Tibor Vas

Oxidative stress and non-enzymatic glycation in IgA nephropathy.

AIMnApproximately 20-50% of IgA nephropathy patients develop end-stage renal disease. We have previously found enhanced oxidative stress and decreased antioxidant capacity in red blood cells of IgA nephropathy patients. In this study we assess oxidative stress, non-enzymatic glycation, oxidative resistance of low-density lipoprotein and its alpha-tocopherol content in these patients.nnnPATIENTS AND METHODSnNon-enzymatic glycation and oxidative stress were assessed in 88 IgA nephropathy patients by measuring advanced glycation end products, Nepsilon-carboxymethyl-lysine, thiobarbituric acid reactive substances, oxidative resistance of low-density lipoprotein and its alpha-tocopherol content.nnnRESULTSnAdvanced glycation end products (2659 +/- 958 a.u.) and Nepsilon-carboxymethyl-lysine (563 +/- 215 ng/ml) were significantly higher in IgA nephropathy patients with decreased renal function compared to those with normal renal function (p < 0.002) or controls (p < 0.001). Thiobarbituric acid-reactive substances in plasma and associated with low-density lipoprotein were significantly elevated and oxidative resistance of low-density lipoprotein was significantly reduced in all groups of IgA nephropathy patients. There was no significant difference in circulating fluorescent advanced glycation end products, Nepsilon-carboxymethyl-lysine, thiobarbituric acid-reactive substances levels, oxidative resistance of low-density lipoprotein and its alpha-tocopherol content between patients with normal vs. impaired glucose metabolism. Low alpha-tocopherol content of low-density lipoprotein was accompanied with decreased oxidative resistance, depletion in polyunsaturated fatty acids, elevated saturated fatty acids and thiobarbituric acid-reactive substances within low-density lipoprotein suggesting enhanced lipid peroxidation.nnnCONCLUSIONSnDecreased oxidative resistance of low-density lipoprotein and enhanced oxidative stress are common features in IgA nephropathy, while increased non-enzymatic glycation occurs as renal function declines.

Different Effect of IgA Nephropathy and Polycystic Kidney Disease on Arterial Stiffness

Background: Renal function is a major predictor of vascular function and cardiovascular diseases. Little information exists about the effect of specific renal diseases on vascular function in chronic kidney diseases (CKD). Methods: One hundred and twenty patients (60 with IgA nephropathy, IgAN, and 60 with polycystic kidney disease, PKD) with CKD stages 1–4 were studied and compared. Pulse-wave velocity was measured by the digital volume pulse (DVP) method and stiffness index (SIDVP) was derived. Results: All CKD (IgAN and PKD) patients had increased SIDVP compared to controls (10.39 vs. 8.87 ± 1.79 m/s, p = 0.008). PKD patients had increased SIDVP compared to IgAN and controls (11.14 ± 2.19, 9.66 ± 2.02 and 8.87 ± 1.79 m/s, respectively, p < 0.001). An inverse correlation was found between SIDVP and glomerular filtration rate in all CKD (IgAN and PKD) patients (p = 0.001) and in IgAN alone (p < 0.01), but not in PKD. With multivariate regression analysis, only age and 24-hour systolic blood pressure exerted independent effects on SIDVP. Conclusions: Compared to controls, arterial stiffness was increased in CKD patients. However, arterial stiffening was more pronounced in PKD than in IgAN, suggesting that vascular function is not similarly altered in etiologically different CKD groups. The fact that blood pressure was an independent risk factor underscores a therapeutic opportunity.

Prevalence of α1-antitrypsin phenotypes in patients with IgA nephropathy

Background: α 1 -antitrypsin (AAT) is the main protease inhibitor in the blood. Several different AAT phenotypes exist. The most common variant is the MM phenotype, which is also associated with normal AAT levels. The less common phenotypes with Z and S variants are associated with low AAT levels. AAT deficiency is a risk factor for pulmonary emphysema, liver impairment and some immune-mediated diseases, some of which are also associated with IgA nephropathy (IgAN). In fact, liver impairment resulting from AAT deficiency may directly contribute to renal abnormalities resembling IgAN. Patients and methods: We investigated AAT phenotype and AAT levels in 100 IgAN patients who did not have end-stage liver disease. Fifteen patients in our sample had secondary IgAN. We also tested for the presence of renal deposition of AAT in patients heterozygous for AAT variants as well as in a randomly chosen group of patients with MM phenotype. We checked for any association between AAT phenotype and the progression of IgAN as well as the prevalence of diseases associated with IgAN (i.e. secondary IgAN). Results: Twelve patients in our sample were heterozygous for AAT variants. Phenotypes were MZ in 5 patients, MS in 3, MF in 1, ML in 2 and ME in 1 patient. AAT levels were lower in these 12 patients than in those homozygous for the M variant (1.17 ± 0.46 vs. 1.44 ± 0.34 g/l, p < 0.05). We found renal deposition of AAT in 2 heterozygous patients and in 1 of the 12 patients which were randomly chosen. End-stage renal (ESRF) failure developed in 3 of the 12 heterozygous patients and in 6 of the 88 homozygous patients (p = 0.07) during the follow-up. The prevalence of heterozygosity was significantly higher in patients with secondary IgAN than in those with primary IgAN ((5/15 vs. 7/85; p < 0.02). Conclusions: AAT phenotype is not associated with the risk of primary IgA nephropathy, but might have an impact on disease outcome as well as on the risk of secondary IgAN.

Role of iron in the interaction of red blood cells with methylglyoxal. Modification of L-arginine by methylglyoxal is catalyzed by iron redox cycling.

Diabetes mellitus is characterized by increased methylglyoxal (MG) production. The aim of the present study was to investigate the role of iron in the cellular and molecular effects of MG. A red blood cell (RBC) model and L-arginine were used to study the effects of MG in the absence and presence of iron. Intracellular free radical formation and calcium concentration were measured using dichlorofluorescein and Fura-2-AM, respectively. Effects of MG were compared to the effect of ferrous iron. Reaction of L-arginine with MG was investigated by electron spin resonance (ESR) spectroscopy and by a spectrophotometric method. MG caused an iron dependent oxidative stress in RBCs and an elevation of the intracellular calcium concentration due to formation of reactive oxygen species. Results of co-incubation of MG with ferrous iron in the RBC model suggested an interaction of MG and iron; one interaction was a reduction of ferric iron by MG. A role of iron in the MG-L-arginine reaction was also verified by ESR spectroscopy and by spectrophotometry. Ferric iron increased free radical formation as detected by ESR in the MG-L-arginine reaction; however, ferrous iron decreased it. The reaction of MG with L-arginine yielded a brown product as detected spectrophotometrically and this reaction was catalyzed at a lower rate with ferric iron but at a higher rate with ferrous iron. These data suggest that MG causes oxidative stress in cells, which is due at least in part to ferric iron reduction by MG and to the modification of amino acids e.g. L-arginine by MG, which is catalyzed by iron redox cycling.

Metabolic syndrome and other cardiovascular risk factors associated with the progression of IgA nephropathy

Background The metabolic syndrome is associated with modest but independent and additive risk of new onset chronic kidney disease (CKD) in several studies. The purpose of our study was to determine whether metabolic syndrome and other cardiovascular risk factors (hyperuricaemia and smoking) are associated with the progression of IgA nephropathy (IgAN). Methods Two hundred and twenty three IgAN patients (107 with and 116 without metabolic syndrome) were examined. The primary renal end point was doubling of serum creatinine; secondary end points were reaching eGFR of ≤ 60 ml/min/1,73m2 or eGFR of ≤30 ml/min/1.73 m2, and end-stage renal disease, ESRD (the composite of serum creatinine ≥500 μmol/l, initiation of dialysis treatment or transplantation). The association of metabolic syndrome with renal end points was examined using the Kaplan-Meier method and Cox models. Results Metabolic syndrome established at the diagnosis or during follow-up of IgAN patients was significantly associated with the primary renal end point (unadjusted hazard ratio of doubling of serum creatinine, 95% confidence interval: 1.96 (1.17–1.33, p = 0.011). The association remained significant after adjustment for confounders: 1.70 (1.02–3.83, p = 0.040). Results were similar for secondary end points except ESRD which was not associated with the presence of metabolic syndrome. Hyperuricaemia and smoking were independent risk factors of progression. Survival curves stratified on metabolic syndrome status showed significant differences for the end points (p = 0.017–0.001) except for ESRD. Conclusions Early diagnosis and treatment of metabolic syndrome, hyperuricaemia and smoking may be an additional cost-effective strategy for preventing the progression of IgAN.

Cigarette smoke and its formaldehyde component inhibit bradykinin-induced calcium increase in pig aortic endothelial cells

Bradykinin-induced increase in the intracellular concentration of free calcium evokes an activation of the endothelial nitric oxide synthase (eNOS) enzyme, producing nitric oxide (NO). Cigarette smoke inhibits the eNOS-NO-cGMP signaling pathway. The pathomechanism of this deleterious effect of smoke on NO production is unknown. The aim of this study was to investigate the effect of gas phase smoke trapped in a buffer (smoke buffer, SB) on the bradykinin-induced calcium increase in cultured endothelial cells. FURA-2-AM was used to detect bradykinin-induced calcium increase. A sensitive, fluorescent method using O-phthaldialdehyde was used for the determination of intracellular reduced glutathione (GSH) and protein-thiol levels. SB caused a time- and concentration-dependent inhibition of bradykinin-induced calcium increase. Formaldehyde, a component of SB, inhibited bradykinin-induced calcium increase in concentrations characteristic for SB. SB decreased both the intracellular GSH (0.22 +/- 0.06 vs. 2.23 +/- 0.32 mumol/g protein, SB vs. control, p < .001) and protein-thiol levels (4.98 +/- 0.54 vs. 7.31 +/- 0.97 microEqu GSH/g protein, SB vs. control, p < .05) in the endothelial cells. Intracellular GSH and protein-thiol levels were not changed by 80 microM formaldehyde. GSH (4 mM) prevented the effect of SB (p < .001) and formaldehyde (p < .05) on the bradykinin-induced calcium increase. Our data support the premise that SB inhibits bradykinin-induced calcium increase. This inhibition is partially due to protein-thiol oxidation but may also be caused by the formaldehyde content of SB, which inhibits calcium increase in a protein-thiol-independent manner.

Effect of tonsillectomy and its timing on renal outcomes in Caucasian IgA nephropathy patients.

PurposeThe role of tonsillectomy in the treatment of IgA nephropathy in Caucasian patients is controversial.MethodsA retrospective cohort study was conducted in 264 patients with biopsy-proven primary IgA nephropathy to examine the association between tonsillectomy and long-term renal survival, defined as the incidence of estimated glomerular filtration rates (eGFRs) of ≤30xa0ml/min/1.73xa0m2 or end-stage renal disease (the composite of initiation of dialysis treatment or renal transplantation). The association of tonsillectomy with renal end-points was examined using the Kaplan–Meier method and Cox models.ResultsOne-hundred and sixty-six patients did not undergo tonsillectomy (Group I, follow-up 130xa0±xa0101 months) and 98 patients underwent tonsillectomy (Group II, follow-up 170xa0±xa0124xa0months). The mean renal survival time was significantly longer for both end-points between those patients who underwent tonsillectomy (Group II) versus patients without tonsillectomy (Group I) (pxa0<xa00.001 and pxa0=xa00.005). The mean renal survival time was significantly longer for both end-points between those patients who had macrohaematuric episodes versus patients who had no macrohaematuric episodes (pxa0=xa00.035 and pxa0=xa00.019). Tonsillectomy, baseline eGFR and 24-h proteinuria were independent risk factors for both renal end-points.ConclusionTonsillectomy may delay the progression of IgA nephropathy mainly in IgA nephropathy patients with macrohaematuria. Prospective investigation of the protective role of tonsillectomy in Caucasian patients is needed.

Heart rate recovery after exercise is associated with renal function in patients with a homogenous chronic renal disease

BACKGROUNDnAttenuated heart rate recovery (HRR) is an independent predictor of cardiac and total mortality. Diminished renal function is a similar predictor. There are no data concerning the interaction between the two risk factors. We studied HRR in patients with a homogeneous renal disease, IgA nephropathy.nnnMETHODSnOne hundred and seven patients with biopsy-proven chronic IgA nephropathy (71 males, 36 females aged 45 +/- 11 years) performed a graded exercise treadmill stress test. HRR was measured as the heart rate difference between the peak value and the heart rate 1 min after exercise. The patients were divided into three groups based on estimated glomerular filtration rate (eGFR): CKD 1, eGFR >or= 90 ml/min (n = 46); CKD 2, eGFR 60-89 ml/min (n = 38), CKD 3-4, eGFR 15-59 ml/min (n = 23). We compared these data with 29 normal controls (aged 46 +/- 14 years).nnnRESULTSnHRR values corresponded to eGFR as follows: 29.9 +/- 8.8 bpm normal controls, 27.8 +/- 9.2 bpm CKD 1, 24.5 +/- 10.5 bpm CKD 2 and 16.3 +/- 9.3 bpm CKD 3-4. The latter differed from the other groups significantly (P < 0.05). Metabolic syndrome was common in IgA nephropathy patients (27%). Metabolic syndrome patients had a HRR of 19.6 +/- 10.1 bpm, compared to 25.8 +/- 10.4 bpm in patients without metabolic syndrome (P = 0.007). Nevertheless, a multivariate regression analysis accepted only eGFR as an independent predictor of HRR.nnnCONCLUSIONneGFR predicts HRR in patients with a homogenous renal disease. Metabolic syndrome influences HRR, albeit not independently in this cohort.

Arterial stiffness may predict renal and cardiovascular prognosis in autosomal-dominant polycystic kidney disease

Background and aims Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common causes of end-stage renal disease (ESRD). The most important cause of death among ADPKD patients is cardiovascular (CV). The aim of this study was to examine the prognostic significance of arterial stiffness on CV and renal outcomes in ADPKD. Methods A total of 55 patients with ADPKD were examined. Pulse wave velocity was determined and stiffness index (SIDVP) was calculated. Combined primary endpoints (CV and renal) were major CV events (myocardial infarction, stroke, and CV intervention) as CV endpoints, and attaining of ESRD or start of renal replacement therapy as renal endpoints. Secondary endpoints were CV or renal endpoints separately. Results The mean age of those 55 ADPKD patients was 45u2009±u200912xa0years, 21 patients were male. The average value of the SIDVP was 11.11u2009±u20092.22xa0m/s. The patients were divided into two groups by the cutoff value of 11xa0m/s of SIDVP and then outcomes were analyzed. In the higher arterial stiffness group (SIDVPu2009>u200911xa0m/s), occurrence of combined primary endpoint (CV and renal) was significantly higher than in the group with more elastic arteries (pu2009=u20090.033). A statistically significant difference was found in the renal endpoints (pu2009=u20090.018), but not in the CV endpoints (pu2009=u20090.952) between the two groups. Conclusions Increased arterial stiffness predicts the onset of ESRD in ADPDK. Assessment of SIDVP appears to be a useful method for estimating the renal and CV prognosis in ADPKD.

Terápiás megfontolások IgA-nephropathiában a legutolsó vizsgálatok (STOP-IgAN, TESTING, NEFIGAN) eredményei alapján

IgA nephropathy is an immune-mediated chronic glomerulonephritis with a great variability in clinical presentation and outcome. The disease can progress to end-stage renal failure in 25% of patients. For this reason we should identify patients with potential to progress. Most important risk factors for progression are persistent proteinuria, hypertension, decreased renal function and some histological lesions. The actually suggested treatment is summarized in KDIGO Clinical Practice Guideline from 2012. They suggest to give firstly non-specific supportive treatment (especially renin-angiotensin system blocking agents). Recommendation about steroid/immunosuppression treatment is based on low level of evidence. Recently three studies were organised concerning benefits and risk of steroid/immunosuppressive treatment added together with specific supportive treatment. In the STOP-IgAN study, systemic steroid/immunosuppressive treatment significantly decreased proteinuria but did not stop progression. In the TESTING study, systemic steroid treatment significantly decreased proteinuria and progression. However, the study was recently discontinued due to several severe side effects of steroid treatment. Involvement of intestinal mucosal immunity in the pathogenesis of IgA nephropathy suggested the NEFIGAN study with budesonide treatment. Budesonide releases corticosteroid in distal small intestine and colon. Proteinuria was significantly decreased and renal function remained stabile. High number of withdrawals owing to adverse effects is a major concern implying a substantial systemic effect of budesonide. We need further information on the characteristics of patients who most likely benefit from steroid/immunosuppressive treatment given after or together with specific supportive treatment. Orv Hetil. 2017; 158(49): 1946-1952.Absztrakt: Az IgA-nephropathia immunologiai eredetű kronikus glomerulonephritis, amelyet a klinikai kep es a kimenetel nagy valtozatossaga jellemez. A betegseg vegstadiumu veseelegtelensegig progredialhat a betegek 25%-aban. Ezert fontos, hogy a progressziora hajlamos betegeket koran felismerjuk. A legfontosabb progresszios rizikofaktorok a perzisztalo proteinuria, hypertonia, csokkent vesefunkcio es bizonyos szovettani elvaltozasok. A jelenleg ajanlott kezelest a 2012-es KDIGO Clinical Practice Guideline foglalja ossze. A meglevő rizikofaktorok alapjan minden betegnek specialis vesevedő terapiat javasolnak (elsősorban renin-angiotenzin rendszert blokkolokat). A guideline-ban a szteroid/immunszuppressziv kezeles javaslata alacsony szintű evidenciakra alapozott. Ujabban harom vizsgalatot szerveztek a specialis vesevedő kezelesekkel egyutt adott szteroid/immunszuppressziv kezeles előnyevel es rizikojaval kapcsolatban. A STOP-IgAN vizsgalatban a szisztemas szteroid/immunszuppressziv kezeles szignifikansan cs...