating levels of ICAM-1, VCAM-1, and MCP-1 are increased in haemodialysis patients: association with inflammation, dyslipidaemia, and vascular events.

BACKGROUND: Increased levels of circulating adhesion molecules and chemokines have been reported in haemodialysis (HD) patients but the influence of the HD membranes on their secretion, as well as their pathophysiological implications, remains largely unknown. METHODS: Circulating levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) were measured by immunosorbent assay (ELISA) in 81 HD patients (45 male, mean age 57+/-13 years) and 35 normal subjects. All patients had been stabilized on renal replacement therapy for >3 months and were free of active infection. Thirty-three patients (40.7%) were routinely dialysed with modified cellulose membranes and 48 patients (59.3%) were dialysed with polysulfone membranes. Blood samples were taken directly from the arteriovenous fistula immediately before and at the end of a routine HD session. RESULTS: Pre-dialysis levels were significantly elevated in HD patients compared with controls (ICAM-1 515+/-177 vs 238+/-664 ng/ml, P<0.0001; VCAM-1 2107+/-648 vs 1012+/-115 ng/ml, P<0.0001; MCP-1 427+/-148 vs 125+/-42 pg/ml, P<0.0001). The HD session resulted in a significant increase in the levels of all three molecules measured (515+/-177 vs 679+/-187 ng/ml, P<0.0001; 2107+/-648 vs 2662+/-800 ng/ml, P<0.0001; 427+/-148 vs 567+/-153 pg/ml, P<0.0001, respectively). There was no difference in pre- or post-dialysis levels of the above molecules between patients routinely dialysed with either modified cellulose or polysulfone membranes. MCP-1 levels had a positive correlation with ICAM-1 levels (r=0.41, P<0.0005). VCAM-1 levels had a negative correlation with HDL levels (r=-0.30, P<0.01) and were significantly elevated in patients with HDL <35 mg/dl compared with patients with HDL > or = 35 mg/dl (2300+/-606 vs 1890+/-633 ng/ml, P<0.005). Log-transformed exact C-reactive protein (CRP) values were significantly correlated with ICAM-1 and VCAM-1 levels (r=0.41, P<0.005 and r=0.43, P<0.005, respectively). In addition, compared with patients with normal CRP values, patients with elevated CRP had significantly increased levels of ICAM-1 (466+/-166 vs 580+/-172 ng/ml, P<0.005). Patients with cardiovascular, cerebrovascular, or peripheral vascular diseases had significantly increased serum CRP and ICAM-1 levels compared with patients with no evidence of vascular disease (19.2+/-12.9 vs 7.9+/-11.8 mg/l, P<0.001 and 608+/-189 vs 474+/-155 ng/ml, P<0.005 respectively). CONCLUSIONS: Serum levels of ICAM-1, VCAM-1, and MCP-1 are increased in HD patients and probably result from either inadequate clearance or enhanced synthesis and release. HD session resulted in a significant increase of the above molecule levels but the exact mechanism(s) responsible for these alterations are yet to be fully elucidated. Increased levels of adhesion molecules are associated with inflammation, dyslipidaemia, and cardiovascular events. However, the potential link between these processes and its clinical significance warrants further investigation.