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The increasing number of examinations and interventional radiological procedures that require the administration of contrast medium (CM) in patients at risk for advanced age and/or comorbidities highlights the problem of CM-induced renal toxicity. A multidisciplinary group consisting of specialists of different disciplines—radiologists, nephrologists and oncologists, members of the respective Italian Scientific Societies—agreed to draw up this position paper, to assist clinicians increasingly facing the challenges posed by CM-related renal dysfunction in their daily clinical practice.The major risk factor for acute renal failure following CM administration (post-CM AKI) is the preexistence of renal failure, particularly when associated with diabetes, heart failure or cancer.In accordance with the recent guidelines ESUR, the present document reaffirms the importance of renal risk assessment through the evaluation of the renal function (eGFR) measured on serum creatinine and defines the renal risk cutoff when the eGFR is The cutoff of renal risk is considered an eGFR Intravenous hydration using either saline or Na bicarbonate solution before and after CM administration represents the most effective preventive measure in patients at risk of post-CM AKI. In the case of urgency, the infusion of 1.4% sodium bicarbonate pre- and post-CM may be more appropriate than the administration of saline.In cancer patients undergoing computed tomography, pre- and post-CM hydration should be performed when the eGFR is In patients with more severe renal risk (i.e., with eGFR In magnetic resonance imaging (MRI) using gadolinium CM, there is a lower risk of AKI than with iodinated CM, particularly if doses 30 ml/min/1.73 m2. Dialysis after MRI is indicated only in patients already undergoing chronic dialysis treatment to reduce the potential risk of systemic nephrogenic fibrosis.

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. We performed a genome-wide association study involving 10,146 kidney biopsy-diagnosed IgAN cases and 28,751 matched controls across 17 international cohorts. We defined 30 independent genome-wide significant risk loci jointly explaining 11% of disease risk. A total of 16 loci were novel, including TNFSF4, REL, CD28, CXCL8/PF4V1, LY86, LYN, ANXA3, TNFSF8/15, REEP3, ZMIZ1, RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The SNP-based heritability of IgAN was estimated at 23%. We observed a positive genetic correlation between IgAN and total serum IgA levels, allergy, tonsillectomy, and several infections, and a negative correlation with inflammatory bowel disease. All significant non-HLA loci shared with serum IgA levels had a concordant effect on the risk of IgAN. Moreover, IgAN loci were globally enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. The explained heritability was enriched in the regulatory elements of cells from the immune and hematopoietic systems and intestinal mucosa, providing support for the pathogenic role of extra-renal tissues. The polygenic risk of IgAN was associated with early disease onset, increased lifetime risk of kidney failure, as well as hematuria and several other traits in a phenome-wide association study of 590,515 individuals. In the comprehensive functional annotation analysis of candidate causal genes across genome-wide significant loci, we observed the convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

Background A cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking. Methods We randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events. Results At 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen. Conclusions This pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial. Clinical trial registry name and registration number Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535.

Vogt, Bruno/0000-0002-1548-6387; Dufek, Stephanie/0000-0002-6323-6673; Liu, Lili/0000-0002-2622-9669; Paczek, Leszek/0000-0003-0160-3009; Cui, Zhao/0000-0002-5837-1926; amoroso, antonio/0000-0002-9437-9407; Rosen, Raphael/0000-0003-1025-1965; Loos, Ruth/0000-0002-8532-5087; coenen, marieke/0000-0001-8796-2031; zanoni, francesca/0000-0001-9567-6713; CUCCA, Francesco/0000-0002-7414-1995; Ars, Elisabet/0000-0002-4118-4358; Hamilton, Patrick/0000-0001-6703-3745 WOS:000563559600001 PubMed ID: 32231244 Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 x 10(-12)) and IRF4 (rs9405192, OR = 1.29, P = 1.4 x 10(-14)), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 x 10(-103)) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 x 10(-49)), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 x 10(-93)), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 x 10(-23) and OR = 3.39, P = 5.2 x 10(-82), respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk. National Institute for Diabetes and Digestive Kidney Diseases (NIDDK) [RC2-DK116690, R01-DK105124, R01-DK097053, R01-DK108805]; National Institute on Minority Health and Health Disparities (NIMHD)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Minority Health & Health Disparities (NIMHD) [R01-MD009223]; Charles Woodson Clinical Research Fund; Nephrotic Syndrome Study Network Consortium (NEPTUNE) [U54-DK-083912]; Columbia University, Columbia Glomerular Center; Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS); National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); University of MichiganUniversity of Michigan System; NephCure Kidney International; Halpin Foundation; National Key Research and Development Program of China [2016YFC0904100]; Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81621092]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81870460, 81570598]; Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee [17441902200]; Shanghai Municipal Education Commission, Gaofeng, Clinical Medicine Grant [20152207]; Shanghai Jiao Tong University School of Medicine, Multi-Center Clinical Research Project [DLY201510]; International Cooperation and Exchange Projects of Shanghai Science and Technology Committee [14430721000]; Outstanding Young Scholar Award [81622009]; Shanghai Health and Family Planning Committee Hundred Talents Program [2018BR37]; Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea - Ministry of Health and Welfare, Republic of Korea; MRCMedical Research Council UK (MRC) [MR/J010847/1]; Manchester Academic Health Science Centre [MAHSC 186/200]; Greater Manchester Local Clinical Research Network; Kidneys for Life Charity; David and Elaine Potter Charitable Foundation; St Peter's Trust for Kidney, Bladder and Prostate Research; Kids Kidney Research UKKidney Research UK (KRUK); Kidney Research UKKidney Research UK (KRUK); Italian Ministry of Health grantMinistry of Health, Italy [GR-2011-02350438]; Department of Excellence Grant 2018-2022 - Italian Ministry of Education for the Department of Medical Sciences of the University of Turin; Columbia University; Poznan University of Medical Sciences, Poland; German Ministry of Education and Research (BMBF)Federal Ministry of Education & Research (BMBF) [01ER0804]; KfH Foundation for Preventive Medicine; Bayer Pharma AG; German Research FoundationGerman Research Foundation (DFG) [CRC 1140, KO 3598/3-1, CRC 992]; European Research CouncilEuropean Research Council (ERC) [ERC-2012ADG_2012-0314, 322947]; 7th Framework Programme of the European Community contract [2012-305608]; National Research Agency grant MNaims [ANR-17-CE17-0012-01]; Dutch Kidney Foundation [OW08, KJPB11.021]; National Human Genome Research Institute (NHGRI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI); NIMHD We are grateful to all study participants across multiple nephrology centres worldwide for their contributions to this work. This work was supported by the following institutions, grants and funding agencies in the US: Columbia University, Columbia Glomerular Center, National Institute for Diabetes and Digestive Kidney Diseases (NIDDK) grants RC2-DK116690 (K.K., M.K.), R01-DK105124 (K.K.), R01-DK097053 (L.H.B., M.K.), R01-DK108805 (M.G.S.), and National Institute on Minority Health and Health Disparities (NIMHD) grant R01-MD009223 (K.K., A.G.G., A.B.). M.G.S. is additionally supported by the Charles Woodson Clinical Research Fund. The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912, is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS) and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK). Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, the NephCure Kidney International and the Halpin Foundation. The recruitment and analysis of the Chinese cohorts were supported by the National Key Research and Development Program of China (2016YFC0904100), Natural Science Foundation of China to the Innovation Research Group (81621092), National Natural Science Foundation of China (No. 81870460, 81570598), Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee (No.17441902200), Shanghai Municipal Education Commission, Gaofeng, Clinical Medicine Grant (No.20152207), Shanghai Jiao Tong University School of Medicine, Multi-Center Clinical Research Project (No.DLY201510), International Cooperation and Exchange Projects of Shanghai Science and Technology Committee (No.14430721000), the Outstanding Young Scholar Award for Zhao Cui (No.81622009), and Shanghai Health and Family Planning Committee Hundred Talents Program for Jingyuan Xie (No.2018BR37). The recruitment of the Korean cohort was supported by the Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea, financed by the Ministry of Health and Welfare, Republic of Korea. P.B. and P.H. acknowledge financial support from MRC project "Autoimmunity in Membranous Nephropathy", grant MR/J010847/1 which funded the sample collection from MN patients across the UK. P.B., P.H. and S.H. acknowledge support from Manchester Academic Health Science Centre (MAHSC 186/200), the Greater Manchester Local Clinical Research Network and Kidneys for Life Charity for supporting research in MN in Manchester. We are grateful to the MENTOR study (clinical trials no. NCT01180036), for contributing blood samples of trial participants. The UK cohort was supported in part by grants from the David and Elaine Potter Charitable Foundation (to S.H.P. and R.K.), St Peter's Trust for Kidney, Bladder and Prostate Research (to D.B., H.C.S., S.H.P. and R.K.), Kids Kidney Research UK and Kidney Research UK (to D.B. and R.K.). The Italian cohorts were supported by the Italian Ministry of Health grant GR-2011-02350438 (G.Z., S.G.) and the Department of Excellence Grant 2018-2022 funded by the Italian Ministry of Education for the Department of Medical Sciences of the University of Turin (A.A.).; The recruitment of Polish cases was sponsored by the Polish Kidney Genetics Network (POLYGENES), a collaborative effort between Columbia University and Poznan University of Medical Sciences, Poland. The full list of POLYGENES collaborators can be found in the Supplementary Materials. The GCKD (German Chronic Kidney Disease) study was funded by grants from the German Ministry of Education and Research (BMBF, No. 01ER0804) and the KfH Foundation for Preventive Medicine, with genotyping supported by Bayer Pharma AG. The list of GCKD investigators can be found in the Supplementary Materials. The work of M.W. and A.K. was funded by the CRC 1140 Initiative and by KO 3598/3-1 and CRC 992 (A.K.) of the German Research Foundation. The work of E.H. and R.A.K.S. was funded by the CRC 1192 from the German Research Foundation (Projects B1 and C1). P.R. is a recipient of European Research Council ERC-2012ADG_2012-0314 grant 322947, 7th Framework Programme of the European Community contract 2012-305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases), and the National Research Agency grant MNaims (ANR-17-CE17-0012-01). The Dutch studies were supported by grants from the Dutch Kidney Foundation to JMH and JFW (Nierstichting Nederland grant OW08 and grant KJPB11.021). We would like to thank the Population Architecture Using Genomics and Epidemiology (PAGE) consortium, funded by the National Human Genome Research Institute (NHGRI) with co-funding from the NIMHD, for providing population controls for this study. For full acknowledgment of the PAGE consortium, please see Supplementary Materials. The funding sources were not involved in the study design, collection, analysis, and interpretation of data, writing of the report, or in the decision to submit the paper for publication.

Background. Patients on kidney replacement therapy comprise a vulnerable population and may be at increased risk of death from coronavirus disease 2019 (COVID-19). Currently, only limited data are available on outcomes in this patient population. Methods. We set up the ERACODA (European Renal Association COVID-19 Database) database, which is specifically designed to prospectively collect detailed data on kidney transplant and dialysis patients with COVID-19. For this analysis, patients were included who presented between 1 February and 1 May 2020 and had complete information available on the primary outcome parameter, 28-day mortality. Results. Of the 1073 patients enrolled, 305 (28%) were kidney transplant and 768 (72%) dialysis patients with a mean age of 60 ± 13 and 67 ± 14 years, respectively. The 28-day probability of death was 21.3% [95% confidence interval (95% CI) 14.3–30.2%] in kidney transplant and 25.0% (95% CI 20.2–30.0%) in dialysis patients. Mortality was primarily associated with advanced age in kidney transplant patients, and with age and frailty in dialysis patients. After adjusting for sex, age and frailty, in-hospital mortality did not significantly differ between transplant and dialysis patients [hazard ratio (HR) 0.81, 95% CI 0.59–1.10, P = 0.18]. In the subset of dialysis patients who were a candidate for transplantation (n = 148), 8 patients died within 28 days, as compared with 7 deaths in 23 patients who underwent a kidney transplantation Conclusions. The 28-day case-fatality rate is high in patients on kidney replacement therapy with COVID-19 and is primarily driven by the risk factors age and frailty. Furthermore, in the first year after kidney transplantation, patients may be at increased risk of COVID-19-related mortality as compared with dialysis patients on the waiting list for transplantation. This information is important in guiding clinical decision-making, and for informing the public and healthcare authorities on the COVID-19-related mortality risk in kidney transplant and dialysis patients.

Background Whether renal revascularization reduces left ventricular hypertrophy in patients with coronary artery disease is uncertain. Study Design Randomized clinical trial testing the effect of renal artery stenting versus medical therapy on left ventricular hypertrophy progression in patients affected by ischemic heart disease and renal artery stenosis. Setting & Participants Incident patients with ischemic heart disease undergoing cardiac catheterization with renal artery stenosis >50%-≤80%. Intervention Revascularization plus standard medical therapy versus medical therapy alone. Outcomes Primary end point was change in echocardiographic left ventricular mass index (LVMI). Measurements Clinical and echocardiographic studies were performed at baseline and after 1 year. Results 84 patients were randomly assigned: 43 to revascularization plus standard medical therapy and 41 to medical therapy alone. At baseline, clinical characteristics were similar in the 2 study groups. After 1 year, there was no statistically significant difference between longitudinal change in the medical therapy group versus that in the medical therapy plus revascularization group for LVMI (2.1; 95% CI, −6.1 to 10.3 g/m 2 ), blood pressure (systolic, −0.2 [95% CI, −9.1 to 8.8 mm Hg]; diastolic, −3.3 [95% CI, −8.4 to 1.8 mm Hg]), or estimated glomerular filtration rate (1.5; 95% CI, −5.8 to 8.9 mL/min/1.73 m 2 ). The number of major cardiovascular events was similar in the 2 groups (revascularization plus standard medical therapy [fatal, n=2; nonfatal, n=11] and medical therapy alone [fatal, n=2; nonfatal, n=11]). Limitations Patients with very severe renal artery stenosis were excluded from the study. Conclusions Our study was unable to detect a clinically significant benefit of renal revascularization on LVMI in patients with coronary artery disease and renal artery stenosis of 50%-80%.

Background. Chest ultrasound (US) is a non-invasive wellvalidated technique for estimating extravascular lung water (LW) in patients with heart diseases and in end-stage renal disease. We systematically applied this technique to the whole peritoneal dialysis (PD) population of five dialysis units. Methods. We studied the cross-sectional association between LW, echocardiographic parameters, clinical [pedal oedema, New York Heart Association (NYHA) class] and bioelectrical impedance analysis (BIA) markers of volume status in 88 PD patients. Results. Moderate to severe lung congestion was evident in 41 (46%) patients. Ejection fraction was the echocardiographic parameter with the strongest independent association with LW (r ¼� 0.40 P ¼ 0.002). Oedema did not associate with LW on univariate and multivariate analysis. NYHA class was slightly associated with LW (r ¼ 0.21 P ¼ 0.05). Among patients with severe lung congestion, only 27% had pedal oedema and the majority (57%) had no dyspnoea (NYHA Class I). Similarly, the prevalence of patients with BIA, evidence of volume excess was small (11%) and not significantly different (P ¼ 0.79) from that observed in patients with mild or no congestion (9%). Conclusions. In PD patients, LW by chest US reveals moderate to severe lung congestion in a significant proportion of asymptomatic patients. Intervention studies are necessary to prove the usefulness of chest US for optimizing the control of fluid excess in PD patients.

Antiphospholipid syndrome is an autoimmune disorder characterized by recurrent venous or arterial thrombosis and/or pregnancy-related problems associated with persistently elevated levels of antiphospholipid antibodies. The kidney is a major target organ in both primary and secondary antiphospholipid syndrome. This review describes several aspects of the renal involvement in the primary form of the syndrome, in particular the histological pattern of the so-called antiphospholipid syndrome nephropathy (APSN). APSN is a vascular nephropathy characterized by small vessel vaso-occlusive lesions associated with fibrous intimal hyperplasia of interlobular arteries, recanalizing thrombi in arteries and arterioles, and focal atrophy, a constellation of morphological lesions suggestive of primary antiphospholipid syndrome.

Several epidemiological and experimental studies suggest an important role of genetic factors in the pathogenesis of hypertensive nephrosclerosis. However, identification of susceptibility genes is difficult. The association between apolipoprotein L1 gene (APOL1) variants and non-diabetic chronic kidney disease in African Americans has modified the approach to hypertensive glomerular sclerosis, as a member of a single disease spectrum: APOL1-associated FSGS.

Background. Some studies suggest that progression of renal disease is slower in women than in men. However, other factors that are also associated with progression of renal disease have not always been taken into account. Therefore, we undertook this analysis to explore the independent association of renal disease progression with gender.Methods. We analysed a pooled database of patients with non-diabetic renal disease enrolled in 11 randomized controlled trials evaluating the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) for slowing renal disease progression. The primary end point was the combined outcome of doubling of baseline serum creatinine or onset of end-stage renal disease (ESRD). The secondary end point was the onset of ESRD alone. We performed multivariable Cox proportional hazards analysis to study the independent effect of gender on these end points after adjusting for baseline patient characteristics, and changes from baseline to follow-up systolic blood pressure (SBP) and urine protein (UP) excretion.Results. The total number of patients was 1860: 645 (35%) females and 1215 (65%) males. Mean duration of follow-up was 2.2 years. The proportions randomized to ACEI (51%), mean baseline serum creatinine (2.2 mg/dl) and mean age (52 years) were similar for both genders. Mean baseline SBP was greater in women than in men: 151 vs 147 mmHg (P Conclusions. Our findings suggest that the rate of renal disease progression may not be slower, and may even be faster in women compared with men, after adjusting for other factors associated with a faster rate of progression. We caution that most women in our database were of post-menopausal age, and thus our findings may not extend to younger women.

Hypertensive nephrosclerosis in African Americans versus Caucasians.BackgroundExtensive global glomerulosclerosis (GS) has been reported in African Americans with hypertension and renal insufficiency, far exceeding that in Caucasians. To assess and compare severity and phenotype of injury in biopsied African Americans and Caucasians who morphologically had hypertensive nephrosclerosis, we performed a retrospective biopsy study.MethodsAll renal biopsies with a histological diagnosis of hypertensive nephrosclerosis from the last 11 years were identified from our clinical files. Lesions of global and segmental sclerosis, interstitial fibrosis and vascular sclerosis were semiquantitatively analyzed as percent involved, or on a 0 to 3 scale, respectively. The phenotypes of global glomerulosclerosis also were categorized as either the solidified (that is, the entire tuft is solidified) or the obsolescent type (that is, Bowman's space is occupied by collagenous material and the tuft is retracted).ResultsSixty-two patients (19 African Americans, 43 Caucasians) were included in the study. At biopsy, African Americans were younger than Caucasians with higher serum creatinine, but no difference in proteinuria or mean arterial pressure (MAP). African Americans had a marked increase in the solidified form of GS (25 ± 6 in African Americans vs. 8 ± 2% in Caucasians, P < 0.01). This extensive solidification of glomeruli was associated with segmental sclerosis in African Americans (38 ± 10%), contrasting low prevalence of solidified GS in Caucasians with segmental sclerosis (10 ± 3%, P < 0.05) and in African Americans without segmental sclerosis (10 ± 4%, P < 0.05). African Americans with segmental sclerosis were younger and clinically expressed a more severe renal disease than Caucasians with this lesion. Interstitial fibrosis was greater in African Americans than in Caucasians (54 ± 6 vs. 33 ± 3%, P < 0.01) and correlated with proteinuria and serum creatinine levels, especially in African Americans, and also with GS. Vascular sclerosis was worse in African Americans than in Caucasians (0.96 ± 0.04 vs. 0.77 ± 0.08 score, P < 0.05) and did not correlate with GS. By modeling, neither MAP nor age was useful in predicting any morphological lesions and proteinuria accounted only minimally for the variability of GS.ConclusionsBlood pressure levels and proteinuria did not account for morphological lesions, suggesting other factors (such as genetic factors, microvascular disease) may play a role. The phenotype of GS differs in biopsied African Americans versus Caucasians with hypertensive nephrosclerosis, with a marked increase in the solidified form of GS in African Americans. The association of extensive solidified GS with segmental sclerosis lesions in African Americans, but not in Caucasians, suggests different mechanisms may contribute to the development and progression of sclerosis in these two patient groups.

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six novel genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geo-spatial distribution of risk alleles is highly suggestive of multi-locus adaptation and the genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.

Background/Aims: Recently, we reported that small renal arteries, defined by a low reference diameter (RD) or minimal luminal diameter (MD), are independently associated with a low GFR, resistant hypertension, and onset of contrast-induced nephropathy and suggested a post-hoc analysis of CORAL trial based on RD categories. Here we hypothesized that RD and MD are markers of nontraditional cardiovascular risk factors and tested whether low RD and MD could impact the prognosis of patients with ischemic heart disease. Methods: Prospective cohort study. We used proportional hazards models to analyze the first onset of cardiovascular events in relation with RD, MD, or percentage of renal artery stenosis (RAS) in those with low-to-moderate RAS (10-70%) (n = 181). Results: During the median follow-up of 4.5 (range, 0.1-5) years, 27.8% participants (n = 623; mean age, 64 years; 29% women) experienced a cardiovascular event (35.4% in those with RAS 10-70%). The presence of low-to-moderate RAS was associated with cardiovascular events. In these subjects, those with low MD were associated with a higher risk of cardiovascular events (MD >4.2 mm, HR: 1; MD 3.2-4.2 mm, HR: 1.66, 95% CI: 0.74-3.72, p = 0.22; MD Conclusions: In patients with ischemic heart disease and low-to-moderate RAS, MD is a significant predictor of cardiovascular events, improves risk prediction, and may represent a valuable biomarker of cardiovascular disease risk. i 2014 S. Karger AG, Basel

Peroxisome proliferator-activated receptor-γ agonist troglitazone protects against nondiabetic glomerulosclerosis in rats.BackgroundPeroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily of ligand-dependent transcriptional factors with beneficial effects in diabetes mediated by improved insulin sensitivity and lipid metabolism, but potential adverse effects in atherosclerosis by promoting in vitro foam cell formation. We explored whether a PPARγ agonist, troglitazone (TGL), affects sclerosis by mechanisms unrelated to insulin and lipid effects in a model of nondiabetic glomerulosclerosis.MethodsAdult male Sprague Dawley rats underwent 5/6 nephrectomy and were treated for 12 weeks as follows: control (CONT), no further treatment; triple antihypertensive therapy (TRX); and TGL or TGL + TRX. Functional, morphological, and molecular analyses were performed.ResultsSystolic blood pressure (SBP) was increased in CONT and TGL groups (161 ± 1 and 160 ± 3 mm Hg), but not in TGL + TRX and TRX (120 ± 3 vs. 126 ± 1 mm Hg, P < 0.0001 vs. non-TRX). Serum triglyceride and cholesterol levels in all groups remained normal except for slightly higher serum cholesterol levels in TRX group. TGL groups had reduced proteinuria, serum creatinine, and glomerulosclerosis versus CONT, in contrast to no significant effect with TRX alone (sclerosis index, 0 to 4+ scale: CONT 1.99 ± 0.42, TGL 0.85 ± 0.12, TGL + TRX 0.56 ± 0.14, TRX 1.30 ± 0.21; TGL, P < 0.05; TGL + TRX, P = 0.01 vs. CONT). Glomerular cell proliferation, assessed by proliferating cell nuclear antigen (PCNA), was decreased after treatment with TGL or TGL + TRX, in parallel with decreases in glomerular p21 mRNA and p27 protein compared with CONT and TRX (PCNA + cells/glomerulus: CONT 2.04 ± 0.64, TGL 0.84 ± 0.21, TGL + TRX 0.30 ± 0.07, TRX 1.38 ± 0.37; TGL, P < 0.05, TGL + TRX, P < 0.01 vs. CONT). Glomerular plasminogen activator inhibitor-1 (PAI-1) immunostaining was decreased in TGL or TGL + TRX groups (0 to 4+ scale, CONT 2.42 ± 0.32, TGL 1.40 ± 0.24, TGL + TRX 1.24 ± 0.17, TRX 2.53 ± 0.24; TGL or TGL + TRX vs. CONT, P < 0.05), with a parallel decrease in PAI-1 mRNA by in situ hybridization. Glomerular and tubular transforming growth factor-β (TGF-β) mRNA expression was decreased with TGL treatment. Glomerular macrophages, present in CONT and TRX rats, did not express PPARγ, in contrast to PPARγ + macrophages in control carotid artery plaque. PPARγ was expressed in resident cells.ConclusionsOur results demonstrate in vivo that the PPARγ ligand TGL ameliorates the progression of glomerulosclerosis in a nondiabetic model. Macrophages show phenotypic diversity in glomerular versus vascular sclerosis, with macrophage PPARγ expression in only the latter. PPARγ beneficial effects are independent of insulin/glucose effects and are associated with regulation of glomerular cell proliferation, hypertrophy, and decreased PAI-1 and TGF-β expression.

Regression of sclerosis in aging by angiotensin inhibition-induced decrease in PAI-1.BackgroundGlomerular and vascular sclerosis increase with aging, and angiotensin inhibitors ameliorate progression of this injury. We investigated the potential for achieving regression of existing age-related sclerosis, and the mechanisms by which angiotensin type 1 receptor antagonist (AIIRA) may affect remodeling of this sclerosis. We focused on plasminogen activator inhibitor-1 (PAI-1) because it is directly induced by angiotensin, inhibits matrix degradation, and may thus be pivotal in remodeling.MethodsEighteen-month-old male Sprague-Dawley rats were treated with the AIIRA losartan (N = 8, 80 mg/L, dry weight), sacrificed at age 21 and 24 months, and compared with age-matched untreated controls (N = 15). Blood pressure and renal function were monitored, and morphological, biochemical, and molecular analyses were done on aorta and kidney.ResultsBody weight increased in both groups. Mean arterial pressure (MAP) and serum creatinine remained normal (24-month MAP 115 ± 8 vs. 113 ± 6 mm Hg, controls vs. AIIRA, P = NS). Aorta wall thickness ratio was reduced by AIIRA at 21 and 24 months vs. age-matched controls (21 months 0.12 ± 0.01 vs. 0.15 ± 0.01, P = 0.006; 24 months 0.10 ± 0.005 vs. 0.14 ± 0.003, AIIRA vs. controls, respectively, P = 0.0027). The aorta wall thickness ratio after treatment with AIIRA for six months was even lower than that of 18-month control rats (P = 0.018). AIIRA reduced proteinuria versus age-matched control at 24 months (253 ± 62 vs. 390 ± 51 mg/24 h, P = 0.0017). AIIRA at 24 months decreased glomerulosclerosis versus age-matched control (sclerosis index, 0 to 4+ scale: 0.06 ± 0.02 vs. 0.49 ± 0.12, P = 0.0082) to levels even lower than the 18-month baseline (0.37 ± 0.14, P = 0.014). Renal collagen content increased with aging and was decreased by AIIRA at 24 months (5.0 ± 0.7 vs. 3.1 ± 0.5% collagen, P < 0.05). Apoptosis, assessed by TUNEL, was increased in tubular and interstitial cells in aging and was reduced by AIIRA versus control and baseline, respectively (TUNEL scoring, AIIRA 24 months 0.33 ± 0.16 vs. 1.06 ± 0.23 and 0.80 ± 0.05, P < 0.05). PAI-1 mRNA in kidney was decreased at 24 months in AIIRA versus age-matched controls (PAI-1/GAPDH density ratio: AIIRA 24 months 0.34 ± 0.05 vs. 24-month controls 0.99 ± 0.05, P < 0.05). Increased glomerular PAI-1 immunostaining with aging was decreased by AIIRA at 24 months versus age-matched controls, even below baseline (staining score 0 to 4+, 0.57 ± 0.15 vs. control 0.90 ± 0.07, P < 0.05; baseline 1.05 ± 0.02, P < 0.01).ConclusionWe conclude that AIIRA not only slows the progression of glomerular and vascular sclerosis in aging, but can also induce regression of these processes. The mechanisms appear to involve modulation of cortical cell turnover and inhibition of PAI-1 expression.

The treatment of systemic hypertension in chronic renal disease is now mostly based on the administration of drugs which are able to reduce proteinuria and to slow down the progressive functional deterioration. Angiotensin-converting-enzyme inhibitors (ACEI), which lower both proteinuria and blood pressure, have emerged as drugs of choice in proteinuric patients with either normal renal function or mild to moderate chronic renal failure. In non proteinuric nephropathies no controlled studies exist demonstrating the superiority of ACEI over other drugs. In these conditions calcium antagonists might also be used. The approach to patients with hypertension and renal disease should always take into consideration the quality of the results that are to be achieved. If the aim is to control blood pressure and to protect other organs at risk, then a variety of drugs can be used. If the aim is to reduce proteinuria and slow down progression, then ACEI, possibly associated with calcium antagonists, are the drugs of choice.

The class of antihypertensive agents that act by blocking angiotensin II has been shown in several experimental models to have the interesting ability to protect the kidney. In patients with nondiabetic renal disease, a number of controlled clinical trials have shown angiotensin converting enzyme inhibitors to achieve a better control of blood pressure and significantly reduce the rate of progression of renal failure in comparison with conventional agents. In addition, treatment with angiotensin converting enzyme inhibitors has helped to achieve new information on the optimal blood pressure target to be reached in order to protect the residual renal function maximally.

The aim of the present study was to externally validate the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II (ESII) in patients undergoing percutaneous coronary intervention (PCI) and to compare its performance with that of its previously released versions, named additive (addES) and logistic EuroSCORE (logES). A total of 537 patients undergoing PCI were analyzed by different measurements of discrimination, calibration, and global accuracy. A significant gradient in all-cause mortality was seen with all the models at 30 days, 1 year, and 5 years, with the exception of the ESII at 30 days. The ESII had the lowest area under the receiver operating characteristic curve at all time points compared with its previous version, being 0.83 (vs 0.90 for both addES and logES) at 30 days, 0.75 (vs 0.82 for both addES and logES) at 1 year, and 0.69 (vs 0.77 for addES and 0.76 for logES) at 5 years. However, the ESII displayed a better calibration than the logES at 30 days, whereas both scores were miscalibrated at 1 and 5 years. The Brier score displayed similar global accuracy between the ESII and logES. In conclusion, the ESII is better calibrated than the logES at 30 days but does not represent a step forward in discrimination and global accuracy compared with its previous versions for predicting early- and long-term mortality of patients undergoing PCI.

Background The aim of the present study was to appraise the comparative ability of different ACEF models incorporating glomerular filtration rate or creatinine clearance estimated by the Modification of Diet in Renal Disease [ACEF MDRD ] or Cokcroft-Gault [ACEF CG ] equations, respectively, over the original ACEF score (ACEF SrCr ) in patients undergoing percutaneous coronary intervention (PCI). Methods A total of 537 patients were analyzed by different measures of discrimination, calibration and net reclassification improvement (NRI). Results A significant gradient in all-cause mortality was consistently seen with all the models at 30days, 1year and 5years. The comparison of the three models showed that the best balance in terms of discrimination and calibration for all-cause mortality was offered by the ACEF CG at 30days, the ACEF MDRD at 1year and similarly by the ACEF CG and ACEF MDRD at 5years. At 30days, the NRI was +32.9% for ACEF MDRD over ACEF SrCr and +16% for ACEF CG over ACEF SrCr . At 1year, the NRI was 13.8% for ACEF MDRD over ACEF SrCr and −7.8% for ACEF CG over ACEF SrCr . At 5years, the NRI was +7.7% for both the ACEF MDRD and the ACEF CG over the ACEF SrCr . Conclusions In patients undergoing PCI, the ACEF score is associated with satisfactory early-, mid- and long-term discrimination regardless of the definition of renal function. However, incorporating glomerular filtration rate or creatinine clearance by the MDRD or CG formulas in the ACEF score yields superior calibration compared with the original SrCr-based equation, with the ACEF MDRD displaying superior reclassification ability over the ACEF CG and ACEF SrCr at 30days and 1year.

BACKGROUND Atherosclerotic renovascular disease is associated with resistant hypertension and chronic kidney disease, although the causal relationship is discussed. To date, the role of renal artery diameter on these pathological conditions was not clearly studied. We aimed to identify the association of reference diameter and minimal luminal renal artery diameter with glomerular filtration rate (GFR) and resistant hypertension in a high cardiovascular risk population. METHODS In this cross-sectional, single-center study, we enrolled 734 patients who underwent a renal angiography immediately after a coronary angiography indicated for a diagnosis of ischemic heart disease. RESULTS Mean age was 64 ± 10 years (men 72%). GFR was 79 ± 22 ml/min per 1.73 m(2). Five hundred and eighteen patients had no luminal narrowing and 216 patients had low-to-moderate luminal narrowing (10-70%, mean 36%). A positive significant association between reference diameter and GFR was detected in patients without luminal narrowing [beta 2.2 ml/min per 1.73 m(2) for 1 mm increase, 95% confidence interval (CI) 0.3-4.0, P

Studies in animal models have shown a convincing role for hypertension in the progression of renal disease. However, in clinical studies, the relationship between hypertension and progression is difficult to demonstrate owing to confounding factors such as age, gender, race, difficulty in identifying blood pressure (BP) parameters that correlate with progression, abnormal circadian BP pattern, and many non-haemodynamic factors of progression. A recent meta-analysis of several studies has shown that pharmacological agents that reduce both BP and proteinuria (U(P)), particularly angiotensin-converting-enzyme (ACE) inhibitors, significantly slow the rate of progression of chronic kidney disease. In these studies, lower achieved BP in patients both with and without U(P) was associated with slower decline in renal function. ACE inhibitors are effective BP-lowering agents and are associated with improved preservation of renal function compared with antihypertensive regimens without ACE inhibitors. The protective effect of ACE inhibition is additional to the effect of reducing BP and U(P).

The education level of women has increased significantly in recent decades. However, although there is a continued positive trend overall, women remain underrepresented (or misrepresented?) in the main fields of science. In Europe the proportion of women in scientific research is growing faster than that of men, but women are more likely than men to choose education, arts and humanities, health and welfare. Moreover, of the total number of women graduating in all faculties (55%), the percentage of women graduating in medicine is 65%-68%, in Europe as in the United States. As far as nephrology is concerned, unpublished data from the Italian Society of Nephrology indicate that female nephrologists make up almost 30% of the total number in the age group between 40 and 55, and this proportion is even higher in the age group younger than 40 years. In comparison with the past, there are some hints that things are going to change, but the path is still a difficult one, much effort is needed and there is a long way ahead.

Introduction: The incidence of contrast-induced nephropathy (CIN) increases in high cardiovascular risk patients. Chronic kidney disease (CKD) is a known risk factor for CIN development. In a previous report, we demonstrated that the mean reference renal artery diameter (RVD) is an important determinant of CKD in patients undergoing coronary angiography for ischemic heart disease. However, RVD was never tested as a predictor of CIN. Aim: To look at the predictors of CIN. Methods: A total of 218 consecutive patients undergoing coronary and renal angiography were enrolled from the cohort of the RAS-CAD study (NCT 01173666). CIN was defined as a relative increase in baseline serum creatinine ≧25% within 1 week of contrast administration. Results: The incidence of CIN was 22%. In a fully adjusted model, contrast medium dose (20 ml increase, OR 1.12, 95% CI 1.06–1.19, p < 0.001), iso-osmolar contrast media (OR 0.28, 95% CI 0.09–0.99, p < 0.05), atherosclerotic renovascular disease (OR 2.69, 95% CI 1.32–5.48, p < 0.05), and RVD (1 mm/1.73 m2 increase, OR 0.59, 95% CI 0.41–0.86, p < 0.05) had the greatest effect on outcome and were identified as independent predictors of CIN. CKD was selected as a predictor of CIN only in a model without RVD. Conclusions: In patients undergoing coronary angiography for ischemic heart disease, RVD is a stronger predictor of CIN than CKD.

Adducins are cytoskeletal actin-binding proteins (α, β, γ) that function as heterodimers and heterotetramers and are encoded by distinct genes. Experimental and clinical evidence implicates α- and β-adducin variants in hypertension and renal dysfunction. Here, we have addressed the role of α- and β-adducin on glomerular function and disease using β-adducin null mice, congenic substrains for α- and β-adducin from the Milan hypertensive (MHS) and Milan normotensive (MNS) rats and patients with IgA nephropathy. Targeted deletion of β-adducin in mice reduced urinary protein excretion, preceded by an increase of podocyte protein expression (phospho-nephrin, synaptopodin, α-actinin, ZO-1, Fyn). The introgression of polymorphic MHS β-adducin locus into MNS (Add2, 529R) rats was associated with an early reduction of podocyte protein expression (nephrin, synaptopodin, α-actinin, ZO-1, podocin, Fyn), followed by severe glomerular and interstitial lesions and increased urinary protein excretion. These alterations were markedly attenuated when the polymorphic MHS α-adducin locus was also present (Add1, 316Y). In patients with IgA nephropathy, the rate of decline of renal function over time was associated to polymorphic β-adducin (ADD2, 1797T, rs4984) with a significant interaction with α-adducin (ADD1, 460W, rs4961). These findings suggest that adducin genetic variants participate in the development of glomerular lesions by modulating the expression of specific podocyte proteins. Electronic supplementary material The online version of this article (doi:10.1007/s00109-009-0549-x) contains supplementary material, which is available to authorized users.

Atherosclerotic renal artery stenosis (RAS) is associated with premature cardiovascular (CV) events and entails a high mortality risk in patients with coronary artery disease (CAD). The effect of renal revascularization on left ventricular mass is not known.The Stenting of Renal Artery Stenosis in Coronary Artery Disease (RAS-CAD) study is a randomized trial designed to study the effect of medical therapy alone versus medical therapy plus renal artery stenting, on left ventricular hypertrophy progression (primary end point), and CV morbidity and mortality (secondary end points), in patients affected by ischemic heart disease and RAS.From April 2006 on, all consecutive patients undergoing nonemergent coronary angiography at a single institution are also to be evaluated for RAS by selective renal arteriography. Patients with RAS50% andor=80% are randomly assigned to undergo stenting angioplasty plus medical therapy (angioplasty group) or medical therapy alone (drug therapy group) and followed up for 5 years. All randomized patients receive antihypertensive, lipid-lowering or antiplatelet drugs according to current clinical guidelines. The estimated sample size needed to achieve a 80% power to detect as statistically significant a 4 g/m2 difference in left ventricular mass index progression (p0.01, 2-tailed) between the 2 arms is 168 (84 in the revascularization arm and 84 in the medical management arm).

The morphological findings of so-called hypertensive nephrosclerosis, rather than implying a linear direct relationship to damage induced by hypertension, may indicate complex environmental and genetic factors, which together foster the coexistence of renal lesion and hypertension in this clinical setting. We discuss the clinical and pathological criteria for diagnosis of arterionephrosclerosis, and possible pathogenetic factors, including hypertension, ethnicity, aberrant autoregulation, prothrombotic mechanisms, low birth weight, decreased nephron number, genetic factors and dysmetabolic syndrome.

This letter to the Editor is the reaction of the previously printed paper "Food groups and renal cell carcinoma: a case-control study from Italy" by Bravi et al. (Int J Cancer 2006 ; 120:681-5). In this study it was found that the incidence of renal cell carcinoma is higher in persons with high consumption of cereals. In the Letter to the Editor we suggested that this fenomenom may be due to the higher exposure of such persons to the carcinogenic and nephrotoxic mycotoxins ochratoxin A and fumonisin B1.

The potential and possible mechanisms for regression of existing glomerulosclerosis by angiotensin II type 1 receptor antagonist (AT1RA) and/or angiotensin I converting enzyme inhibitor (ACEI) were investigated. Adult male Sprague Dawley rats underwent 5/6 nephrectomy (Nx). Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into groups with equal biopsy sclerosis and treated for the next 4 wk until they were killed at 12 wk as follows: Control with no further treatment (CONT), high-dose AT1RA, high-dose ACEI, and varying AT1RA+ACEI combinations. Hypertension and proteinuria induced by 5/6 Nx were significantly decreased by all treatments, except high-dose ACEI, which showed persistent proteinuria. High-dose AT1RA and ACEI markedly decreased progression of sclerosis, with -2.3% average decrease in sclerosis from biopsy to autopsy in AT1RA versus 194% increase in CONT (P < 0.0001). Glomerulosclerosis regressed, with less severe lesions at the time when the rats were killed than at biopsy in 62% of AT1RA-treated and 57% of ACEI-treated rats. In contrast, only 17 to 33% of rats in combination groups had regression. Alternatively, these data might be viewed as reflecting halting of progression, as some groups had higher BP and proteinuria. However, this potential confounding effect does not negate the effects to achieve regression of sclerosis in these rats. Regression was not explained by changes in mRNA of TGF-beta1 and matrix metalloproteinase-2 and -9 but was linked to decreased tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1. It is concluded that angiotensin inhibition mediates regression in part by effects on matrix modulation.

Glomerulosclerosis was reported in mice transgenic for the simian polyomavirus SV40 early region that contains the transforming sequences encoding the SV40 large T-antigen (TAG). This was discovered when an SV40 epidemic occurred following the use of contaminated polio vaccines during 1955-1963, and led to investigations that showed an association between SV40 infection and tumors in humans. We investigated the possible association of SV40 infection and idiopathic focal segmental glomerulosclerosis (FSGS).The study was performed in 17 Bouin-fixed, paraffin-embedded renal biopsies from FSGS patients and 10 matched biopsies from patients with IgA glomerulonephritis; all patients had undergone polio vaccination in the early 1960s. Extracted DNA was polymerase chain reaction (PCR) amplified using SV.for3/SV.rev primers and GabE1/GabE2 primers; both sets of primers map in the region of SV40 TAG sequences, and amplify a fragment of respectively 105-bp and 135-bp. The biopsies considered were those in which the DNA was sufficiently intact to allow amplification of a fragment of 102-bp of the ApoE gene.Three FSGS and none of the IgA biopsies were positive for the SV.for3/SV.rev fragment. Conversely, amplification with GabE1/GabE2 primers did not lead to any specific product in either the IgA or FSGS biopsies. Restriction fragment length polymorphism and sequencing analyses revealed that the positive results obtained with the SV.for3/SV.rev primers were due to amplicons generated by multiple dimerization of forward and reverse primers.With the limited number of patients investigated, this study excludes the hypothesis that SV40 is associated with idiopathic FSGS.

The role of systemic hypertension in the progression of nondiabetic renal disease. Background A role for hypertension in the progression of renal disease has been convincingly shown in experimental animals only. In human studies, the relation between hypertension and progression is difficult to demonstrate due to several confounding factors: age, gender, race; the difficult choice of blood pressure (BP) parameters that correlate with progression; the abnormal circadian BP pattern; and the many non-hemodynamic factors of progression. An important role for hypertension in progressive nondiabetic renal disease has been suggested by observational studies and clinical trials originally intended to evaluate the effect of dietary protein restriction on progression. In addition, several studies, summarized by a recent meta-analysis, have shown that pharmacological agents which lower both BP and proteinuria, mainly the angiotensin-converting enzyme inhibitors (ACEI), significantly slow the rate of progression in these diseases. Methods In this article we review the effect of lowering BP on the progression of nondiabetic chronic renal disease, the patient characteristics that are associated with a greater or lesser benefit of blood pressure reduction, and the choice of antihypertensive regimens associated with better outcomes in patients with renal disease. Results Lower levels of achieved BP are associated with a slower decline in renal function, both in patients with and without proteinuria. ACEI are effective BP lowering agents and are associated with better preservation of renal function as opposed to antihypertensive regimens without ACEI. This protective effect of ACEI is in addition to their BP and urine protein lowering effects. The protective effect of ACEI on renal function is more pronounced in patients with proteinuria. Conclusion In patients with nondiabetic renal disease and proteinuria, the risk of progression can be minimized by lowering both BP and proteinuria. ACEI have an additional beneficial effect.

A multicentre, comparative, randomized study was performed to compare the efficacy and tolerability of two antibiotic regimens in the treatment of peritonitis in continuous ambulatory peritoneal dialysis (CAPD) patients: teicoplanin plus tobramycin versus cephalothin plus tobramycin. After informed consent had been obtained, 68 patients were randomized prospectively to receive either teicoplanin plus tobramycin or cephalothin plus tobramycin. Patients were followed throughout the study and for up to 4 weeks after the end of treatment, when clinical and microbiological parameters were assessed again. The incidence of clinical failure was 4.6 times higher in the cephalothin plus tobramycin group than in the teicoplanin plus tobramycin group (7/28 versus 2/37; P < 0.05). There was no significant difference in bacterial eradication between the two groups. Local and systemic tolerability were good for both regimens. The study shows that teicoplanin plus tobramycin is more effective than cephalothin plus tobramycin and might become a 'first-line' treatment for peritonitis in CAPD patients.

Microangiopathic injury and augmented PAI-1 in human diabetic nephropathy.BackgroundMicrovascular injury and mesangial dysfunction contribute to the pathogenesis of diabetic glomerulosclerosis. We investigated the extent of microvascular injury characterized by fragmented red blood cells (RBCs) in the mesangium of glomeruli in diabetic nephropathy, and its clinicopathologic significance. We also investigated the possible contributions of plasminogen activator inhibitor-1 (PAI-1), which has been implicated in thrombosis and sclerosis, and the novel steroid receptor superfamily member, peroxisome proliferator-activated receptorγ (PPARγ), implicated in monocyte-foamy macrophage transformation in atherosclerosis and improved insulin responsiveness in diabetes.MethodsSixty-four diabetic nephropathy (DN) cases in our renal biopsy files at VUMC, diagnosed between 1997 and 1999, were reviewed. Patients were classified based on the presence or absence of fragmented RBCs in the mesangium (M+, M-). PAI-1 and PPARγ immunostaining was performed with double staining for the macrophage marker CD68.ResultsM+ lesions were present in 21.9% of cases, and in positive cases, involved on average 10.2 ± 2.1% of glomeruli. M+ patients were 40- to 78-years-old (mean ± SD, 60.4 ± 9.8), the female/male ratio was 2.5, and the white/black ratio was 6. In M-, the patients' ages ranged from 29 to 81 years (57.6 ± 13.3, P = NS vs. M+), the female/male ratio was 0.5 (P < 0.05 vs. M+), and the white/black ratio was 2.3 (P = 0.1 vs. M+). Mean 24-hour urine protein in M+ was 9.9 ± 13.6 g/24 h, versus 4.0 ± 2.8 g/24 h in M- (P < 0.05). The fragmented RBCs in M+ cases localized exclusively within Kimmelstiel-Wilson nodules. PAI-1 and PPARγ immunostaining was increased in areas of sclerosis in arteries and glomeruli, with expression of both in glomerular mesangial, parietal and visceral epithelial cells. Infiltrating macrophages in glomeruli were PPARγ negative, contrasting positivity in macrophages in control cases of carotid artery plaque and in renal interstitial macrophages. The Kimmelstiel-Wilson nodules in M+ patients showed increased PAI-1 staining.ConclusionsMesangial RBC fragments are indicative of microvascular injury and mesangiolysis in DN and are associated with worse proteinuria, and possible worse prognosis. Possible pathogenic mechanisms involve the fibrinolytic/proteolytic system and locally activated PAI-1.

Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease.BackgroundAngiotensin-converting enzyme (ACE) inhibitors reduce urine protein excretion and slow the progression of renal disease. The beneficial effect in slowing the progression of renal disease is greater in patients with higher urine protein excretion at the onset of treatment. We hypothesized that the greater beneficial effect of ACE inhibitors on the progression of renal disease in patients with higher baseline levels of proteinuria is due to their greater antiproteinuric effect in these patients.MethodsData were analyzed from 1860 patients enrolled in 11 randomized controlled trials comparing the effect of antihypertensive regimens, including ACE inhibitors to regimens not including ACE inhibitors on the progression of non-diabetic renal disease. Multivariable linear regression analysis was used to assess the relationship between the level of proteinuria at baseline and changes in urine protein excretion during follow-up. The Cox proportional hazards analysis was used to assess the relationship between changes in urine protein excretion during follow-up and the effect of ACE inhibitors on the time to doubling of baseline serum creatinine values or onset of end-stage renal disease.ResultsMean (median) baseline urine protein excretion was 1.8 (0.94) g/day. Patients with higher baseline urine protein excretion values had a greater reduction in proteinuria during the follow-up in association with treatment with ACE inhibitors and in association with lowering systolic and diastolic blood pressures (interaction P < 0.001 for all). A higher level of urine protein excretion during follow-up (baseline minus change) was associated with a greater risk of progression [relative risk 5.56 (3.87 to 7.98) for each 1.0 g/day higher protein excretion]. After controlling for the current level of urine protein excretion, the beneficial effect of ACE inhibitors remained significant [relative risk for ACE inhibitors vs. control was 0.66 (0.52 to 0.83)], but there was no significant interaction between the beneficial effect of ACE inhibitors and the baseline level of urine protein excretion.ConclusionsThe antiproteinuric effects of ACE inhibitors and lowering blood pressure are greater in patients with a higher baseline urine protein excretion. The greater beneficial effect of ACE inhibitors on renal disease progression in patients with higher baseline proteinuria can be explained by their greater antiproteinuric effects in these patients. The current level of urine protein excretion is a modifiable risk factor for the progression of non-diabetic renal disease. ACE inhibitors provide greater beneficial effect at all levels of current urine protein excretion.