Laurent Juillard

Paraneoplastic glomerular diseases and malignancies

Paraneoplastic glomerulopathies are rare manifestations of neoplastic disease to be distinguished from iatrogenic renal damage. Solid tumors are preferentially associated with membranous nephropathy, whereas Hodgkins lymphomas are associated with minimal change disease. The most common neoplasia associated with paraneoplastic glomerular disease are carcinomas of the lung and of the gastrointestinal tract. Nephrotic syndrome is the most frequent presentation of paraneoplastic glomerulopathy and the most critical glomerular disease regarding prognosis and patient care. Renal biopsy is recommended in patients with glomerular proteinuria or nephrotic syndrome and cancer, depending on life expectancy and therapeutic options. The primary treatment must be directed at the cancer in all cases. Symptomatic treatment of the nephrotic syndrome with diuretics and ACE inhibitors is justified. Prevention of nephrotic syndrome complications, i.e. thromboses and infections, should also be addressed and systematic regular renal follow-up is warranted. All treatments should be regularly reviewed to avoid toxicity, associated renal function loss or low albumin levels for patients receiving albumin-binding drugs. Epidemiologic studies have low evidence-based value. There is no widely accepted experimental model of the association of glomerulopathy and cancer. Thus, epidemiologic and mechanistic studies are needed to determine the true prevalence of paraneoplastic glomerulopathies and investigate new pathophysiologic approaches.

Early impairment of trabecular microarchitecture assessed with HR-pQCT in patients with stage II-IV chronic kidney disease.

Bone fragility is a complication of chronic kidney disease (CKD). The aim of this study was to assess whether volumetric bone mineral density (vBMD) and microarchitecture could be impaired early in the course of CKD. Bone microarchitecture was examined with a noninvasive 3D imaging technique [high‐resolution peripheral quantitative computed tomography (HR‐pQCT)] at the tibia and radius in 70 stage II‐IV CKD patients older than 50 years of age; controls belonged to two cohorts of healthy subjects comparable for age and gender (OFELY cohort in women and STRAMBO cohort in men). We examined 46 men and 24 women; 19 patients were diabetic. Mean age was 70.8u2009±u20098.5 years, mean glomerular filtration rate (GFR) was 34u2009±u200912u2009mL/min per 1.73u2009m2, and mean serum parathyroid hormone (PTH) level was 87u2009±u200959u2009pg/mL. Both CKD men and women experienced a moderate but significant trabecular (Tb) impairment, positioning CKD patient values between those of normal and osteopenic controls (e.g., CKD men versus healthy controls: Tb vBMD 172u2009±u200935 versus 188u2009±u200934u2009mg HA/cm3; Tb number 1.75u2009±u20090.27 versus 1.86u2009±u20090.26u2009mm−1, and Tb separation 503u2009±u200994 versus 465u2009±u200978u2009µm; pu2009<u2009.05). Cortical thickness (Ct.Th) in men also was significantly decreased compared with healthy controls (e.g., CKD men versus healthy controls: tibial Ct.Th 1171u2009±u2009331 versus 1288u2009±u2009283u2009µm; pu2009<u2009.05). In conclusion, this study, using a noninvasive bone‐imaging device, shows for the first time an early impairment of trabecular microarchitecture in stage II‐IV CKD patients. Further longitudinal studies should be performed to validate HR‐pQCT as a tool for predicting the fracture risk in CKD.

Evolution of renal oxygen content measured by BOLD MRI downstream a chronic renal artery stenosis

BACKGROUNDnA decrease in renal oxygen content can be measured non-invasively by the increase of the R2* value derived from blood oxygen level-dependent magnetic resonance imaging (BOLD MRI). The aim of this study was to test if renal hypoxia occurs in kidneys downstream a chronic and unilateral renal artery stenosis.nnnMETHODSnChronic renal ischaemia was induced in rats using a calibrated clip inserted on the right renal artery. R2* was determined, using a multiple recalled gradient-echo sequence, before and once a week after a clip insertion over 4 weeks, in a group of clipped (n = 8) and sham-operated (n = 7) rats.nnnRESULTSnAt baseline, in stenotic kidneys, R2* was higher in the outer stripe of outer medulla (105 ± 4.6) and the outer medulla (99 ± 2.5) than in the cortex (84 ± 2.5; P < 0.002 for comparison with both areas). R2* was unchanged in the cortex, the outer stripe of outer medulla and the outer medulla in stenotic kidneys, sham-operated kidneys and contralateral kidneys during the 4 weeks. Mean blood pressure was higher in rats with clipped kidney than in sham-operated rats from Day 11 and remained increased thereafter. The renal volume increased progressively in sham-operated kidneys and contralateral kidneys, whereas it slightly decreased in stenotic kidneys.nnnCONCLUSIONSnOur study shows that after 4 weeks, no renal hypoxia can be detected in the kidney downstream to a renal artery stenosis, suggesting that atrophy could be induced by other factors.

Results of the HepZero study comparing heparin-grafted membrane and standard care show that heparin-grafted dialyzer is safe and easy to use for heparin-free dialysis.

Heparin is used to prevent clotting during hemodialysis, but heparin-free hemodialysis is sometimes needed to decrease the risk of bleeding. The HepZero study is a randomized, multicenter international controlled open-label trial comparing no-heparin hemodialysis strategies designed to assess non-inferiority of a heparin grafted dialyzer (NCT01318486). A total of 251 maintenance hemodialysis patients at increased risk of hemorrhage were randomly allocated for up to three heparin-free hemodialysis sessions using a heparin-grafted dialyzer or the center standard-of-care consisting of regular saline flushes or pre-dilution. The first heparin-free hemodialysis session was considered successful when there was neither complete occlusion of air traps or dialyzer, nor additional saline flushes, changes of dialyzer or bloodlines, or premature termination. The current standard-of-care resulted in high failure rates (50%). The success rate in the heparin-grafted membrane arm was significantly higher than in the control group (68.5% versus 50.4%), which was consistent for both standard-of-care modalities. The absolute difference between the heparin-grafted membrane and the controls was 18.2%, with a lower bound of the 90% confidence interval equal to plus 7.9%. The hypothesis of the non-inferiority at the minus 15% level was accepted, although superiority at the plus 15% level was not reached. Thus, use of a heparin-grafted membrane is a safe, helpful, and easy-to-use method for heparin-free hemodialysis in patients at increased risk of hemorrhage.

Bone Imaging and Chronic Kidney Disease: Will High-Resolution Peripheral Tomography Improve Bone Evaluation and Therapeutic Management?

Bone damage because of chronic kidney disease (CKD) represents a daily challenge for nephrologists. The impact of CKD on bone health may be immediate (serum phosphocalcic disturbances) or delayed (bone fractures and vascular calcifications). Histomorphometry remains the gold standard to evaluate bone, but it is rarely performed in clinical practice. Areal measurement of bone mineral density by dual x-ray absorptiometry is routinely performed to evaluate bone mass. However, this technique presents some limitations. In 2000, the United States National Institutes of Health defined new quality criteria for the diagnosis of osteoporosis in addition to decreased bone mass. Bone strength actually integrates two concepts: bone quantity and bone quality (i.e., microarchitectural organization, bone turnover, bone material properties such as mineralization, collagen traits, and microdamage) that cannot be evaluated by dual x-ray absorptiometry. New three-dimensional, noninvasive bone-imaging techniques have thus been developed, e.g., high-resolution peripheral quantitative computed tomography. High-resolution peripheral quantitative computed tomography allows evaluation of both volumetric density and microarchitecture in different compartments of bone, at the distal radius and tibia. High-resolution peripheral quantitative computed tomography may be useful in predicting fractures and assessing bone preventive or therapeutic strategies in CKD patients. It should be evaluated in long-term, longitudinal follow-ups.

Endovascular Treatment of Juxta-anastomotic Venous Stenoses of Forearm Radiocephalic Fistulas: Long-term Results and Prognostic Factors

PURPOSEnTo evaluate long-term results of endovascular procedures in treatment of venous juxta-anastomotic stenoses (JASs) of native forearm radiocephalic arteriovenous fistulas (AVFs) and to identify prognostic factors influencing these results.nnnMATERIALS AND METHODSnDuring a 124-month period, 147 endovascular interventions were performed in 75 forearm radiocephalic AVFs with JASs defined as stenoses located within the first 5 cm of the outflow vein. Prognostic factors included patient characteristics (age, sex, diabetes), AVF-related characteristics (location on forearm, age, maturity), stenosis-related characteristics (position relative to anastomosis, length, and degree), and degree of residual stenosis and delay of restenosis after the first endovascular procedure.nnnRESULTSnAt 1 and 3 years, access primary patency (PP) rates were 46.6% (95% confidence interval [CI], 36.3%-59.9%) and 25.5% (95% CI, 15.7%-41.6%) and assisted PP (APP) rates were 81.3% (95% CI, 72.6%-91.1%) and 63.2% (95% CI, 50.6%-79.0%), respectively. Stenosis degree of 50%-75% (P = .017), stenosis length of 10 mm or more (P = .017), and time before first restenosis of less than 6 months (P = .03) significantly increased the frequency of endovascular procedures during follow-up. However, only the degree of residual stenosis after the first endovascular treatment significantly affected long-term APP (P = .039). When residual stenosis was less than 50%, 1- and 2-year access APP rates were 84.6% (95% CI, 75.8%-94.4%) and 76.1% (95% CI, 64.6%-89.6%), respectively. When it was at least 50%, the respective APP rates were 62.3% (95% CI, 38.9%-99.9%) and 46.8% (95% CI, 22.4%-97.7%).nnnCONCLUSIONSnEndovascular treatment of JASs in forearm radiocephalic AVFs provides good long-term results except when the residual stenosis after the first procedure is 50% or more. In that case, the optimal treatment remains to be determined.

Impact of prior CKD management in a renal care network on early outcomes in incident dialysis patients: a prospective observational study

BackgroundEffective therapeutic strategies are available to prevent adverse outcomes in patients with chronic kidney disease (CKD) but their clinical results are hindered by unplanned implementation. Coordination of care emerges as a suitable way to improve patient outcomes. In this study, we evaluated the effect of planned and coordinated patient management within a dedicated renal care network comparatively to standard renal care delivered in nephrology departments of teaching hospitals.MethodsThis observational matched cohort study included 40 patients with CKD stage 4–5 in the network group as compared with a control group of 120 patients matched for age, sex and diabetic status. Main outcome was a composite endpoint of death from cardiovascular cause and cardiovascular events during the first year after dialysis initiation.ResultsThere was no difference between the two groups neither for the primary outcome (40% vs 41%) nor for the occurrence of death from cardiovascular cause or cardiovascular events. Whereas the proportion of patients requiring at least one hospitalization was identical (83.3% vs 75%), network patients experienced less individual hospitalizations than control patients (2.3±2.0 vs 1.6±1.7) during the year before dialysis start. Patients of the network group had a slower renal function decline (7.7±2.5 vs 4.9±1.1 ml/min/1,73m2 per year; p=0.04).ConclusionsIn this limited series of patients, we were unable to demonstrate a significant impact of the coordinated renal care provided in the network on early cardiovascular events in incident dialysis patients. However, during the predialysis period, there were less hospitalizations and a slower slope of renal function decrease.

Non-drug-induced nephrotoxicity

Several drugs and other compounds can induce acute and/or chronic nephrotoxicity. The goal of this study was to review clinical features of nephrotoxicity induced by ‘atypical’ or ‘unconventional’ agents, such as environmental agents (metals, minerals, animals), food agents (mushrooms, aristolochic acid, medicinal traditional herbals, dietary supplements, melamine), drugs, and other products (ethylene glycol). Nephrotoxicity varies according to local background, dependent on different food and cultural customs, as well as to differences in local fauna and flora. The incidence of such a phenomenon is not well known. Many different pathophysiological pathways are involved, and the spectrum of renal lesions is rather wide. ‘Epidemic nephrotoxicity’ may occur, as recently illustrated by the melamine epidemics in Chinese infants receiving powdered milk formulas; a rapid reaction to unusual increased frequency of acute kidney injury and nephrolithiasis in young children has led to a rapid analysis from international experts, with subsequent recommendations for diagnosis and care. Nephrotoxicity should be considered when there is any unexplained renal impairment, especially in children.

Impaired microbial killing by neutrophils from patients with protein kinase C delta deficiency

Health, University of Genoa, Genoa, Italy; the Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Md; ‘‘Angelo Nocivelli’’ Institute for Molecular Medicine, University of Brescia, Brescia, Italy; the Pediatric Hematology Oncology Unit, Spedali Civili, Brescia, Italy; the Division of Allergy and Clinical Immunology, Rebagliati Martins National Hospital, Lima, Peru; the Division of Pediatric Hematology, Children’s Hospital Orange County, University of California at Irvine, Irvine, Calif; the Department of Immunology, ‘‘Aghia Sophia’’ Children’s Hospital, Athens, Greece; the Division of Pediatric Immunology, Hospital Luis CalvoMackenna, Santiago, Chile; the Clinic of Pediatric Hematology-Oncology, Department for Woman and Child Health, University Hospital, Padua, Italy; and the Department of Pediatrics and Adolescent Medicine, American University of Beirut, Beirut, Lebanon. E-mail: luigi. notarangelo@childrens.harvard.edu. *These authors contributed equally to this work. Supported by a grant from the National Heart, Lung, and Blood Institute/National Institutes of Health (grant 5P01HL059561-13 to L.D.N.); an educational grant (5T32AI007512) from the National Institute of Allergy and Infectious Diseases (to E.C. [Dr Raif S. Geha, principal investigator]); an educational grant from the National Heart, Lung and Blood Institute/National Institutes of Health (grant 5T32HL00757433 to J.C.); and a grant from the UNIL-CHUV (CGRB 29583 to F.C.). Disclosure of potential conflict of interest: F. Candotti has received a grant from University of Lausanne-Centre hospitalier universitaire vaudois and is employed by Centre hospitalier universitaire vaudois. J. Chu has received a grant from the National Institutes of Health (NIH). J. Chou is employed by Boston Children’s Hospital and has received grants from the NIH and the JeffreyModell Foundation. F. Porta has received payment for lectures from Pfizer. S.-Y. Pai has received a grant from Translational Investigator Service, is employed by Boston Children’s Hospital, and has a grant pending from the National Heart, Lung, and Blood Institute. L. D. Notarangelo has received grants from the NIH and the March of Dimes; is an Associate Editor for the Journal of Allergy and Clinical Immunology and the Journal of Clinical Immunology; has consultant arrangements with Novimmune and Sigma-Tau; is employed by Children’s Hospital Pediatric Associates; and has received royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest.

Adsorption as a Contributor for Inflammatory Mediators Removal by Different Hemofiltration Membranes: A Pilot Study

Atherosclerosis is an important predictor of mortality in patients with chronic kidney disease (CKD) and is associated with a wide inflammatory response. The aim of this study is to evaluate in vitro how different membranes can remove mediators associated with this pathology in a closed loop dialysis model. We performed experimental hemofiltration in vitro using three different membrane materials. Human plasma was preliminarily incubated with various inflammatory mediators and filtered in a closed loop circulation model for 240 min. Respective concentrations of 17 different mediators were measured over time to study the removal mechanisms of each membrane, including associated removal time course. The experiment was repeated three times for the assay of tumor necrosis factor (TNF)-α to document the model variability. Means were compared using Mann-Whitney test. Most of the investigated mediators were effectively removed with the different dialysis membranes. Adsorption mechanism was mainly at the origin of the decrease in mediators circulating concentrations and was maximized in the region 10 000-20 000 Da. Especially, the HeprAN membrane showed fast removal capacities of mediators with elevated isoelectric point including complement factors and chemokines or having basic groups located in the protein periphery, plasminogen activator inhibitor (PAI-1), and TNF-α-like. The latter was further significantly removed with HeprAN and polymethylmethacrylate (PMMA) compared to polyethersulfone (PES) material (Pu2009<u20090.01). We concluded that dialysis using ionic adsorptive membrane could have a beneficial impact for CKD patients with atherosclerosis and would deserve further clinical investigations.