Tungsten toxicity on kidney tubular epithelial cells induces renal inflammation and M1-macrophage polarization.

Tungsten is widely used in medical, industrial, and military applications. The environmental exposure to tungsten has increased over the past several years, and few studies have addressed its potential toxicity. In this study, we evaluated the effects of chronic oral tungsten exposure (100 ppm) on renal inflammation in male mice. We found that 30- or 90-day tungsten exposure led to the accumulation of LAMP1-positive lysosomes in renal tubular epithelial cells. In addition, the kidneys of mice exposed to tungsten showed interstitial infiltration of leukocytes, myeloid cells, and macrophages together with increased levels of proinflammatory cytokines and p50/p65-NFkB subunits. In proximal tubule epithelial cells (HK-2) in vitro, tungsten induced a similar inflammatory status characterized by increased mRNA levels of CSF1, IL34, CXCL2, and CXCL10 and NFkB activation. Moreover, tungsten exposure reduced HK-2 cell viability and enhanced reactive oxygen species generation. Conditioned media from HK-2 cells treated with tungsten induced an M1-proinflammatory polarization of RAW macrophages as evidenced by increased levels of iNOS and interleukin-6 and decreased levels of the M2-antiinflammatory marker CD206. These effects were not observed when RAW cells were exposed to conditioned media from HK-2 cells treated with tungsten and supplemented with the antioxidant N-acetylcysteine (NAC). Similarly, direct tungsten exposure induced M1-proinflammatory polarization of RAW cells that was prevented by NAC co-treatment. Altogether, our data suggest that prolonged tungsten exposure leads to oxidative injury in the kidney ultimately leading to chronic renal inflammation characterized by a proinflammatory status in kidney tubular epithelial cells and immune cell infiltration.

SMOC2 promotes an epithelial-mesenchymal transition and a pro-metastatic phenotype in epithelial cells of renal cell carcinoma origin.

Renal Cell Carcinoma (RCC) is the most common form of all renal cancer cases, and well-known for its highly aggressive metastatic behavior. SMOC2 is a recently described non-structural component of the extracellular matrix (ECM) that is highly expressed during tissue remodeling processes with emerging roles in cancers, yet its role in RCC remains elusive. Using gene expression profiles from patient samples, we identified SMOC2 as being significantly expressed in RCC tissue compared to normal renal tissue, which correlated with shorter RCC patient survival. Specifically, de novo protein synthesis of SMOC2 was shown to be much higher in the tubular epithelial cells of patients with biopsy-proven RCC. More importantly, we provide evidence of SMOC2 triggering kidney epithelial cells into an epithelial-to-mesenchymal transition (EMT), a phenotype known to promote metastasis. We found that SMOC2 induced mesenchymal-like morphology and activities in both RCC and non-RCC kidney epithelial cell lines. Mechanistically, treatment of RCC cell lines ACHN and 786-O with SMOC2 (recombinant and enforced expression) caused a significant increase in EMT-markers, -matrix production, -proliferation, and -migration, which were inhibited by targeting SMOC2 by siRNA. We further characterized SMOC2 activation of EMT to occur through the integrin ß3, FAK and paxillin pathway. The proliferation and metastatic potential of SMOC2 overexpressing ACHN and 786-O cell lines were validated in vivo by their significantly higher tumor growth in kidneys and systemic dissemination into other organs when compared to their respective controls. In principle, understanding the impact that SMOC2 has on EMT may lead to more evidence-based treatments and biomarkers for RCC metastasis.

Subchronic oral exposure of tungsten induces myofibroblast transformation and various markers of kidney fibrosis.

Tungsten is a naturally occurring transition element used in a broad range of applications. As a result of its extensive use, we are increasingly exposed to tungsten from our environment, including potable water, since tungsten can become bioaccessible in ground sources. The kidneys are particularly susceptible to tungsten exposure as this is the main site for tungsten excretion. In this study, we investigated the prolonged effects of tungsten on the kidneys and how this may impact injury and function. When mice were exposed to tungsten in their drinking water for 1 mo, kidney function had not significantly changed. Following 3-mo exposure, mice were presented with deterioration in kidney function as determined by serum and urine creatinine levels. During 3 mo of tungsten exposure, murine kidneys demonstrated significant increases in the myofibroblast marker α-smooth muscle actin (αSMA) and extracellular matrix products: fibronectin, collagen, and matricellular proteins. In addition, Masson's trichrome and hematoxylin-eosin (H&E) staining revealed an increase in fibrotic tissue and vacuolization of tubular epithelial cells, respectively, from kidneys of tungsten-treated mice, indicative of renal injury. In vitro treatment of kidney fibroblasts with tungsten led to increased proliferation and upregulation of transforming growth factor ß1 (TGFß1), which was consistent with the appearance of fibroblast-to-myofibroblast transition (FMT) markers. Our data suggest that continuous exposure to tungsten impairs kidney function that may lead to the development of chronic kidney disease (CKD).

Qualitative and Quantitative Dosage of the Anti M-Type Phospholipase A2 Receptor Autoantibody: One-Year Experience in Quebec's Reference Center.

BACKGROUND: Quantification of the M-type phospholipase A2 receptor antibodies (anti-PLA2R) is now an essential tool for diagnosis and management of primary membranous nephropathy (MN). Since October 2018, Hôpital Maisonneuve-Rosemont (HMR) has been designated as Quebec's reference center for serum anti-PLA2R antibody testing by the Institut National d'Excellence en Santé et Services Sociaux (INESSS), the regulatory body on drugs and tests usage in Quebec. OBJECTIVES: To describe the 2-step method of serum qualitative and quantitative anti-PLA2R antibody testing during its first year of use in Quebec and analyze its diagnostic value in the province's population. DESIGN: Retrospective cohort study. SETTING: Single-center academic teaching hospital in Quebec, Canada. PATIENTS: All patients who had a serum anti-PLA2R antibody test analyzed at HMR from October 1, 2018, to October 1, 2019, were included in the study. MEASUREMENTS: Serum anti-PLA2R antibodies were screened by indirect immunofluorescence tests. If results were positive or undetermined, it was followed by a quantitative enzyme-linked immunosorbent assay (ELISA) test. Both tests were based on a commercial kit developed by the same company. METHODS: We calculated sensitivity, specificity, predictive value, and likelihood ratio for both tests, using kidney biopsy findings performed at HMR as the gold standard. RESULTS: In Quebec, a total of 1690 tests were performed among 1025 patients during the study year. A small proportion of these patients (8%) were followed at HMR. Patients tested at HMR and in the rest of Quebec had similar characteristics. Test validity was only characterized for patients tested at HMR. Sensitivity and specificity were, respectively, 58% and 100% for the qualitative test, and 71% and 100% for the quantitative test. The combined net sensitivity was 42% and the net specificity 100%. The net positive and negative predictive value were 100% and 84% respectively, whereas the net negative likelihood ratio was 0.58. LIMITATIONS: As the detailed analysis was only possible in the small proportion of patients clinically followed at HMR, there is a possible selection bias. Another potential selection bias was the focus on patients who were selected to have a kidney biopsy, probably because of more severe disease, higher probability of glomerulonephritis, or lesser number of comorbidities. Given the retrospective nature of this study, there was no systematic kidney biopsy or serum PLA2R antibody testing performed. Finally, we were unable to provide detailed information on the timing between immunosuppressive therapy and anti-PLA2R results. CONCLUSIONS: Serum anti-PLA2R antibody testing was widely used in Quebec during its first year of availability. A 2-step approach, using a qualitative test first, followed by a quantitative test if the results are positive or undetermined, appears efficient to avoid useless quantitative testing in negative patients and to better characterize undetermined results on immunofluorescence. TRIAL REGISTRATION: Due to the retrospective nature of this study, no trial registration was performed.

CONTEXTE: La quantification des anticorps des récepteurs de la phospholipase A2 de type M (anti-PLA2R) est désormais un outil essentiel pour le diagnostic et la prise en charge de la glomérulonéphrite extra-membraneuse primaire (GEMp). Depuis octobre 2018, l'Hôpital Maisonneuve-Rosemont (HMR) a été désigné par l'Institut National d'Excellence en Santé et Services Sociaux (INESSS)­l'organisme règlementant l'usage des médicaments et des tests au Québec­comme le centre hospitalier de référence dans la province pour le dépistage des anticorps sériques anti-PLA2R. OBJECTIFS: Décrire la méthode en deux étapes du test qualitatif et quantitatif des anticorps anti-PLA2R sériques au cours de sa première année d'utilisation au Québec et évaluer sa valeur diagnostique dans la population de la province. TYPE D'ÉTUDE: Étude de cohorte rétrospective. CADRE: Un centre hospitalier universitaire du Québec (Canada). SUJETS: Ont été inclus tous les patients dont le test des anticorps sériques anti-PLA2R a été analysé à HMR entre le 1er octobre 2018 et le 1er octobre 2019. MESURES: Les anticorps sériques anti-PLA2R ont été détectés par immunofluorescence indirecte. Les résultats positifs ou indéterminés ont été suivis d'un test ELISA quantitatif. Les deux tests ont été réalisés à l'aide de trousses commerciales développées par la même entreprise. MÉTHODOLOGIE: Nous avons analysé la sensibilité, la spécificité, la valeur prédictive et le rapport de vraisemblance des deux tests avec comme référence des résultats de biopsie rénale obtenus à HMR. RÉSULTATS: Au Québec, au cours de l'année de l'étude, 1 690 tests ont été effectués sur 1 025 patients; une faible proportion de ces patients (8 %) étaient suivis à HMR. Les patients, qu'ils aient été testés à HMR et ailleurs au Québec, présentaient des caractéristiques semblables. La validité du test n'a été caractérisée que pour les patients testés à HMR. La sensibilité et la spécificité s'établissaient respectivement à 58 % et à 100 % pour le test qualitatif, et à 71 % et 100 % pour le test quantitatif. La sensibilité nette combinée était de 42 % et la spécificité nette, de 100 %. Les valeurs prédictives nettes, positive et négative, étaient respectivement de 100 % et de 84 %, alors que le ratio net de probabilité négative était de 0,58. LIMITES: L'étude présente un possible biais de sélection puisque l'analyse détaillée n'était possible que pour la faible proportion de patients suivis à HMR. L'accent mis sur les patients sélectionnés pour une biopsie rénale, probablement en raison d'une maladie plus grave, d'une probabilité plus élevée de glomérulonéphrite ou d'un moins grand nombre de comorbidités, constitue un autre possible biais de sélection. Aucune biopsie rénale ou test d'anticorps de PLA2R sérique systématique n'a été effectué puisque l'étude est rétrospective. Enfin, il n'a pas été possible de fournir des informations détaillées sur le temps écoulé entre le traitement immunosuppresseur et les résultats du test d'anticorps anti-PLA2R. CONCLUSION: Le test d'anticorps sériques anti-PLA2R a été largement utilisé au Québec au cours de sa première année de disponibilité. Une approche en deux étapes, constituée d'un test qualitatif suivi d'un test quantitatif si le résultat est positif ou indéterminé, semble efficace pour éviter de procéder inutilement à des tests quantitatifs chez les patients négatifs et pour caractériser plus précisément les résultats indéterminés par immunofluorescence. ENREGISTREMENT DE L'ESSAI: L'essai n'a pas été enregistré puisqu'il s'agit d'une étude rétrospective.

Vitamin C-Induced Oxalate Nephropathy in a Septic Patient.

Vitamin C is a novel treatment currently under investigation in the management of sepsis. Adverse renal effects of vitamin C through hyperoxaluria have been described in the past. DATA SOURCES: We report the case of a 63-year-old man admitted in a community-based hospital with a diagnosis of sepsis of pulmonary origin. DATA EXTRACTION: On day 19, despite a having developed oligoanuric acute kidney injury, a regimen of IV vitamin C, hydrocortisone, and thiamine was undertaken for 4 days. On day 23, the patient required renal replacement therapy with an estimated glomerular filtration rate of 7 mL/min. Renal biopsy revealed extensive acute tubular necrosis associated with the presence of intratubular crystal of calcium oxalate. CONCLUSION: Although vitamin C seems to be a possible therapeutic asset in the supportive care of sepsis patients, larger cohorts are required to ensure its safety and underlying or novel kidney injury should forewarn clinicians as to its use.

Arteriovenous Fistula Creation and Estimated Glomerular Filtration Rate Decline in Advanced CKD: A Matched Cohort Study.

Background: Kidney failure is associated with a high burden of morbidity and mortality. Previous studies have raised the possibility that arteriovenous fistula (AVF) creation may attenuate eGFR decline. This study aimed to compare eGFR decline in predialysis patients with an AVF, matched to patients oriented toward peritoneal dialysis (PD). Methods: Predialysis patients with an AVF and those oriented toward PD were retrospectively matched using a propensity score. Time zero was defined as the "AVF creation date" for the AVF group and the "date when eGFR was closest to the matched patient's eGFR at AVF creation" for the PD group. Crude and predicted eGFR decline in AVF and PD groups were compared before and after time zero using mixed-effect linear regressions. Results: In total, 61 pairs were matched. Crude annual eGFR decline before AVF creation/time zero was -4.1 ml/min per m2 per year in the AVF group versus -5.3 ml/min per m2 per year in the PD group (P=0.75) and after time zero, -2.5 ml/min per m2 per year in the AVF group versus -4.5 ml/min per m2 per year in the PD group (P=0.02). The predicted annual decline decreased from -5.1 ml/min per m2 per year in the AVF group before AVF creation to -2.8 ml/min per m2 per year after (P<0.01), whereas there was no difference in the PD group (-5.5 versus -5.1 ml/min per m2 per year respectively, P=0.41). Conclusions: In this matched study, AVF creation was associated with a deceleration of kidney function decline compared with a control PD-oriented group. Prospective studies are needed to assess the potential mechanisms between vascular access creation and eGFR slope attenuation.

Use of Desmopressin Prior to Kidney Biopsy in Patients With High Bleeding Risk.

INTRODUCTION: To prevent bleeding after native kidney biopsy (NKB), nephrologists often prescribe desmopressin, especially for patients with reduced estimated glomerular filtration rate (eGFR) at risk of uremia-related platelet dysfunction. However, only 1 randomized study has suggested a beneficial effect for desmopressin in patients with eGFR ≥60 ml/min per 1.73 m2. This retrospective cohort study aimed to evaluate desmopressin effect on postbiopsy bleeding in all patients, regardless of eGFR and other comorbidities. METHODS: In this retrospective cohort study, all adult patients who underwent an NKB from April 1, 2013, to April 30, 2018, in a tertiary hospital were identified. The association between desmopressin use and bleeding complications, including hemoglobin fall, transfusion, hematoma, symptomatic hematoma, urgent radiologic study, and hypotension, was analyzed using multivariable logistic regression models. RESULTS: A total of 413 native kidney biopsies were studied, 79% of which were performed after receiving desmopressin. Patients receiving desmopressin had worse chronic kidney disease (eGFR 28 vs. 45 ml/min per 1.73 m2; P < 0.001) and were more often hospitalized (48% vs. 32%; P = 0.009). Despite higher bleeding risk, patients using desmopressin had a similar likelihood of symptomatic hematomas (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.13-1.14) and a lower need for urgent radiologic studies (OR, 0.33; 95% CI, 0.11-0.98). CONCLUSION: Patients at higher risk of bleeding using desmopressin before kidney biopsy had bleeding complications similar to those not using desmopressin. These results highlight potential important clinical and financial benefits of desmopressin use before kidney biopsy.

Alk1 haploinsufficiency causes glomerular dysfunction and microalbuminuria in diabetic mice.

Endothelial dysfunction has been shown to play an important role in the pathogenesis of glomerular damage during diabetic kidney disease (DKD). As such, a better understanding of the molecular mechanisms involved in glomerular endothelial dysfunctions could provide novel therapeutic strategies for the prevention of DKD. We have previously shown that Alk1/BMP9 signaling plays an important function to maintain vascular integrity in diabetic animals. As such, we evaluated the effects of Alk1 suppression on glomerular endothelial function in diabetic mice. In the present study, we used mice with conditional heterozygote deletion of Alk1 in the endothelium (Alk1ΔEC) to evaluate the role of Alk1 on kidney function during STZ-induced diabetes. DKD was investigated in diabetic control and Alk1ΔEC mice euthanized eight weeks after the onset of diabetes. We showed that Alk1 expression is reduced in the glomeruli of human DKD patients. While renal function was not altered in Alk1ΔEC non-diabetic mice, we showed that Alk1 haploinsufficiency in the glomerular endothelium leads to microalbuminuria, thickening of the glomerular basement membrane, glomerular apoptosis and podocyte loss in diabetic mice. These data suggest that Alk1 is important for the proper function of glomerular endothelial cells and that decreased Alk1 combined with chronic hyperglycemia can impair renal function.

Prospective study of the changes in pharmacokinetics of immunosuppressive medications after laparoscopic sleeve gastrectomy.

Laparoscopic sleeve gastrectomy induces weight loss via the creation of a restrictive gastric tube for early satiety and is associated with an accelerated gastric transit time. A prospective, single-dose pharmacokinetic study was performed, prior to and after laparoscopic sleeve gastrectomy, for tacrolimus, extended-release tacrolimus, mycophenolate mofetil, and enteric-coated mycophenolate sodium. The study included 12 morbidly obese patients in chronic renal failure. The median decrease in body mass index was 8.8 kg/m2 with an excess body weight loss of 54.9%. The AUC24 of all drugs were increased after laparoscopic sleeve gastrectomy by 46%, 55%, 77%, and 74%, respectively. The maximum concentrations were increased for tacrolimus, extended-release tacrolimus, and mycophenolate mofetil by 43%, 46%, and 65%. The apparent total clearances were decreased for tacrolimus, mycophenolate mofetil, and enteric-coated mycophenolate sodium by 36%, 57%, and 38%. Laparoscopic sleeve gastrectomy can be associated with significant changes in pharmacokinetics of the drugs evaluated. The mechanism is likely decreased apparent drug clearance due to an increased drug exposure (from a more distal site of intestinal absorption with decreased intestinal metabolism), or decreased clearance (liver metabolism). Adapting the monitoring of immunosuppression will be important to avoid overdosing and potential side effects.

Impact of Arteriovenous fistula creation on estimated glomerular filtration rate decline in Predialysis patients.

BACKGROUND: Arteriovenous fistula (AVF) is the vascular access of choice for patients on hemodialysis. Recent evidence suggests that AVF creation may slow estimated glomerular filtration rate (eGFR) decline. The study objective was to assess the impact of the AVF creation on eGFR decline, after controlling for key confounding factors. METHODS: This retrospective cohort study included adult patients followed in a single-center predialysis clinic between 1999 and 2016. Patients with a patent AVF were followed up to 2 years pre- and post-AVF creation. Estimated GFR trajectory was reported using linear mixed models adjusted for demographic characteristics, comorbidities and use of renin-angiotensin-aldosterone blockade. RESULTS: A total of 146 patients were studied with a median age 68.7 (60.5-75.4) years and a median eGFR at time of AVF creation of 12.8 (11.3-13.9) mL/min/1.73m2. The crude annual eGFR decline rates were - 3.60 ± 4.00 mL/min/1.73 m2 pre- and - 2.28 ± 3.56 mL/min/1.73 m2 post-AVF, resulting in a mean difference of 1.28 mL/min/1.73 m2 (95% CI 0.49, 2.07). In a mixed effect linear regression model, monthly eGFR decline was - 0.63 (95% CI -0.81, - 0.46; p <  0.001) mL/min/1.73m2/month. The period after AVF creation was associated with a relatively higher eGFR (ß 0.94, 95% CI 0.61-1.26, p <  0.001). There was a significant association between follow-up time and the period pre/post AVF (ß 0.19, 95% CI 0.16, 0.22; p <  0.001) such that eGFR decline was more attenuated each month after AVF creation. CONCLUSIONS: In this cohort, AVF creation was associated with a significant reduction of eGFR decline. Further prospective studies are needed to confirm this association.

Metabolic Activation of Flavin Monooxygenase-mediated Trimethylamine-N-Oxide Formation in Experimental Kidney Disease.

Cardiovascular disease (CVD) remains the leading cause of death in chronic kidney disease (CKD) patients despite treatment of traditional risk factors, suggesting that non-traditional CVD risk factors are involved. Trimethylamine-N-oxide (TMAO) correlates with atherosclerosis burden in CKD patients and may be a non-traditional CVD risk factor. Serum TMAO concentrations are significantly increased in CKD patients, which may be due in part to increased hepatic flavin monooxygenase (FMO)-mediated TMAO formation. The objective of this work was to elucidate the mechanism of increased FMO activity in CKD. In this study, FMO enzyme activity experiments were conducted in vitro with liver microsomes isolated from experimental CKD and control rats. Trimethylamine was used as a probe substrate to assess FMO activity. The FMO activator octylamine and human uremic serum were evaluated. FMO gene and protein expression were also determined. FMO-mediated TMAO formation was increased in CKD versus control. Although gene and protein expression of FMO were not changed, metabolic activation elicited by octylamine and human uremic serum increased FMO-mediated TMAO formation. The findings suggest that metabolic activation of FMO-mediated TMAO formation is a novel mechanism that contributes to increased TMAO formation in CKD and represents a therapeutic target to reduce TMAO exposure and CVD.

Pharmacodynamics of 250 mg and 500 mg oral furosemide in peritoneal dialysis
.

Residual renal function and diuresis preservation are associated with improved volume control and lower mortality in peritoneal dialysis (PD). Loop diuretics are used to maintain diuresis, although their optimal dosage remains unclear. This study aimed to compare the pharmacodynamics of a 250-mg and a 500-mg dose of oral furosemide in PD patients. 12 patients with a diuresis > 100 mL per day were randomized in a crossover pattern to successively receive an oral dose of 250 mg and 500 mg of furosemide. Twelve-hour natriuresis and diuresis were measured before and after each furosemide dose. Fractional excretion of sodium (FENa) and absolute sodium excretion increased after each dose, although these rises were not statistically significantly different (5.8% (250 mg) vs. 6.9% (500 mg), p = 0.57 for FENa and 42.6 mmol/12h (250 mg) vs. 70.8 mmol/12h (500 mg), p = 0.07 for absolute sodium excretion). Urinary volume was significantly increased after the 500-mg dose, whilst the difference did not reach statistical significance after the 250-mg dose. Furthermore, the higher dose was associated with a greater increase in diuresis than the lower dose (226 mL (250 mg) vs. 522 mL (500 mg), p = 0.04). Furosemide could be used at oral single doses reaching 500 mg in PD patients requiring greater volume control.

Effects of Renal Impairment on the Pharmacokinetics of Once-Daily Amantadine Extended-Release Tablets.

BACKGROUND: An extended-release formulation of amantadine (Osmolex ER™, Osmotica Pharmaceutical US LLC) was approved in February 2018 to treat Parkinson's disease and drug-induced extrapyramidal reactions in adults. OBJECTIVES: To determine the pharmacokinetic profile of extended-release amantadine in subjects with varying degrees of renal impairment. METHODS: Adults with normal renal function (creatinine clearance > 89 mL/min/1.73 m2), moderate renal impairment (creatinine clearance 30-59 mL/min/1.73 m2), or severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2) received a single 129-mg dose (160 mg amantadine hydrochloride) of extended-release amantadine. Blood and urine samples for pharmacokinetic analysis were taken at scheduled intervals. A two-compartment pharmacokinetic population model was employed to determine optimum extended-release amantadine dosing in subjects with renal impairment. RESULTS: Following a single oral dose of the 129-mg extended-release amantadine tablet, amantadine plasma concentration increased slowly, reaching a peak at approximately 11 h. Amantadine elimination was reduced in subjects with renal impairment. Renal clearance decreased from 10,965 to 2618 mL/h in subjects with severe renal impairment compared to those with normal renal function. Pharmacokinetic modeling and simulation methods were used to recommend the oral administration of 129-mg extended-release amantadine tablets at intervals of 24, 48, 72, 96, 120, or 168 h depending on the degree of renal function. CONCLUSIONS: Renal impairment was associated with reduced amantadine clearance. Based on pharmacokinetic modeling and simulations, dose regimens were recommended for subjects with impaired renal function to provide systemic amantadine exposure similar to subjects with normal renal function taking a once-daily extended-release amantadine tablet.

Clinical Value of Complement Activation Biomarkers in Overt Diabetic Nephropathy.

BACKGROUND: Experimental studies support a role of complement activation in diabetic nephropathy (DN), yet few clinical correlates exist. We evaluated urinary levels of sC5b-9 membrane attack complex (MAC) in patients with overt DN, and examined its association with the glomerular filtration rate (GFR) decline, proteinuria, and inflammatory biomarkers. We explored different complement pathways and compared our findings to autoimmune glomerulonephritis. METHODS: We prospectively followed 83 patients with DN and obtained repeated measurements of proteinuria, complement fragments (sC5b-9, C4a, C1q, mannose-binding lectin-associated serine protease [MASP]-1, and factor Bb), monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor (TGF)-ß1. We assessed independence and interactions using general linear models and repeated measures analyses and compared levels with subjects with active focal and segmental glomerulosclerosis, ANCA-associated vasculitis, and membranous and IgA nephropathies (n = 63). RESULTS: The diabetic cohort had an initial GFR of 25 ± 9 ml/min per 1.73 m2 and a renal function decline of 2.9 ± 3.0 ml/min per 1.73 m2 per year. All complement biomarkers were strongly intercorrelated and associated with biomarker inflammation and fibrosis, proteinuria, and the rate of renal function decline. There was a significant interaction (P = 0.03) between the level of proteinuria and urinary sC5b-9: in individuals with higher levels of urinary MAC, the relationship between proteinuria and the rate of renal function decline was more pronounced than in those with low urinary MAC. Finally, patients with DN had levels of urinary sC5b-9 comparable to autoimmune glomerulonephritis, when stratified by the level of proteinuria. CONCLUSION: Urinary MAC is present in patients with overt DN at levels comparable to autoimmune glomerulonephritis and correlates with the GFR decline, supporting that complement activation and its measurement are clinically relevant in DN.

Association of Neutrophil-to-Lymphocyte Ratio With Inflammation and Erythropoietin Resistance in Chronic Dialysis Patients.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) was widely studied as a prognostic marker in various medical and surgical specialties, but its significance in nephrology is not yet established. OBJECTIVE: We evaluated its accuracy as an inflammation biomarker in a dialysis population. DESIGN SETTING: Single-center retrospective study. PATIENTS: The records of all 550 patients who were treated with hemodialysis (HD) or peritoneal dialysis (PD) from September 2008 to March 2011 were included. MEASUREMENTS: NLR was calculated from the monthly complete blood count. METHODS: Association between NLR and markers of inflammation (C-reactive protein [CRP], serum albumin, and erythropoietin resistance index [ERI]) was measured using Spearman coefficient. RESULTS: In total, 120 patients were eligible for the correlation analyses. We found a positive correlation between NLR and CRP (all patients: r = 0.45, P < .001; HD: r = 0.47, P < .001; PD: r = 0.48, P = .13). NLR and albumin were inversely correlated (r = -0.51, P < .001). Finally, high NLR was associated with a nonsignificant increased ERI, but we have not demonstrated a direct correlation. LIMITATIONS: CRP and albumin are not measured routinely and were ordered for a specific clinical reason leading to an indication bias. Also, no relationship with clinical outcome was established. CONCLUSIONS: NLR seems to be a good inflammatory biomarker in dialysis in addition to being easily available. However, controlled studies should be conducted to properly assess and validate NLR levels that would be clinically significant and relevant, as well as its prognostic significance and utility in a clinical setting.

CONTEXTE: La qualité de marqueur pronostique du ratio neutrophiles/lymphocytes a fait l'objet d'études approfondies dans plusieurs disciplines médicales et spécialités chirurgicales. En revanche, son importance n'est toujours pas établie dans le domaine de la néphrologie. OBJECTIF DE L'ÉTUDE: Nous avons voulu évaluer l'efficacité du ratio neutrophiles/lymphocytes comme biomarqueur de l'inflammation chez une population de patients dialysés. MODÈLE DE L'ÉTUDE: Il s'agit d'une étude rétrospective restreinte à un seul établissement. PARTICIPANTS: Les dossiers médicaux des 550 patients ayant été traités par hémodialyse (HD) ou par dialyse péritonéale (DP) entre septembre 2008 et mars 2011 ont été retenus pour cette étude. MESURES: Le ratio neutrophiles/lymphocytes a été calculé à partir de la formule sanguine complète prélevée mensuellement. MÉTHODOLOGIE: On a utilisé le coefficient de Spearman pour mesurer la corrélation entre le ratio neutrophiles/lymphocytes et certains marqueurs de l'inflammation : la protéine C-réactive, l'albumine sérique et l'index de résistance à l'érythropoïétine (IRE). RÉSULTATS: De tous les dossiers médicaux retenus, seuls 120 patients étaient admissibles à l'analyse de corrélation. Nous avons pu établir une corrélation positive entre le ratio neutrophiles/lymphocytes et la protéine C-réactive (r=0,45; p<0,001 pour l'ensemble des patients, r=0,47; p<0,001 chez les patients en HD, et r=0,48; p=0,13 chez les patients sous DP), alors que la corrélation était inversée dans le cas de l'albumine sérique (r=0,51; p<0,001). Nous avons également observé qu'un ratio neutrophiles/lymphocytes élevé était associé à une élévation non significative de l'IRE, sans toutefois établir une corrélation directe. LIMITES DE L'ÉTUDE: Règle générale, l'albumine sérique et la protéine C-réactive ne sont mesurées que lorsqu'une raison d'ordre clinique le demande, ce qui pourrait signaler un biais. De plus, aucun lien n'a été établi entre le ratio neutrophiles/lymphocytes et les devenirs cliniques des patients. CONCLUSION: Le calcul du ratio neutrophiles/lymphocytes semble être un bon indicateur de l'état inflammatoire chez les patients dialysés. Qui plus est, les données nécessaires pour évaluer ce ratio sont faciles à obtenir. Néanmoins, des études contrôlées devraient être menées pour déterminer les valeurs de ratio neutrophiles/lymphocytes qui seraient significatives du point de vue clinique, de même que pour établir l'importance du ratio neutrophiles/lymphocytes sur le plan du pronostic et sa pertinence dans un cadre clinique.

The impact of renal protection clinics on prescription of and adherence to cardioprotective drug therapy in chronic kidney disease patients.

Background: The aim of this study was to assess the impact of follow-up in renal protection clinics on the prescription of and adherence to cardioprotective drugs in patients with chronic kidney disease (CKD). Methods: We studied stage 4 and 5 CKD patients who initiated follow-up in three renal protection clinics. The prescription pattern of antihypertensive agents (AHA) and lipid-lowering agents (LLAs) was measured as the percentage of patients who are prescribed the agents of interest at a given time. Adherence to drug therapy was defined as the percentage of days, during a pre-defined observation period, in which patients have an on-hand supply of their prescribed medications. Results: A total of 259 CKD patients were enrolled and followed for up to 1 year after referral to renal protection clinics. There was a significant increase in the prescription of angiotensin-converting enzyme inhibitors (34-39%), angiotensin II receptor blockers (11-14%), beta-blockers (40-51%), calcium channel blockers (62-74%), diuretics (66-78%) and LLAs (39-47%) during follow-up in the renal protection clinic compared with baseline (P-values <0.01 for all comparisons). The proportions of patients with good (≥ 80%) and poor (< 80%) adherence to AHA (P = 0.41) and LLAs (P = 0.11) were similar in the year preceding and the year following the first visit to the renal protection clinics. Conclusion: Our results suggest that referral and follow-up in a renal protection clinic may increase the prescription of cardioprotective agents in CKD patients, but does not appear to improve adherence to these medications.

Mechanism of insulin resistance in a rat model of kidney disease and the risk of developing type 2 diabetes.

Chronic kidney disease is associated with homeostatic imbalances such as insulin resistance. However, the underlying mechanisms leading to these imbalances and whether they promote the development of type 2 diabetes is unknown. The effect of chronic kidney disease on insulin resistance was studied on two different rat strains. First, in a 5/6th nephrectomised Sprague-Dawley rat model of chronic kidney disease, we observed a correlation between the severity of chronic kidney disease and hyperglycemia as evaluated by serum fructosamine levels (p<0.0001). Further, glucose tolerance tests indicated an increase of 25% in glycemia in chronic kidney disease rats (p<0.0001) as compared to controls whereas insulin levels remained unchanged. We also observed modulation of glucose transporters expression in several tissues such as the liver (decrease of ≈40%, p≤0.01) and muscles (decrease of ≈29%, p≤0.05). Despite a significant reduction of ≈37% in insulin-dependent glucose uptake in the muscles of chronic kidney disease rats (p<0.0001), the development of type 2 diabetes was never observed. Second, in a rat model of metabolic syndrome (Zucker Leprfa/fa), chronic kidney disease caused a 50% increased fasting hyperglycemia (p<0.0001) and an exacerbated glycemic response (p<0.0001) during glucose challenge. Similar modulations of glucose transporters expression and glucose uptake were observed in the two models. However, 30% (p<0.05) of chronic kidney disease Zucker rats developed characteristics of type 2 diabetes. Thus, our results suggest that downregulation of GLUT4 in skeletal muscle may be associated with insulin resistance in chronic kidney disease and could lead to type 2 diabetes in predisposed animals.

Retrospective Study Looking at Cinacalcet in the Management of Hyperparathyroidism after Kidney Transplantation.

Objectives. The primary objective of this study is to evaluate the use of cinacalcet in the management of hyperparathyroidism in kidney transplant recipients. The secondary objective is to identify baseline factors that predict cinacalcet use after transplantation. Methods. In this single-center retrospective study, we conducted a chart review of all patients having been transplanted from 2003 to 2012 and having received cinacalcet up to kidney transplantation and/or thereafter. Results. Twenty-seven patients were included with a mean follow-up of 2.9 ± 2.4 years. Twenty-one were already taking cinacalcet at the time of transplantation. Cinacalcet was stopped within the first month in 12 of these patients of which 7 had to restart therapy. The main reason for restarting cinacalcet was hypercalcemia. Length of treatment was 23 ± 26 months. There were only 3 cases of mild hypocalcemia. There was no statistically significant association between baseline factors and cinacalcet status a year later. Conclusions. Discontinuing cinacalcet within the first month of kidney transplantation often leads to hypercalcemia. Cinacalcet appears to be an effective treatment of hypercalcemic hyperparathyroidism in kidney transplant recipients. Further studies are needed to evaluate safety and long-term benefits.

Conversion of oral alfacalcidol to oral calcitriol in the treatment of secondary hyperparathyroidism in chronic hemodialysis patients.

PURPOSE: The optimal vitamin D3 therapy for the treatment of secondary hyperparathyroidism (SHPT) in chronic hemodialysis patients is still controversial. Recent studies suggest that uremia in end-stage renal disease is associated with enzymatic hepatic dysfunction altering 25-hydroxylation of vitamin D3. The goal of our study was to compare the efficacy of calcitriol, the fully hydroxylated active form of vitamin D3, to alfacalcidol which needs 25-hydroxylation to be effective, for the treatment of SHPT in chronic hemodialysis patients. METHODS: We retrospectively reviewed 45 chronic hemodialysis patients who were switched from oral alfacalcidol to oral calcitriol for the treatment of SHPT. Parathyroid hormone (PTH), serum calcium and serum phosphorus levels were compared pre- and post-conversion using paired Student's t tests. RESULTS: The mean dose of active vitamin D3 decreased from 3.50 mcg/week at baseline to 2.86 mcg (P < 0001) after the switch from alfacalcidol to calcitriol. PTH significantly decreased from 94.4 to 82.6 pmol/L (-11.8 pmol/L, P = 0.02). The mean corrected calcium increased from 2.17 to 2.25 mmol/L (+0.08 mmol/L, P < 0.001) without any clinically significant hypercalcemia, and phosphorus levels were stable. Results were similar in a subgroup of patients (n = 17) for whom the medication was administrated during the hemodialysis session, ensuring a complete compliance. CONCLUSIONS: According to our study, calcitriol in equal dosage is more effective than alfacalcidol in lowering serum PTH level in chronic hemodialysis patients. This suggests that calcitriol may be the optimal active vitamin D3 for the treatment of SHPT in chronic hemodialysis patients.

Changes in Urinary and Serum Levels of Novel Biomarkers after Administration of Gadolinium-based Contrast Agents.

OBJECTIVE: The aim of our study is to describe the changes in urinary and serum levels of novel biomarkers after gadolinium contrast administration in patients with normal renal function. METHODS: We measured four biomarkers in 28 volunteers: interleukin-18 (IL-18), N-acetyl-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin, and cystatin C. Urinary and serum samples were collected at 0, 3, and 24 hours following gadolinium administration. RESULTS: Baseline serum creatinine was 57.8 ± 34.5 µmol/L and remained stable. Urinary IL-18 levels increased significantly at three hours (10.7 vs. 7.3 ng/mg creatinine; P < 0.05). Similarly, urinary NAG levels increased significantly at three hours (3.9 vs. 2.2 IU/mg creatinine; P < 0.001). For both these markers, the difference was no longer significant at 24 hours. No statistically significant differences were observed for urinary and serum neutrophil gelatinase-associated lipocalin levels and for serum cystatin C levels. CONCLUSIONS: Urinary IL-18 and NAG levels increased transiently after administration of gadolinium-based contrast agents in patients with normal renal function.