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Background and Aims Patients undergoing hemodialysis (HD) often develop cerebral disease complications. Cerebral tissue regional oxygen saturation (rSO2) through near-infrared spectroscopy (NIRS) is a non-invasive method for cerebral tissue oxygenation monitoring. The aim of the study was to investigate the relationship between rSO2 and hemodialysis in stable HD patients. Additionally, we wanted to investigate how blood pressure during HD is associated with rSO2. Method This is a single centre cross-sectional study in clinically stable HD patients. Cerebral rSO2 was monitored at the forehead 10min before, during and 10min after HD, using an INVOS 5100C device (Medtronic, United Kingdom). Results Thirty-nine stable HD patients (23 men and 16 women; mean age, 62.4 ± 14.6 years were recruited. Dialysis vintage was 65.7 ± 72.1 months, 9 patients had diabetes mellitus, 12 had vascular disease while 14 were smokers. The baseline rSO2 levels (49.6±9.1 %) were significantly lower in HD patients compared with historic results on healthy subjects. We found no difference in rSO2 results in patients with diabetes mellitus, vascular disease or smoking. Although we found a decrease (figure) in rSO2 when patients start dialysis (10min before vs 10min after starting dialysis 49.6±9.1 vs 48.1±9.9 %, p=0.021) rSO2 value returned to baseline after dialysis (10min before vs 10min after dialysis 49.6±9.1 vs 49.9±5.9 %, p=ns. Systolic blood pressure scientifically dropped during the first hour of dialysis (146.7 ± 21.1 vs 137.3 ± 24.6, p=0.03) and systolic blood pressure drop correlated with rSO2. Three patients developed hypotensive episodes requiring iv fluids but these hypotensive episodes had no correlation with rSO2 variations. Conclusion Cerebral rSO2 decreases while patients are on dialysis but return to baseline after dialysis. Blood pressure variations correlate with rSO2 levels but rSO2 do not forecast hypotensive episodes on dialysis.

Objective: Steroids and im- munosuppressants can delay progression of renal function in IgAN, but their possible ef- fect in local cytokines has not been studied. Material and methods: Histology in 53 IgAN patients (M/F 35/18 age 40.5 years (17 - 65)) was evaluated using the Oxford classifica- tion system. IL-1β, -2, -4, -5, -6, -10, -12 and -17, INF-γ and MCP-1 were measured subsequently by multiplex cytokine assay in first morning urine samples taken at the day of renal biopsy. After a 6-month course with RAASinhibitors + fish oils (FO), 35/53 patients, Group A, responded and continued on the same treatment, while in 18/53 who did not respond, Group B, steroids + azathio- pine were added. Results: The presence of endocapillary proliferation had significant correlation with the urinary excretion of pro-inflammatory and pro-fibrotic cytokines (IL-1β, MCP-1, IL-17, INF-γ, IL-6 and IL- 10). Serum creatinine at time of diagnosis had significant correlation with proteinuria (p = 0.02), urinary levels of IL-1β (p = 0.03), IL-2 (p = 0.01) and MCP-1 (p = 0.03). GFR was reduced from 65 ± 29 to 57 ± 34 ml/min, p = 0.005 in Group A and remained stable in Group B patients (GFR from 63 ± 24 to 61 ± 30 ml/min, p = NS). Most of the mea- sured cytokines in the urine predicted dete- rioration of renal function in Group A, but the urinary excretion of IL-6 seemed to pre- dict renal function outcome in both groups of patients. Conclusion: Several cytokines are excreted in the urine of patients with IgAN, and their levels predict the outcome of the disease. Steroids + aza may exert their beneficial effect through suppression of the production or activation of most cytokines.

Aim: We evaluated the influence of C-344T polymorphism of the aldosterone synthase gene, associated with aldosterone levels and the development of arterial hypertension, on focal segmental glomerulosclerosis (FSGS). Methods: We studied 81 patients with primary FSGS followed up for 8.0 ± 12 years. Patients were classified according to their slope of reciprocal serum creatinine into group A (slow progressors, n = 57) and B (fast progressors, n = 24). One hundred healthy volunteers were analysed as controls. The biopsies of n = 50 patients were reviewed and analysed by the same pathologist. C-344T polymorphism was determined by polymerase chain reaction. Results: The allele frequencies differed significantly between patients (C-allele: 0.55, T-allele: 0.45) and controls (C-allele: 0.45, T-allele: 0.55; P

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Angiotensin-converting enzyme inhibitor (ACEi)-induced angio-oedema is an underestimated clinical life-threatening problem. • The incidence of this non-allergic, bradykinin-induced drug side-effect is 1 : 4000. • Although most ACEi-treated patients probably have an increased bradykinin plasma concentration, only 0.5% of them develop an angio-oedema and nothing is known about potential risk factors. WHAT THIS STUDY ADDS • In our attempt to elucidate the unpredictable character of ACEi-induced angio-oedema, we investigated bradykinin B2 receptor 2/3 and c.C181T polymorphisms as well as the ACE insertion/deletion polymorphism in combination with serum ACE activity in 65 patients. • ACE insertion/deletion and bradykinin B2 receptor polymorphisms are not involved in the development of ACEi-induced angio-oedema. • Further studies should be carried out to clarify whether a combination of these polymorphisms might be a risk factor for ACEi-induced angio-oedema. AIMS The pathophysiology of angiotensin-converting enzyme inhibitor (ACEi)-induced angio-oedema remains unclear. We have investigated the impact of ACE insertion/deletion (I/D) polymorphism in combination with serum ACE activity as well as the bradykinin B2 receptor 2/3 and c.C181T polymorphisms. METHODS We analysed the ACE I/D as well as bradykinin B2 (2/3 and C181T) receptor polymorphisms in 65 patients with documented episodes of ACEi-induced angio-oedema and 65 patients matched for age and sex being under ACEi treatment without history of angio-oedema. Furthermore, we determined serum ACE activity in 47 of the 65 angio-oedema patients 3 months after the angio-oedema attack and compared these values with 51 healthy individuals (control II). RESULTS No risk association was identified between ACE I/D (I-allele: 0.42 vs. 0.41, D-allele: 0.58 vs. 0.59; P= 0.095) or bradykinin B2 receptor polymorphisms and the development of angio-oedema during ACEi treatment. We found a trend of lower serum ACE activity in ACE I/I genotypes in comparison with control II (I/I: 28 ± 4.5 vs. 33 ± 1.8 U l−1; ID: 39 ± 3.3 vs. 41 ± 1 U l−1; DD: 56 ± 6.7 vs. 52 ± 1.8 U l−1; P= 0.9). CONCLUSIONS Our data suggest that polymorphism of ACE I/D and the bradykinin B2 receptor polymorphisms are not involved in the development of ACEi-induced angio-oedema when considered individually. Further studies should be carried out to clarify whether a combination of these polymorphisms might be a risk factor for ACEi-induced angio-oedema.

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.

SUMMARY: 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.

Aims. Recently, polymorphisms of cytokine genes have been associated with altered gene expression and modified cytokine production. We evaluated the impact of TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A and IL-6 gene G-174C polymorphisms on the clinical manifestations of IgA nephropathy. Patients and methods. The clinical course of 127 patients with biopsy-proven IgA nephropathy followed up for 6.6 +/- 6.0 years was studied. Patients were classified according to the slope of reciprocal serum creatinine into group A (slow progressors, n = 78) and group B (fast progressors, n = 49). TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A and IL-6 gene G-174C polymorphisms were determined by PCR amplification followed by restriction digestion with the endonucleases Sau96 I, Nco I, and Lwe I respectively. Results. The genotype distribution of the investigated polymorphisms was similar in patients and control subjects (ns). Age, initial renal function, proteinuria, and blood pressure did not differ significantly between patients with different genotypes. The investigated polymorphisms were not associated with the progression of the IgA nephropathy, as shown by the similar genotype distribution in group A and group B (slow progressors: TGF-beta1, 92.3%; TNFalpha, 25.6%; IL-6, 74.4%; fast progressors: TGF-beta1, 85.7%; TNFalpha, 22.4%; IL-6: 81.6%, ns). Furthermore, these polymorphisms had no impact on renal survival in the Kaplan Meier analysis (ns). Conclusion. Our results suggest that TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A, and IL-6 gene G-174C polymorphisms are not risk factors or markers of progression in Caucasian patients with IgA nephropathy.

Background: Recently, polymorphisms of cytokine genes have been associated with modified gene expression and increased cytokine production. We evaluated the influence of interleukin-10 (IL-10) gene G-1082A, tumour necrosis factor alpha (TNFα) gene G-308A and IL-6 gene G-174C polymorphisms on the rejection rate, renal function and long-term outcome in renal transplantation. Patients and methods: We studied n = 224 consecutive patients, who underwent renal transplantation at our centre from 1998 to 2001 (cadaveric: n = 175, living related: n = 49) followed up for 4.9 ± 2.0 yr and n = 100 healthy volunteers. IL-10 gene G-1082A, TNFα gene G-308A and IL-6 gene G-174C polymorphisms were determined by polymerase chain reaction (PCR) amplification. Results: The genotype distribution of the investigated polymorphisms was similar in patients and controls (ns). The age of donor and the recipient, the number of HLA mismatches and cold and warm ischemic time did not differ among patients with different genotypes (ns). No association between cytokine polymorphisms and the incidence of acute rejection episodes was detected (ns). The cytokine genotypes did not correlate with serum creatinine or creatinine clearance at any time during follow up (ns). Furthermore, there was no significant difference in the genotype frequencies among patients experiencing graft failure (ns). Patients with different cytokine gene polymorphisms showed similar outcomes in the Kaplan–Meier analysis of graft survival (ns). Finally, cytokine polymorphisms had no influence on the acute rejection rate or graft outcome also in the subgroup of HLA-DR mismatched grafts (ns). Conclusion: Our results suggest that IL-10 gene G-1082A, TNFα gene G-308A and IL-6 gene G-174C polymorphisms are no major risk factors in renal transplantation.

Background: β3 integrin subunit is expressed as αIIbβ3 integrin on platelets and as αvβ3 integrin on a variety of cells including renal endothelial, mesangial and tubular cells. Leu33/Pro33 polymorphism of β3 integrin has been associated with altered platelet functions, cardiovascular complications and the incidence of acute rejection episodes in renal transplantation. We investigated its influence on IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephritis (MGN). Methods: We studied 251 patients with biopsy-proven primary glomerulonephritis (IgAN n = 127, FSGS n = 71, MGN n = 53) followed up for 6.3 ± 5.3 years and 100 control subjects. Patients were classified according to the slope of reciprocal serum creatinine into slow (n = 162) and fast progressors (n = 89). Leu33/Pro33 polymorphism was determined by PCR amplification followed by restriction with the endonuclease Bcnl. Results: The genotype frequencies were similar in patients and controls (n.s.). Initial renal function, proteinuria and blood pressure did not differ significantly between patients with different genotypes (n.s.). The genotype frequencies were similar in slow and fast progressors (n.s.). Furthermore, Leu33/Pro33 polymorphism had no impact on renal survival in the Kaplan-Meier analysis (n.s.). Conclusion: Our results indicate that β3 integrin Leu33/Pro33 polymorphism is not a risk factor or a marker of progression in primary glomerulonephritis.

Association of interleukin-10 gene G-1082A polymorphism with the progression of primary glomerulonephritis.BackgroundInterleukin-10 (IL-10) is a cytokine with immunosuppressive properties. We evaluated the influence of G-1082A polymorphism in the IL-10 gene promoter, which has been associated with modified IL-10 production, on the two most common forms of primary glomerulonephritis: IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS).MethodsWe studied Caucasian patients (N = 191) with biopsy-proven glomerulonephritis (IgAN: N = 123, FSGS: N = 68) followed-up for 6.5 ± 5.5 years. Patients were classified according to the slope of reciprocal serum creatinine (≥ or

Background: Recently, polymorphisms of cytokine genes have been associated with modified gene expression and increased cytokine production. We evaluated the influence of TGF-β1 gene Arg25→Pro, TNFα gene G-308A and IL-6 gene G-174C polymorphisms on the clinical manifestations of focal segmental glomerulosclerosis (FSGS). Methods: The clinical course of 71 patients with biopsy-proven primary FSGS followed up for 6.0 ± 4.4 years was studied. Patients were classified according to the slope of reciprocal serum creatinine into slow (n = 49) and fast (n = 22) progressors. One hundred healthy volunteers were analysed as controls. Genetic polymorphisms were determined by PCR amplification. Results: The genotype distribution of the studied polymorphisms was similar in patients and controls (n.s.). Age, initial renal function, proteinuria and blood pressure did not differ significantly between patients with different genotypes (n.s.). The investigated polymorphisms were not associated with the progression of FSGS as shown by the similar genotype frequencies among slow and fast progressors (n.s.) and the renal survival in the Kaplan-Meier analysis (n.s.). Conclusion: Our results indicate that TGF-β1 gene Arg25→Pro, TNFα gene G-308A and IL-6 gene G-174C polymorphisms are not risk factors or markers of progression in focal segmental glomerulosclerosis.

We evaluated the influence of C-344T polymorphism of the aldosterone synthase gene, associated with aldosterone levels and the development of arterial hypertension, on focal segmental glomerulosclerosis (FSGS).We studied 81 patients with primary FSGS followed up for 8.0 ± 12 years. Patients were classified according to their slope of reciprocal serum creatinine into group A (slow progressors, n = 57) and B (fast progressors, n = 24). One hundred healthy volunteers were analysed as controls. The biopsies of n = 50 patients were reviewed and analysed by the same pathologist. C-344T polymorphism was determined by polymerase chain reaction.The allele frequencies differed significantly between patients (C-allele: 0.55, T-allele: 0.45) and controls (C-allele: 0.45, T-allele: 0.55; P0.05). Patients carrying the C-allele tended to have a higher percentage of sclerosed glomeruli (41.8 ± 30% vs 31. 2 ± 19% in TT genotype, ns) and tubulointerstitial fibrosis (22.8 ± 18% vs 16.0 ± 5%, ns). The rate of deterioration of renal function was higher in the CC/CT genotypes (-0.216 ± 0.449 dL/mg per year) compared to the TT genotype (-0.030 ± 0.041 dL/mg per year, P = 0.002). Furthermore, 36.4% of the C-allele carriers and none of the patients with the TT genotype belonged to group B (P = 0.005). C-allele carriers also had a worse kidney survival in the Kaplan-Meier analysis (P = 0.027).Our results indicate that aldosterone synthase gene C-344T polymorphism not only acts as a risk factor for the development of FSGS, but also may influence its pathologic appearance and could serve as a marker of disease progression.

Detection of urinary cytokines in pauci-immune focal segmental necrotizing glomerulonephritis (FSNGN) may provide valuable information about disease pathogenesis and prognosis.Epidermal growth factor (EGF), transforming growth factor (TGF-β1) and vascular endothelial growth factor (VEGF) were measured by ELISA, and Interleukins, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein (MIP1β) by a multiplex cytokine assay, in 38 patients with FSNGN. Their levels were correlated with severity of histological findings and renal function outcome in short and long term.The percentage of crescents in renal biopsy had positive correlation with TGF-β1 (p=0.004) and IL-15 urinary excretion (p=0.01), and negative correlation with EGF (p=0.01). Increased urinary excretion of IL-6, IL-15, VEGF and MIP-1β was associated with poor renal function outcome, but increased levels of EGF, IL-2 and IL-9 predicted a favourable prognosis. In multiple regression analysis IL-6 and VEGF urinary levels were independent predictors of no-response at the acute phase (p=0.001 and p0.0001, respectively), while, IL-6 was the only factor (p=0.03) predicted worse outcome at the end of follow-up (39.4±45 months).Increased urinary excretion of IL-6, IL-15, VEGF, TGF-β1, MCP-1 and MIP-1β and reduced EGF, IL-2, IL-9 may be associated with histological damage and influence response to treatment in pauci-immune FSNGN.

In the past years, aldosterone has been identified as an important mediator of renal injury. In this study, we evaluated the influence of C-344T polymorphism of aldosterone synthase gene, associated with serum aldosterone levels and the development of arterial hypertension, on IgA nephropathy (IgAN).We studied n = 143 patients with biopsy-proven IgAN followed up for 7.1 ± 6.2 years. Patients were classified according to the slope of reciprocal serum creatinine into group A (slow progressors, n = 93) and group B (fast progressors, n = 50). One hundred healthy volunteers were analyzed as controls. The biopsies of n = 79 patients were reviewed and analyzed by the same pathologist. Aldosterone synthase gene C-344T polymorphism was determined by polymerase chain reaction amplification.The genotype distribution was similar in patients and control subjects [not significant (ns)]. Age, initial renal function, proteinuria, and blood pressure did not differ significantly between patients with different genotypes (ns). The percentage of sclerosed glomeruli tended to be higher among patients carrying the CC/CT genotypes (29.4 ± 26.5% vs. 21.7 ± 25.2% in TT genotype; ns). C-344T polymorphism was associated with the progression of IgAN as shown by the different genotype frequencies in group Α (slow progressors,60.2%, TT: 39.8%) and group B (fast progressors,78.0%, TT: 22:0%; p = 0.032).Our results indicate that aldosterone synthase gene C-344T polymorphism is a risk factor for accelerated progression in Caucasian patients with IgAN.

Background. Inflammation is a well recognized central component of atherosclerotic processes in chronic kidney disease. Interleukin-6 (IL-6) levels are a strong determinant of cardiovascular mortality in dialysis patients. We evaluated the impact of IL-6 gene G-174C polymorphism associated with modified IL-6 production on the development of coronary artery disease (CAD), cardiovascular events and mortality in chronic dialysis patients. Methods. We studied n = 463 patients on chronic dialysis with angiographically confirmed (n = 218) or excluded (n = 245) CAD followed up for 65 months after initiation of dialysis. Monitored were arterial hypertension, diabetes mellitus, hyperlipidemia, smoking, CRP and fibrinogen. IL-6 gene G-174C polymorphism was determined by PCR amplification. Results. The CC genotype was associated with an impaired patient survival (p < 0.05) remaining an independent risk factor for death in multivariate analysis (HR for CC genotype: 3.58, CI: 1.41-9.07,p < 0.01). CC genotype carrying CAD patients suffered significant frequently cardiovascular events (revascularization, myocardial infarction, death) compared to GG/GC genotype carriers (85.2% vs. 66.5,p < 0.05). However, the IL-6 gene G-174C polymorphism was not related to the onset and development of CAD itself (ns) and the inflammation parameters CRP and fibrinogen did not differ between the genotypes under investigation (ns). Conclusions. Our results suggest that IL-6 gene G-174C polymorphism is associated with the incidence of cardiovascular events and mortality in chronic dialysis patients.

The G-1082A polymorphism of the interleukin-10 (IL-10) gene has been associated with modified gene expression and the progression of primary IgA nephropathy (IgAN). In the present study, we evaluated its influence on recurrent IgAN after renal transplantation.We studied 103 patients who suffered from IgAN and underwent renal transplantation, followed up for 5.8 -/+ 3.4 years. A cohort of 206 matched renal allograft recipients with other primary diseases was analyzed as a control group. IL-10 gene G-1082A polymorphism was determined by PCR amplification.Microscopic hematuria and/or proteinuria of more than 500 mg/24 hours occurred in 22 patients (21%). Histological confirmation of IgAN recurrence was obtained in 16 patients. Young recipient age was associated with biopsy-proven IgAN recurrence in the Kaplan-Meier analysis of recurrence-free survival (p=0.05). The presence of IgAN recurrence had no impact on graft survival (not significant [NS]). Furthermore, graft survival was similar in patients with IgAN and patients with other primary diseases (NS). The IL-10 GG genotype was associated with a higher recurrence rate in the Kaplan-Meier analysis of recurrence-free survival (p0.05).IgAN recurrence is a common complication, especially in younger renal transplant recipients. IL-10 gene G-1082A polymorphism was associated with an increased recurrence rate.

IgA nephropathy (IgAN) and focal segmental necrotizing glomerulonephritis (FSNGN) are characterized by proliferation of native glomerular cells and infiltration by inflammatory cells. Several cytokines act as mediators of kidney damage in both diseases. The aim of the present study was to investigate the role of Th1, Th2 and Treg/T17 cytokines in these types of proliferative glomerulonephritis. Simultaneous measurement of Th1 interleukin (IL-2, IL-12, tumor necrosis factor-alpha [TNF-α], interferon-gamma [INF-γ]), Th2 (IL-4, IL-5, IL-6, IL-10, IL-13), Treg/T17 transforming growth factor-beta 1 (TGF-β1, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-17) cytokines and C-C chemokines Monocyte chemoattractant protein-1 (MCP-1, macrophage inflammatory protein-1 [MIP-1] β) was performed in first-morning urine samples, at the day of renal biopsy, using a multiplex cytokine assay. Cytokine concentrations were correlated with histological findings and renal function outcome. Urinary excretion of Th1, Th2 and Treg/Th17 cytokines were significantly higher in FSNGN compared to IgAN patients. In IgAN patients (n = 50, M/F: 36/14, M age: 40.7 [17–67] years), Th1, Th2 and T17 cytokines correlated significantly with the presence of endocapillary proliferation, while in FSNGN patients (n = 40, M/F: 24/16, M age: 56.5 [25–80] years), MCP-1 and TGF-β1 had a positive correlation with severe extracapillary proliferation (P = 0.001 and P = 0.002, respectively). Urinary IL-17 was the only independent parameter associated with endocapillary proliferation in IgAN and with MCP-1 urinary excretion in FSNGN. Response to treatment was mainly predicted by IL-6 in IgAN, and by Th2 (IL-4, IL-6), Treg (GM-CSF) cytokines and MIP-1 β in FSNGN. Th1, Th2 and T17 cytokines were directly implicated in renal pathology in IgAN and possibly through MCP-1 production in FSNGN. IL-17 and IL-6 seem to have a central role in inflammation and progression of kidney injury.

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.

Background: Tumor necrosis factor-α (TNF-α) is a major pro-inflammatory cytokine. Recently, the G-308A polymorphism of the TNF-α gene has been associated with modified gene expression and increased TNF-α production in the -308A allele. We evaluated its influence on the incidence and clinical course of membranous glomerulonephritis. Methods: We studied 53 patients with biopsy-proven primary membranous glomerulonephritis followed up for 5.7 ± 4.9 years. 100 volunteers were analyzed as controls. According to the slope of the curve of reciprocal serum creatinine against time, group A (slow progressors, n = 35) and group B (fast progressors, n = 18) were defined. TNF-α G-308A polymorphism was determined by polymerase chain reaction amplification. Results: The frequency of the A-allele (associated with higher TNF-α levels) was significantly higher in patients than control subjects (patients: G-allele: 0.66, A-allele: 0.34; controls: G-allele 0.85, A-allele 0.15, p < 0.001). Similarly, the genotype distribution differed significantly between our study and control populations (patients: GG-genotype: 41.5%, GA: 49.1%, AA 9.4%; controls: GG: 71%, GA: 27%, AA 2%, p = 0.001). Age, renal function, proteinuria and blood pressure were similar at the time of renal biopsy between patients with different genotypes (NS). There was also a tendency towards an overpresentation of the A-allele in group B indicating a possible impact on the progression of membranous nephropathy, but a significance was not reached. Furthermore, no impact on renal survival in the Kaplan- Meier analysis was detected (NS). Conclusion: Our results suggest that TNF-α gene G-308A polymorphism is a risk factor for the development of membranous glomerulonephritis.

Background: We evaluated the impact of the three major genetic polymorphisms of the renin-angiotensin system [angiotensinogen (AGT) gene M235T, angiotensin-converting enzyme (ACE) gene-I/D and angiotensin II-type 1 receptor (AT1R) gene A1166C polymorphisms] as risk factors in IgA nephropathy. Methods: The clinical course of 107 patients with biopsy proven IgA nephropathy followed up for 6.6 ± 5.8 years was examined. The genetic polymorphisms were determined by PCR amplification. Results: The allele frequencies of the polymorphisms studied were similar in patients and control subjects. AGT-M235T genotype was associated with the presence of nephrotic syndrome (p < 0.05), correlated to the number of antihypertensive drugs agents taken (p < 0.01) and influenced the rate of deterioration of renal function (p < 0.05). Combined analysis of AGT-M235T and ACE-I/D polymorphisms detected an interaction on affecting progression (p < 0.05). ACE-inhibition had a more pronounced effect in certain AGT-M235T and ACE-I/D genotypes (p < 0.05) and their combined analysis showed a synergistic effect (p < 0.01). No association between AT1R-A1166C polymorphism and any of the parameters studied was observed. Conclusions: Our results suggest that angiotensinogen-M235T polymorphism is an important marker of progression in IgA nephropathy in Caucasian patients, especially when analyzed in combination with ACE-I/D polymorphism.

Background/Aims: We analyzed the influence of angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and angiotensin-II-type-1 receptor (AT1R) A1166C genetic polymorphisms on the clinical course of focal segmental glomerulosclerosis (FSGS). Methods: This study consisted of 71 patients with nephrotic syndrome due to biopsy proven FSGS and 100 healthy controls. According to the slope of the reciprocal serum creatinine (1/Cr, ≧ or –1· year–1) patients were classified into group A (slow progressors, n = 50) and group B (fast progressors, n = 21). Genotyping was performed using polymerase chain reaction (PCR). Results: There were no relevant differences in the allele frequencies of the investigated polymorphisms between patients with FSGS and controls. Patients carrying the T- allele of the AGT polymorphism required a larger number of antihypertensive agents (MM: 1.35 ± 1.0 vs. MT/TT: 2.0 ± 1.2, p < 0.05). The ACE-ID/DD genotypes were more frequently found in patients with fast progression (group A: II: 38.0%, ID/DD: 62.0% vs. group B: II: 14.3%, ID/DD: 85.7%, p < 0.05). The AT1R-A1166C polymorphism was not associated with any of the parameters studied. Conclusion: The course of FSGS is in part genetically determined by polymorphisms of the renin-angiotensin-system. The ACE-I/D polymorphism was shown to be a risk factor of progression of renal disease and the AGT-M235T polymorphism was associated with the severity of arterial hypertension.

Beta3 integrin subunit is expressed as alpha(IIb)beta3 integrin on platelets and as alpha(v)beta3 integrin on a variety of cells including renal endothelial, mesangial and tubular cells. Leu33/Pro33 polymorphism of beta3 integrin has been associated with altered platelet functions, cardiovascular complications and the incidence of acute rejection episodes in renal transplantation. We investigated its influence on IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephritis (MGN).We studied 251 patients with biopsy-proven primary glomerulonephritis (IgAN n = 127, FSGS n = 71, MGN n = 53) followed up for 6.3 +/- 5.3 years and 100 control subjects. Patients were classified according to the slope of reciprocal serum creatinine into slow (n = 162) and fast progressors (n = 89). Leu33/Pro33 polymorphism was determined by PCR amplification followed by restriction with the endonuclease Bcnl.The genotype frequencies were similar in patients and controls (n.s.). Initial renal function, proteinuria and blood pressure did not differ significantly between patients with different genotypes (n.s.). The genotype frequencies were similar in slow and fast progressors (n.s.). Furthermore, Leu33/Pro33 polymorphism had no impact on renal survival in the Kaplan-Meier analysis (n.s.).Our results indicate that beta3 integrin Leu33/Pro33 polymorphism is not a risk factor or a marker of progression in primary glomerulonephritis.