Search

Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a randomized controlled trial.Setting & Participants: Participants in the CREDENCE trial.Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (Results: The mean age of the cohort was 63.0 ± 9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791.

Introduction: Prior cross-sectional studies suggest that health-related quality of life (HRQOL) worsens with more severe glomerular disease. This longitudinal analysis was conducted to assess changes in HRQOL with changing disease status. Methods: Cure Glomerulonephropathy (CureGN) is a cohort of patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA vasculitis, or IgA nephropathy. HRQOL was assessed at enrollment and follow-up visits 1 to 3 times annually for up to 5 years with the Patient-Reported Outcomes Measurement Information System (PROMIS). Global health, anxiety, and fatigue domains were measured in all; mobility was measured in children; and sleep-related impairment was measured in adults. Linear mixed effects models were used to evaluate HRQOL responsiveness to changes in disease status. Results: A total of 469 children and 1146 adults with PROMIS scores were included in the analysis. HRQOL improved over time in nearly all domains, though group-level changes were modest. Edema was most consistently associated with worse HRQOL across domains among children and adults. A greater number of symptoms also predicted worse HRQOL in all domains. Sex, age, obesity, and serum albumin were associated with some HRQOL domains. The estimated glomerular filtration rate (eGFR) was only associated with fatigue and adult physical health; proteinuria was not associated with any HRQOL domain in adjusted models. Conclusion: HRQOL measures were responsive to changes in disease activity, as indicated by edema. HRQOL over time was not predicted by laboratory-based markers of disease. Patient-reported edema and number of symptoms were the strongest predictors of HRQOL, highlighting the importance of the patient experience in glomerular disease. HRQOL outcomes inform understanding of the patient experience for children and adults with glomerular diseases.

Introduction Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease. Methods Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort, n = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy, Graphical abstract

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., Graphical abstract

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 theTo 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.Retrospective cohort study.Single-center academic teaching hospital in Quebec, Canada.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.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.We calculated sensitivity, specificity, predictive value, and likelihood ratio for both tests, using kidney biopsy findings performed at HMR as the gold standard.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.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.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.Due to the retrospective nature of this study, no trial registration was performed.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 Québec—comme le centre hospitalier de référence dans la province pour le dépistage des anticorps sériques anti-PLA2R.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.Étude de cohorte rétrospective.Un centre hospitalier universitaire du Québec (Canada).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.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.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.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.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.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.L’essai n’a pas été enregistré puisqu’il s’agit d’une étude rétrospective.

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)-β1. 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., Graphical abstract

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 2/month. The period after AVF creation was associated with a relatively higher eGFR (β 0.94, 95% CI 0.61–1.26, p Conclusions In this cohort, AVF creation was associated with a significant reduction of eGFR decline. Further prospective studies are needed to confirm this association.

Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1.73 m(2) of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0.75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for >= 30 days) or end-stage kidney disease (eGFR = 90 days, chronic dialysis for >= 90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials. gov, number NCT01858532.Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2.2 years (IQR 1.4-2.9). 79 (6.0%) of 1325 patients in the atrasentan group and 105 (7.9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49-0.88]; p=0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1325 patients in the atrasentan group and 34 (2.6%) of 1323 patients in the placebo group (HR 1.33 [95% CI 0.85-2.07]; p=0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75-1.59]; p=0.65).Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

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. 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. The mean dose of active vitamin D3 decreased from 3.50 mcg/week at baseline to 2.86 mcg (P

Introduction The Cure Glomerulonephropathy Network (CureGN) is a 66-center longitudinal observational study of patients with biopsy-confirmed minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (IgAN), including IgA vasculitis (IgAV). This study describes the clinical characteristics and treatment patterns in the IgA cohort, including comparisons between IgAN versus IgAV and adult versus pediatric patients. Methods Patients with a diagnostic kidney biopsy within 5 years of screening were eligible to join CureGN. This is a descriptive analysis of clinical and treatment data collected at the time of enrollment. Results A total of 667 patients (506 IgAN, 161 IgAV) constitute the IgAN/IgAV cohort (382 adults, 285 children). At biopsy, those with IgAV were younger (13.0 years vs. 29.6 years, P < 0.001), more frequently white (89.7% vs. 78.9%, P = 0.003), had a higher estimated glomerular filtration rate (103.5 vs. 70.6 ml/min per 1.73 m2, P < 0.001), and lower serum albumin (3.4 vs. 3.8 g/dl, P < 0.001) than those with IgAN. Adult and pediatric individuals with IgAV were more likely than those with IgAN to have been treated with immunosuppressive therapy at or prior to enrollment (79.5% vs. 54.0%, P < 0.001). Conclusion This report highlights clinical differences between IgAV and IgAN and between children and adults with these diagnoses. We identified differences in treatment with immunosuppressive therapies by disease type. This description of baseline characteristics will serve as a foundation for future CureGN studies.

The prevalence and incidence of chronic kidney disease (CKD) has steadily increased over the past two decades attributed to an important raise of cases of diabetes, hypertension and obesity, leading risk factors of renal failure. CKD is known to impair drug disposition of non-renally eliminated medications that may lead to unintended toxicity or lower therapeutic effect despite dose adjustment according to glomerular filtration rate (GFR). Modulation of metabolism enzymes (cytochrome P450, phase II) and drug transporters in various organs (intestines, liver, kidneys and brain) are being held responsible for altered pharmacokinetics where uremic toxins, inflammatory cytokines and parathyroid hormone, common factors present in CKD, may be considered possible culprits. This review gives a thorough summary of the recent preclinical, clinical studies and Food and Drug Administration (FDA) guidelines and allows a current understanding of drug absorption, distribution, metabolism and excretion in CKD.

Hyperphosphatemia and metabolic acidosis are frequently encountered in advanced chronic kidney disease (CKD) patients. Correction of metabolic acidosis in patients with advanced CKD leads to a decrease in the progression of renal impairment and improves nutritional outcomes. Lanthanum carbonate is used for control of hyperphosphatemia. This study evaluated the effect of lanthanum carbonate on metabolic acidosis in CKD IV-V patients and in patients on dialysis.Retrospective data of patients in whom lanthanum carbonate therapy was initiated were collected from 2009 to 2013 in a single dialysis center. Of the 79 patients in whom lanthanum carbonate was introduced, 51 patients were included in the analysis. Of the 51 patients, 39 patients received chronic hemodialysis, two patients received peritoneal dialysis therapy, and 10 patients had stage IV-V CKD not on dialysis. The primary outcome was the serum bicarbonate change after the introduction of lanthanum carbonate.There was a significant increase in mean serum bicarbonate concentration of 2.79 mmol/L (p ≤ 0.001) compared to baseline. The increase remained in the CKD IV-V patients (2.50 mmol/L, p = 0.005) and in the patients on dialysis (2.81 mmol/L, p0.001). Serum bicarbonate remained higher (p0.05) than baseline up to 6 months after lanthanum carbonate introduction.In this study, lanthanum carbonate introduction increased serum bicarbonate concentration in a small sample of CKD IV-V patients and in patients on dialysis. Further studies are needed to confirm this effect and investigate whether the correction of metabolic acidosis by using lanthanum carbonate in CKD IV-V patients can improve clinical outcomes.

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.We evaluated its accuracy as an inflammation biomarker in a dialysis population.Single-center retrospective study.The records of all 550 patients who were treated with hemodialysis (HD) or peritoneal dialysis (PD) from September 2008 to March 2011 were included.NLR was calculated from the monthly complete blood count.Association between NLR and markers of inflammation (C-reactive protein [CRP], serum albumin, and erythropoietin resistance index [ERI]) was measured using Spearman coefficient.In total, 120 patients were eligible for the correlation analyses. We found a positive correlation between NLR and CRP (all patients: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.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.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.Nous avons voulu évaluer l’efficacité du ratio neutrophiles/lymphocytes comme biomarqueur de l’inflammation chez une population de patients dialysés.Il s’agit d’une étude rétrospective restreinte à un seul établissement.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.Le ratio neutrophiles/lymphocytes a été calculé à partir de la formule sanguine complète prélevée mensuellement.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).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;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.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.

International audience; 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

Contains fulltext : 174174.pdf (Publisher’s version ) (Open Access) 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 /= 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.

Calcidiol insufficiency is highly prevalent in chronic kidney disease (CKD), but the reasons for this are incompletely understood. CKD associates with a decrease in liver cytochrome P450 (CYP450) enzymes, and specific CYP450 isoforms mediate vitamin D(3) C-25-hydroxylation, which forms calcidiol. Abnormal levels of parathyroid hormone (PTH), which also modulates liver CYP450, could also contribute to the decrease in liver CYP450 associated with CKD. Here, we evaluated the effects of PTH and uremia on liver CYP450 isoforms involved in calcidiol synthesis in rats. Uremic rats had 52% lower concentrations of serum calcidiol than control rats (P0.002). Compared with controls, uremic rats produced 71% less calcidiol and 48% less calcitriol after the administration of vitamin D(3) or 1alpha-hydroxyvitamin D(3), respectively, suggesting impaired C-25-hydroxylation of vitamin D(3). Furthermore, uremia associated with a reduction of liver CYP2C11, 2J3, 3A2, and 27A1. Parathyroidectomy prevented the uremia-associated decreases in calcidiol and liver CYP450 isoforms. In conclusion, these data suggest that uremia decreases calcidiol synthesis secondary to a PTH-mediated reduction in liver CYP450 isoforms.

ESRD can affect the pharmacokinetic disposition of drugs subject to nonrenal clearance. Cytochrome P450 (CYP) enzymes, including CYP3A, and multiple intestinal and hepatic drug transporters are thought to mediate this process, but the extent to which kidney disease alters the function of these proteins in humans is unknown. We used midazolam and fexofenadine to assess CYP3A (intestinal and hepatic) and drug transport, respectively, in patients with ESRD and healthy control subjects. We evaluated the effect of uremia on CYP3A and transporter expression in vitro by incubating normal rat hepatocytes and enterocytes with serum drawn from study participants. ESRD dramatically reduced nonrenal transporter function, evidenced by a 63% decrease in clearance (P < 0.001) and a 2.8-fold increase in area under the plasma concentration–time curve for fexofenadine (P = 0.002), compared with control subjects. We did not observe significant differences in midazolam or 1′-hydroxymidazolam clearance or area under the curve after oral administration, suggesting that CYP3A function is not changed by ESRD. Changes in hepatocyte and enterocyte protein expression in the presence of uremic serum were consistent with in vivo results. These findings demonstrate a mechanism for altered drug disposition in kidney disease, which may partially account for the high rates of drug toxicity in this population.

Calcidiol insufficiency is highly prevalent in chronic kidney disease (CKD) and osteoporotic patients. We assessed and compared calcidiol levels in these two groups from the same geographical area to differentiate environmental factors from characteristics related to CKD.We measured calcidiol levels in 160 predialysis (group 1) and 53 osteoporotic (group 2) patients from a single center. Calcidiol insufficiency was defined as a level between 37.5 and 75 nmol/l and calcidiol deficiency was defined as a level below 37.5 nmol/l.In group 1, mean glomerular filtration rate (GFR), calcidiol, and parathyroid hormone (PTH) levels were 18.3 +/- 4.7 ml/min, 38.7 +/- 15.1 nmol/l, and 21.9 +/- 19.1 pmol/l. Calcidiol insufficiency and deficiency were present in 98.7% of patients. There was an inverse correlation between calcidiol and PTH levels (r = -0.25; P = 0.001). In group 2, mean GFR, calcidiol levels, and PTH levels were 68.6 +/- 17.6 ml/min, 73.8 +/- 27.1 nmol/l, and 4.23 +/- 1.83 pmol/l, respectively. Calcidiol insufficiency and deficiency were present in 50.9% of patients. There was an inverse correlation between calcidiol and PTH levels (r =-0.44; P = 0.02).In our predialysis population, calcidiol insufficiency and deficiency are present in almost every patient, being more common than previously reported. It is also more frequent than in a similar osteoporotic population, suggesting a cause unrelated to environmental factors. Interestingly, there is a significant inverse correlation between calcidiol and parathyroid levels in both populations. Further studies are needed to enable understanding of the mechanisms underlying calcidiol insufficiency.

Background and objectives Hyperkalemia affects up to 10% of patients with CKD. Sodium polystyrene sulfonate has long been prescribed for this condition, although evidence is lacking on its efficacy for the treatment of mild hyperkalemia over several days. This study aimed to evaluate the efficacy of sodium polystyrene sulfonate in the treatment of mild hyperkalemia. Design, setting, participants, & measurements In total, 33 outpatients with CKD and mild hyperkalemia (5.0–5.9 mEq/L) in a single teaching hospital were included in this double–blind randomized clinical trial. We randomly assigned these patients to receive either placebo or sodium polystyrene sulfonate of 30 g orally one time per day for 7 days. The primary outcome was the comparison between study groups of the mean difference of serum potassium levels between the day after the last dose of treatment and baseline. Results The mean duration of treatment was 6.9 days. Sodium polystyrene sulfonate was superior to placebo in the reduction of serum potassium levels (mean difference between groups, −1.04 mEq/L; 95% confidence interval, −1.37 to −0.71). A higher proportion of patients in the sodium polystyrene sulfonate group attained normokalemia at the end of their treatment compared with those in the placebo group, but the difference did not reach statistical significance (73% versus 38%; P=0.07). There was a trend toward higher rates of electrolytic disturbances and an increase in gastrointestinal side effects in the group receiving sodium polystyrene sulfonate. Conclusions Sodium polystyrene sulfonate was superior to placebo in reducing serum potassium over 7 days in patients with mild hyperkalemia and CKD.

Chronic renal failure (CRF) is associated with a decrease in drug metabolism secondary to a decrease in liver cytochrome P450 (P450). The predominant theory to explain this decrease is the presence of factors in the blood of uremic patients. This study tested the hypothesis that parathyroid hormone (PTH) could be this factor. The objectives of this study were to determine (1) the role of PTH in the downregulation of hepatocyte P450 induced by rat uremic serum, (2) the role of PTH in the downregulation of liver P450 in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes. For this purpose, (1) hepatocytes were incubated with serum from rat with CRF that was depleted with anti-PTH antibodies or with serum from parathyroidectomized (CRF-PTX) rat with CRF, (2) the effect of PTX on liver P450 was evaluated in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes were determined. The depletion of PTH from CRF serum completely reversed the downregulating effect of CRF serum on P450 in hepatocytes. Addition of PTH (10(-9) M) to depleted CRF serum induced a decrease in P450 similar to nondepleted CRF serum. The serum of CRF-PTX rats had no effect on P450 in hepatocytes compared with CRF serum. Adding PTH to CRF-PTX serum induced a similar decrease in P450 as obtained with CRF serum. Finally, PTX prevented the decrease of liver P450 in rats with CRF. In summary, PTH is the major mediator implicated in the downregulation of liver P450 in rats with CRF.

Background/Aims: The osteocalcin-related gene (ORG) is a mouse-specific member of the osteocalcin gene cluster predicted to encode a γ-carboxyglutamic acid-rich protein. ORG mRNA has been predicted to encode nephrocalcin and shown to be expressed in the kidney where it could serve as an important crystallization inhibitor. To determine whether ORG encodes mouse nephrocalcin, we investigated its in vivo and in vitro expression. Methods: We expressed fluorescent fusion ORG proteins in kidney cell lines and generated transgenic mice expressing enhanced green fluorescent protein under the control of the ORG promoter. Results:ORG mRNA was shown to be expressed in mouse kidneys and in a variety of other tissues. Fusion constructs transfected in opossum kidney cells demonstrated integrity of the open reading frame with the presence of a protein of the expected molecular weight. However, kidneys from transgenic mice carrying the enhanced green fluorescent protein gene under the control of the ORG promoter (5.8 kb fragment) demonstrated no expression of the transgene in kidneys or other tissues. Conclusion: We conclude that ORG, the third gene of the mouse osteocalcin gene cluster is silent and unlikely to play a major role in mouse renal physiology.

A decrease in renal phosphate reabsorption with mild hypophosphatemia (phosphate leak) is found in some hypercalciuric stone-formers. The NPT2a gene encodes a sodium-phosphate cotransporter, located in the proximal tubule, responsible for reclaiming most of the filtered phosphate load in a rate-limiting manner. To determine whether genetic variation of the NPT2a gene is associated with phosphate leak and hypercalciuria in a cohort of 98 pedigrees with multiple hypercalciuric stone-formers, we sequenced the entire cDNA coding region of 28 probands, whose tubular reabsorption of phosphate normalized for the glomerular filtration rate (TmP/GFR) was 0.7 mmol/l or lower. We performed genotype/phenotype correlations for each genetic variant in the entire cohort and expressed NPT2a variant RNAs in Xenopus laevis oocytes to test for cotransporter functionality. We identified several variants in the coding region including an in-frame 21 bp deletion truncating the N-terminal cytoplasmic tail of the protein (91del7), as well as other single-nucleotide polymorphisms that were non-synonymous (A133V and H568Y) or synonymous. Levels of TmP/GFR and urine calcium excretion were similar in heterozygote carriers of NPT2a variants compared to the wild-type (wt) homozygotes. The transport activity of the H568Y mutants was identical to the wt, whereas the N-terminal-truncated version and the 91del7 and A133V mutants presented minor kinetic changes and a reduction in the expression level. Although genetic variants of NPT2a are not rare, they do not seem to be associated with clinically significant renal phosphate or calcium handling anomalies in a large cohort of hypercalciuric stone-forming pedigrees.

Aims: Our objectives were to review the characteristics of patients who developed atheroembolic renal disease requiring dialysis as well as their renal function recovery and survival rates. Methods: All cases of atheroembolic disease with renal failure severe enough to require dialysis were reviewed from January 1984 to December 2000 in two centers. The diagnosis of atheroemboli was based on clinical presentation and/or biopsy. Acute renal failure was defined as a serum creatinine >200 µmol/l if normal at baseline or doubling from baseline if chronic renal failure, whereas renal function recovery was the ability to discontinue renal replacement therapy for ≧3 months. Results: Forty-three cases were identified (37 males and 6 females; mean age 67 ± 5 years); the average time to acute renal failure and to diagnosis was similar at 36 days. The majority of patients had at least one precipitating factor identified (58% coronary angiography, 26% angiography, 16% vascular surgery, 2% anticoagulation); 1 had a spontaneous presentation whereas 7 had more than one factor. More than 90% had underlying hypertension and chronic renal dysfunction with a baseline creatinine of 195 ± 81 µmol/l, approximately 80% had coronary artery disease, 80% were smokers, 60% had a history of abdominal aorta aneurysm, >50% presented with intermittent claudication, and 56% were anticoagulated at the time of the event. Most patients were nonoliguric (80%), had increased hypertension (71%), blue toes (67%), livedo reticularis (52%), whereas abdominal pain and central nervous system symptoms were present in 33 and 7% of the cases, respectively. Eosinophilia was found in 88%, while hypocomplementemia was present in less than 15%. When compared to the 12 patients with recovery of renal function (after a mean delay of 409 ± 336 days), the 31 patients who did not recover function presented with more severe intermittent claudication and underlying chronic renal dysfunction (p < 0.05). Indeed, the only variable found to unfavorably influence renal function recovery was the presence of intermittent claudication. Patients were mainly treated by intermittent hemodialysis except for 5 (2 on CRRT and 3 on peritoneal dialysis). Renal function recovery was associated with a higher chance of survival; 33% of patients died in the first year after diagnosis. Conclusion: Atheroembolic renal disease carries a high mortality rate reflective of the extensive cardiovascular disease of affected patients; nevertheless, the potential for renal function recovery appears greater than for other vascular causes of renal failure.

Aim: This multicenter, open-label study determined safety and efficacy of once-every-other-week administration of darbepoetin alfa for anemia of chronic kidney disease in erythropoietin-naive patients not on dialysis. Methods: Participants with hemoglobin levels Results: Six hundred and eight patients were enrolled, and 463 completed the study; 95% (95% confidence interval: 0.93, 0.97) of the patients who completed treatment achieved a hemoglobin response. The mean darbepoetin alfa dose at the time of response was 63.5 ± (SD) 16.9 µg, and the mean time to hemoglobin response was 5.7 ± (SD) 4.5 weeks. Oral iron therapy was administered to 60% and intravenous iron to 16% of the participants. Darbepoetin alfa was well tolerated, and adverse events were consistent with those expected in patients with chronic kidney disease. Conclusion: Darbepoetin alfa administered once every other week is effective and safe for achieving and maintaining target hemoglobin levels in anemic patients with chronic kidney disease.

The aim of our study was to evaluate the efficacy and bioavailibility of a commonly used oral furosemide dose (500 mg) compared to a 250 mg intravenous (IV) dose in PD patients with significant residual renal function (urine volume > 100 mL). We also evaluated the immediate blood pressure effect in these patients. The data were obtained from a study we performed for the homologation of a 500-mg dose of furosemide by Health Canada.

Thirty-eight intensive care unit (ICU) patients (26 men and 12 women with a mean age of 57.0 +/- 16.6 years) with acute renal failure (ARF) treated by venovenous continuous renal replacement therapy (CRRT) were evaluated while in relatively steady metabolic control. Twenty-seven were undergoing continuous venovenous hemodialysis, nine were undergoing continuous venovenous hemodiafiltration, and two were undergoing continuous venovenous hemofiltration. Periods of analysis varied between 24 and 408 hours (mean duration, 82.7 +/- 70.6 hours; median, 72 hours). Their mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score within 24 hours of admission to the ICU was 21.3 +/- 6.3 and survival rate was 31.6%. Urea nitrogen and creatinine concentrations were determined every 6 to 12 hours in both serum (Cun and Cc, respectively) and effluent (spent dialysate and/or ultrafiltrate). The mean effluent rate was 1,472 +/- 580 mL/h and blood flow rate, 166 +/- 32 mL/min. Urine was collected daily for urea nitrogen and creatinine measurement. Urea nitrogen appearance rate (UnA) and creatinine production rate (Pc), calculated from urea nitrogen (UnMR) and creatinine mass removal (CMR) from both the effluent and the urine, using Garred mass balance equations and the Forbes-Bruining formula, allowed normalized protein catabolic rate (nPCR) and estimates of lean body mass (LBM) to be derived. Creatinine metabolic degradation rate (Dc), estimated by the Mitch formula, was included in the calculation. The lowest body weight recorded during the study period was considered as dry weight (BW). The creatinine index (CI) was also obtained. For each parameter, the results are presented as mean, median, and range values: UnMRe (from effluent), 13.6 +/- 7.2, 12.5, 1.6 to 32.6 mg/min; UnMRu (from urine), 0.13 +/- 0.40, 0, 0 to 2.30 mg/min; UnA, 13.6 +/- 7.0, 12.5, 3.8 to 32.1 mg/min; nPCR, 1.75 +/- 0.82, 1.60, 0.61 to 4.23 g/kg/d; CMRe (from effluent), 942.0 +/- 362.3, 918.0, 211.2 to 1,641.6 mg/d; CMRu (from urine), 44.4 +/- 138.8, 0, 0 to 698.5 mg/d; Dc, 94.6 +/- 49.9, 81.9, 31.0 to 294.1 mg/d; Pc total, 1,067.1 +/- 409.7, 1,053.7, 261.5 to 1,988.2 mg/d; LBM, 38.3 +/- 11.9, 37.9, 15.0 to 65.0 kg; LBM/BW ratio, 49.5% +/- 14.0%, 50.3%, 22.5% to 86.0%; and CI, 13.7 +/- 4.7, 14.2, 4.1 to 25.8 mg/kg/d. When Pc was estimated from the Cockcroft-Gault equations (as Pc'), the mean value for Pc and Pc' was similar (1,067.1 +/- 409.7 v 1,284.9 +/- 484.1 mg/d), but there were relatively large differences for the majority of cases. A positive correlation was observed between UnA and Pc (R = 0.42). Serum albumin and LBM/BW correlated poorly (R = 0.20). Outcome was weakly related to UnA and to nPCR (R = 0.29 and R = 0.31, respectively). Urea nitrogen appearance appears widely variable in critically ill ARF patients. This simple approach can provide useful information for an easy estimate of net protein catabolism in critically ill patients with ARF undergoing CRRT.

Background Recent trends in parathyroidectomy rates are not known. Our objective was to investigate the trend in parathyroidectomy rates between 2001 and 2010, and to evaluate if the availability and reimbursement of cinacalcet modified that trend. Methods Using a provincial administrative database, we included all adult patients receiving chronic dialysis treatments between 2001 and 2010 (incident and prevalent) in a time series analysis. The effect of cinacalcet availability on parathyroidectomy bimonthly rates was modeled using an ARIMA intervention model using different cut-off dates: September 2004 (Health Canada cinacalcet approval), January 2005, June 2005, January 2006, June 2006 (date of cinacalcet provincial reimbursement), and January 2007. Results A total of 12 795 chronic dialysis patients (mean age 64 years, 39% female, 82% hemodialysis) were followed for a mean follow-up of 3.3 years. During follow-up, 267 parathyroidectomies were identified, translating to an average rate of 7.0 per 1000 person-years. The average parathyroidectomy rate before cinacalcet availability was 11.4 /1000 person-years, and 3.6 /1000 person-years after cinacalcet public formulary listing. Only January 2006 as an intervention date in the ARIMA model was associated with a change in parathyroidectomy rates (estimate: -5.58, p = 0.03). Other intervention dates were not associated with lower parathyroidectomy rates. Conclusions A reduction in rates of parathyroidectomy was found after January 2006, corresponding to cinacalcet availability. However, decreased rates may be due to other factors occurring simultaneously with cinacalcet introduction and further studies are needed to confirm these findings.

Inherited hemolytic-uremic syndrome (HUS) is unusual. We report the occurrence of HUS in two siblings; one died at an early age while the other (the proband) has presented with three episodes of HUS since the age of 19 years. The finding of a persistently low serum C3 level in this patient led to a thorough evaluation of her complement cascade and a family investigation. The proband and her asymptomatic younger sister were found to have very low serum levels (5% of normal) of factor H, a regulatory protein of the alternative complement pathway. Both patients had low levels of serum C3, factor B, CH50 and VAH50, reflecting persistent alternative pathway activation. The father and mother both had half-normal serum factor H levels but an otherwise normal complement profile. Other members of the extended pedigree were also found to have half-normal serum factor H levels. In conclusion, in this family, factor H deficiency appears to be associated with HUS and is transmitted as an autosomal recessive trait. Persistent C3 hypocomplementemia in the setting of familial and/or recurrent HUS should be a clue to a possible inherited complement deficiency.

A continuous dialysis technique such as continuous arteriovenous hemodialysis (CAVHD) could be an interesting alternative to frequent intermittent hemodialysis to treat acute renal failure (ARF) secondary to tumor lysis syndrome (TLS). However, because of massive release of intracellular solutes in TLS, CAVHD clearances need to be increased to treat this syndrome. Continuous arteriovenous hemodialysis using a high dialysate flow rate at 4 L/hr was assessed in TLS and ARF associated with severe hyperphosphatemia. A 0.6-m 2 hollow-fiber polyacrylonitrile dialyzer (Multiflow 60; Hospal, St-Leonard, Quebec, Canada) was used. Blood urea nitrogen and serum creatinine levels decreased, respectively, from 102.5 to 27.2 mg/dL and from 3.1 to 1.8 mg/dL during the 36 hours of treatment. Serum urate concentration was normal at the beginning of treatment (4.5 mg/dL) and decreased to 2.1 mg/dl by the end of CAVHD. Serum phosphorus decreased from 16.7 to 4.4 mg/dL after the 36 hours of treatment. The calcium × phosphorus product decreased from 111.1 to 42.1 by 28 hours and remained under 50 thereafter. Serum potassium was easily controlled with the addition of 2.5 mEq/L of KCI in dialysate and replacement solutions. No rebound increases in phosphorus or potassium were noted after cessation of therapy. Continuous arteriovenous hemodialysis clearances of urea, creatinine, phosphorus, and urate were measured at 2-hour intervals for the first 24 hours and at 4-hour intervals for the remaining 12 hours. They were 53.0 ± 2.3 mL/min, 43.7 ± 2.2 mL/min, 40.4 ± 1.9 mL/min, and 39.3 ± 1.9 mL/min (n =15), respectively. The 24-hour CAVHD clearance of urea was 76 L, which is equivalent to 8.5 hours of conventional hemodialysis. Extraction of phosphorus and potassium with CAVHD was, respectively, 8.28 g and 188.5 mEq for 36 hours. In conclusion, CAVHD optimized by high dialysate flow rate becomes a powerful purifying technique for the treatment of ARF and TLS. It provides excellent continuous clearances of small molecular weight solutes, resulting in a rapid and sustained control of serum urate, potassium, and calcium × phosphorus product, avoiding the potentially deleterious rebound effects seen after hemodialysis.

Background Reliable biomarkers are needed to identify patients with glomerular disease at risk of progression. Transforming growth factor beta 1 (TGF-β1) and monocyte chemotactic protein 1 (MCP-1) play key roles in promoting renal tissue injury. Whether their urinary measurement adds value to current predictors of progression is uncertain. Methods We enrolled patients with diabetic (n=53) and nondiabetic (n=47) proteinuric renal disease and retrospectively studied their rate of renal function decline over a defined period of 2 years. We simultaneously measured urinary protein, MCP-1 and TGF-β1, standardized to urinary creatinine. Results The initial estimated glomerular filtration rate, proteinuria and rate of renal function decline (slope) were 36 ml/min per 1.73 m2, 1.1 g/day and -4.0 ± 7.2 ml/ min per 1.73 m2 year. Median urinary TGF-β1 and MCP- 1 levels were 0.3 (range 0.0-28.1) and 18 (range 3-370) ng/mmol of creatinine, respectively. Urinary protein and MCP-1 to creatinine ratios were associated with slope, and this applied to both diabetic and nondiabetic patients separately. Urinary TGF-β1 showed no relation to slope. However, the majority of its measurements were below the suggested reproducibility threshold. Using linear regression, both normalized urinary protein and MCP-1 were independently associated with the slope. Adding urinary MCP-1 to the model statistically raised the adjusted R2 from 0.35 to 0.40, refining patient risk stratification. Using cutoffs for urinary protein and MCP-1 obtained by receiver operating characteristic curves, the risk of progression was confidently determined in 80% of patients. Conclusion Urinary MCP-1 is a marker of renal function decline in diabetic and nondiabetic proteinuric renal disease, independent of and additive to proteinuria.

The purpose of this study was to determine the effects of high inlet dialysate flow rates (IDFR) on the clearances of urea and creatinine and to measure the absorption of glucose through the dialyzer in continuous arteriovenous hemodialysis (CAVHD). Ten anuric acute renal failure patients in the intensive care unit were studied. Increasing the IDFR from 0 to 33.3 mL/min (0 to 2 L/h) produced linear increments in the clearances of urea and creatinine, whereas further increases in the IDFR from 33.3 to 66.7 mL/min (2 to 4 L/h) produced less important, but still significant, increases in the clearances. At 66.7 mL/min, the clearances for urea and creatinine were 48.5 ± 3.4 and 42.2 ± 2.5 mL/min, respectively. Using a dialysate with a glucose concentration of 25.3 mmol/L (0.5 g/dL), the net transfer of glucose through the dialyzer did not change significantly, from 16.7 to 66.7 mL/min of IDFR. Increasing the inlet dialysate glucose concentration from 25.3 to 75.8, 126.3, and 214.6 mmol/L (0.5 to 1.5, 2.5, and 4.25 g/dL) at a fixed IDFR of 16.7 mL/min produced linear increments in the net glucose transferred to the patient, from 0.12 ± 0.02 to 0.67 ± 0.05, 1.25 ± 0.06 and 2.30 ± 0.14 mmol/min, respectively (21.4, 121.0, 225.7, and 414.5 mg/min). No significant changes in the ultrafiltration and plasma flow rates through the dialyzer were recorded at these different IDFR or inlet dialysate glucose concentrations. Ten patients were treated for 4 days or more with 16.7 mL/min (1 L/h) IDFR CAVHD with excellent control over kidney function parameters. We conclude that CAVHD with an IDFR of 16.7 mL/min is generally sufficient to control uremia, as it yields urea clearances of 35 L/d, equivalent to 4 hours of conventional hemodialysis. Since 60% of the glucose is absorbed through the dialyzer, intradialytic parenteral nutrition can be achieved with dialysate solutions containing glucose concentrations of 75.8 and 126.3 mmol/L (1.5 and 2.5 g/dL) yielding 2,900 to 5,500 kJ/d (700 to 1,300 kcal/24 h). High IDFR of 66.7 mL/min provide daily urea clearances of 70 L, equivalent to 8 hours of daily conventional hemodialysis. Potential new applications of such high IDFR CAVHD include lithium and methanol intoxications, as well as hyperkalemia, hyperuricemia, hyperphosphatemia, and hypercalcemia.

High levels of proteinuria predict renal deterioration, suggesting that interventions to reduce proteinuria may postpone the development of severe renal impairment. This multicenter Canadian trial evaluated whether supramaximal dosages of candesartan would reduce proteinuria to a greater extent than the maximum approved antihypertensive dosage. The authors randomly assigned 269 patients who had persistent proteinuria (or =1 g/d) despite 7 wk of treatment with the highest approved dosage of candesartan (16 mg/d) to 16, 64, or 128 mg/d candesartan for 30 wk. The median serum creatinine level was 130.0 micromol/L (1.47 mg/dl), and the median urinary protein excretion was 2.66 g/d; most (53.9%) patients had diabetic nephropathy. The mean difference of the percentage change in proteinuria for patients receiving 128 mg/d candesartan compared with those receiving 16 mg/d candesartan was -33.05% (95% confidence interval -45.70 to -17.44; P0.0001). Reductions in BP were not different across the three treatment groups. Elevated serum potassium levels (K+5.5 mEq/L) led to the early withdrawal of 11 patients, but there were no dosage-related increases in adverse events. In conclusion, proteinuria that persists despite treatment with the maximum recommended dosage of candesartan can be reduced by increasing the dosage of candesartan further, but serum potassium levels should be monitored during treatment.

Drug metabolism can be affected by chronic renal failure (CRF). Although it is known that several drugs that are known to be acetylated accumulate in CRF, the effect of CRF on N-acetyltransferase (NAT), the enzyme responsible for this acetylation, is unknown. Herein is reported that protein and gene expression of both Nat isoforms in the liver was reduced by >30% and Nat2 activity was reduced by 50% in rats with CRF compared with control rats. Incubation of hepatocytes with serum from rats with CRF suggested that a circulating factor is responsible for the decrease in protein and gene expression. For testing the hypothesis that parathyroid hormone may be this factor, CRF was induced in parathyroidectomized rats; downregulation of Nat expression and activity was not observed in these rats. Furthermore, addition of parathyroid hormone to cultured hepatocytes induced a decrease in Nat2 protein and gene expression. In conclusion, liver acetylation of drugs in a rat model of CRF is reduced by a downregulation of Nat1 and Nat2 isoforms, secondary to decreased gene expression. Parathyroid hormone seems to be an important mediator of this phenomenon.

Encapsulating peritoneal sclerosis is a rare, but potentially lethal, complication of peritoneal dialysis. Treatment of patients with encapsulating peritoneal sclerosis is controversial. Conservative treatment carries a poor outcome, and immunosuppressive drugs are now used frequently. Most commonly, these immunosuppressive regimens include steroids with or without azathioprine or cyclosporine. Mycophenolate mofetil is a reversible DNA synthesis inhibitor that frequently replaces azathioprine in renal transplantation because of its improved immunosuppressive potency and better side-effect profile. We report 3 cases of encapsulating peritoneal sclerosis in continuous ambulatory peritoneal dialysis patients for which an association of prednisone and mycophenolate mofetil significantly modified the evolution of the disease. All 3 patients showed significant improvement within a month and are still alive more than 2 years after the diagnosis of encapsulating peritoneal sclerosis. None experienced a relapse or abdominal symptoms, and body weights are stable. This is the first report of 3 cases of successful treatment of patients with encapsulating peritoneal sclerosis with prednisone and mycophenolate mofetil.

Secondary hyperparathyroidism develops early in patients with chronic kidney disease (CKD). Clinical guidelines from the National Kidney Foundation-Kidney/Disease Outcomes Quality Initiative emphasize the need to control parathyroid hormone (PTH), calcium, and phosphorus levels in patients with CKD not receiving dialysis to reduce poor outcomes. This phase 2 study evaluated the effects of the oral calcimimetic cinacalcet hydrochloride in patients with CKD not on dialysis therapy.A randomized, double-blind, placebo-controlled, 18-week study enrolled adults with an estimated glomerular filtration rate of 15 to 50 mL/min/1.73 m2 (0.25 to 0.83 mL/s/1.73 m2) and an intact PTH (iPTH) level greater than 130 pg/mL (ng/L). Cinacalcet (or placebo) was titrated from 30 to 180 mg once daily to obtain a 30% or greater reduction in iPTH levels from baseline.Baseline mean iPTH levels were 243 pg/mL (ng/L) in the cinacalcet group (n = 27) and 236 pg/mL (ng/L) in the control group (n = 27). At baseline, 28% of subjects were being administered vitamin D sterols and 43% were being administered phosphate binders or calcium supplements. The addition of cinacalcet significantly decreased iPTH concentrations compared with controls during the efficacy-assessment phase: 56% versus 19% of subjects achieved a 30% or greater reduction in iPTH levels (P = 0.006), and mean iPTH levels decreased by 32% in the cinacalcet group, but increased by 6% in the control group (P0.001). Mean serum calcium and phosphorus levels remained within normal range throughout the study. Cinacalcet generally was well tolerated; the most frequent adverse events were gastrointestinal.This preliminary study provides evidence that cinacalcet is efficacious for the treatment of secondary hyperparathyroidism in subjects with CKD not receiving dialysis.

Background: Over the last decade, the age of dialysis patients has been increasing steadily in several units in Canada. Our main objective was to assess prevalence, co-morbidity and outcome of ESRD patients over 75 years old at the beginning of dialysis treatment in our center. As a group, they were compared to younger dialysis patients treated simultaneously. Methods: In the last 5 years, all cases beginning dialysis in our institution who were above 75 years of age were reviewed, as well as cases aged between 50 and 60 years who started dialysis during the same period. Between January 1996 and December 2000, among a total of 429 new chronic dialysis patients, 67 ESRD patients over 75 years (15.6%) and 66 patients between 50 and 60 years (15.4%) began dialysis treatment. Results – Primary and Secondary: Diabetes was present in 37% of elderly and in 56% of the younger patients. Younger patients had been referred earlier to our nephrologists than the older ones (42 vs. 27%). Elderly were more frequently treated by hemodialysis than peritoneal dialysis (81 vs. 19%) when compared to their younger counterparts (65 vs. 35%). Long-term catheters for hemodialysis were used more often in elderly patients. No renal transplantation were performed in older patients while 7 younger patients received a renal graft. Survival rates after 1 and 3 years were, respectively, 93 and 74% for patients between 50 and 60 years, whereas it decreased to 80 and 45% for those over 75 years (p = 0.002). More than 50% of patients older than 75 years died within 2 years after starting dialysis; their mean survival was 31 months; patients starting dialysis between 50 and 60 years survived on the average 44 months during the study period. According to the multivariate logistic regression model, risk factors for increased mortality in the older group were: number of hospitalization days during the past 3 months (OR 34.8, 95% CI 8.3–145.7, p < 0.001) and lower weight (OR 16.6, 95% CI 2.0–139.0, p = 0.001). Conclusion: We may conclude that, in our hands, life expectancy of patients who began dialysis above 75 years is significantly shorter than for patients for whom dialysis is initiated between age 50 and 60 years, especially if they have a low weight, lose weight and/or require hospitalization.

Dialysate leakage represents a major noninfectious complication of peritoneal dialysis (PD). An exit-site leak refers to the appearance of any moisture around the PD catheter identified as dialysate; however, the spectrum of dialysate leaks also includes any dialysate loss from the peritoneal cavity other than via the lumen of the catheter. The incidence of dialysate leakage is somewhat more than 5% in continuous ambulatory peritoneal dialysis (CAPD) patients, but this percentage probably underestimates the number of early leaks. The incidence of hydrothorax or pleural leak as a complication of PD remains unclear. Factors identified as potentially related to dialysate leakage are those related to the technique of PD catheter insertion, the way PD is initiated, and weakness of the abdominal wall. The pediatric literature tends to favor Tenckhoff catheters over other catheters as being superior with respect to dialysate leakage, but no consensus on catheter choice exists for adults in this regard. An association has been found between early leaks (< or =30 days) and immediate CAPD initiation and perhaps median catheter insertion. Risk factors contributing to abdominal weakness appear to predispose mostly to late leaks; one or more of them can generally be identified in the majority of patients. Early leakage most often manifests as a pericatheter leak. Late leaks may present more subtly with subcutaneous swelling and edema, weight gain, peripheral or genital edema, and apparent ultrafiltration failure. Dyspnea is the first clinical clue to the diagnosis of a pleural leak. Late leaks tend to develop during the first year of CAPD. The most widely used approach to determine the exact site of the leakage is with computed tomography after infusion of 2 L of dialysis fluid containing radiocontrast material. Treatments for dialysate leaks include surgical repair, temporary transfer to hemodialysis, lower dialysate volumes, and PD with a cycler. Recent recommendation propose a standard approach to the treatment of early and late dialysate leaks: 1-2 weeks of rest from CAPD, and surgery if recurrence. Surgical repair has been strongly suggested for leakage causing genital swelling. Delaying CAPD for 14 days after catheter insertion may prevent early leakage. Initiating CAPD with low dialysate volume has also been recommended as a good practice measure. Although peritonitis and exit-site infections are the most frequent causes of technical failure in peritoneal dialysis (PD), dialysate leaks represent one of the major noninfectious complications of PD. In some instances, dialysate leakage may lead to discontinuation of the technique (1). Despite its importance, the incidence, risk factors, management, and outcome of dialysate leakage are poorly characterized in the literature. We will review the limited available information on this topic in the next few sections.

Chronic renal failure (CRF) is associated with a decrease in drug metabolism. The mechanism remains poorly understood. The present study investigated the repercussions of CRF on liver cytochrome P450 (CYP450). Three groups of rats were defined: control, control paired-fed, and CRF. Total CYP450 activity, protein expression of several CYP450 isoforms as well as their mRNA, and the in vitro N-demethylation of erythromycin were assessed in liver microsomes. The regulation of liver CYP450 by dexamethasone and phenobarbital was assessed in CRF rats. Compared with control and control paired-fed rats, creatinine clearance was reduced by 60% (P:0.01) in CRF rats. Weight was reduced by 30% (P:0.01) in control paired-fed and CRF rats, compared with control animals. There was no difference in the CYP450 parameters between control and control paired-fed. Compared with control paired-fed rats, total CYP450 was reduced by 47% (P:0.001) in CRF rats. Protein expression of CYP2C11, CYP3A1, and CYP3A2 were considerably reduced (40%, P:0.001) in rats with CRF. The levels of CYP1A2, CYP2C6, CYP2D, and CYP2E1 were the same in the three groups. Northern blot analysis revealed a marked downregulation in gene expression of CYP2C11, 3A1, and 3A2 in CRF rats. Although liver CYP450 was reduced in CRF, its induction by dexamethasone and phenobarbital was present. N-demethylation of erythromycin was decreased by 50% in CRF rats compared with control (P:0.001). In conclusion, CRF in rats is associated with a decrease in liver cytochrome P450 activity (mainly in CYP2C11, CYP3A1, and 3A2), secondary to reduced gene expression.

Objectives: To determine the serum status in folate, pyridoxal-5′-phosphate (the active moiety of pyridoxine), cobalamin, and total homocysteine of chronic dialysis patients not routinely supplemented with B-complex vitamins and to evaluate induced intradialytic losses during high-efficiency hemodialysis. Design: A cross-sectional study. Setting: A university medical center providing tertiary care. Patients: Thirty-six chronic dialysis patients (23 men and 13 women, mean age 57 ± 13 years) treated since 3.8 ± 2.2 years by hemodialysis and not supplemented with hydrosoluble vitamins. Methods: Thrice-weekly hemodialysis was performed using CT-190G (Baxter, IL) or F-20 (Hospal, St-Leonard, Canada) reused dialyzers with a mean blood flow rate of 371 ± 40 mL/min, a dialysate flow rate of 500 mL/min, and a mean session time of 3.7 ± 0.4 hours. Prehemodialysis serum vitamin B 12 and homocysteine, and predialysis and postdialysis serum folate, pyridoxal-5′-phosphate, and urea were measured. Blood-side folate and pyridoxal-5′-phosphate clearances were calculated. Results: Predialysis serum total homocysteine was above normal in all patients, with values ranging from 14.4 to 158.0 μmol/L (mean 40.2 ± 29.6 μmol/L, median 33.5 μmol/L). Whereas the majority, 21 patients, had evidence of coronary, cerebrovascular, and/or peripheral vascular diseases, there was no difference in total homocysteine in patients with or without vascular disease (respectively, 40.8 ± 37.0 μmol/L v 39.4 ± 15.1 μmol/L, P = NS). Predialysis serum concentrations of pyridoxal-5′-phosphate were reduced in 20 patients (56%) and were in the lower normal range for 14 patients. Predialysis and postdialysis serum folate concentrations were 12.4 ± 6.1 nmol/L and 8.6 ± 3.6 nmol/L, whereas predialysis and postdialysis serum pyridoxal-5′-phosphate concentrations were 11.1 ± 7.5 nmol/L and 8.0 ± 5.9 nmol/L. Percent reduction ratios were 68.4% ± 6.6% for urea, 26.3% ± 16.0% for folates, and 27.9% ± 14.2% for pyridoxal-5′-phosphate. Blood-side clearances reached 134.7 ± 22.2 mL/min for folates and 54.4 ± 38.2 mL/min for pyridoxal-5′-phosphate. There was no significant difference in predialysis serum folate and pyridoxal-5′-phosphate in patients with or without evidence of vascular disease. Conclusion: This study confirms that: (1) total serum homocysteine levels are very high in chronic hemodialysis patients not supplemented with B-complex vitamins; (2) folate is significantly cleared or lost during high-efficiency hemodialysis; and (3) pyridoxal-5′-phosphate, the active moiety of pyridoxine, is depleted in most chronic hemodialysis patients without supplementation and that high-efficiency hemodialysis contributes to its depletion.

poisoning They infused 95% ethanol at the dialysate inlet tubing of the dialyser at a constant rate of 40 ml/min. They added phosphate in the base concentrate of the dialys

Although ammonium acid urate (AAU) stones are endemic in Asia, pure AAU calculi have almost disappeared from industrialized countries and clinical pathophysiologic relevance of sporadic stones containing AAU crystals is currently unknown. We reviewed 1,396 crystallographic stone analyses performed in our institution over a 10-year period. Prevalence of stones containing AAU crystals and predominantly AAU stones were 3.1% and 0.2%, respectively. In more than two thirds of cases, AAU crystals represented less than 10% of stone crystal composition. No pure AAU stone was found. According to crystalline predominance, 42%, 35%, and 12% of these calculi were uric acid, infectious, and calcium oxalate stones, respectively. AAU crystals were detected as discrete intercrystalline or peripheral deposits in 74.4% of stones. In only one calculus was AAU crystals detected in the nucleus. The hospital charts of 37 patients who presented with 43 calculi containing AAU crystals were also reviewed. The mean age was 53.1 +/- 16.6 years. Fifty-seven percent of calculi were upper urinary tract stones and 43% were bladder stones. Upper urinary tract calculi were more frequently uric acid stones, followed by infectious and calcium oxalate stones. Lower urinary tract calculi were more frequently infectious stones, followed by uric acid stones. Upper urinary tract stones were passed spontaneously in 13 patients and removed surgically in nine patients. Nine of these subjects were idiopathic recurrent stone formers who had passed other calculi with no trace of AAU crystal. Fifty-seven percent of lower urinary tract stones were associated with documented bladder dysfunction. In conclusion, although AAU-containing urolithiases are occasionally seen in our population, predominantly or primarily AAU stones are exceptional. AAU crystal formation usually appears as a minor and secondary phenomenon of no primary pathophysiologic relevance in stone formation.

Organ transplantation is associated with an early bone loss that subsequently increases the risk of osteopenia and bone fractures. It is not known whether bone loss continues in long-term survivors, but persistent bone demineralization could further jeopardize an already diminished bone mass. To better define long-term bone status of kidney transplant recipients (KTR), we conducted cross-sectional and longitudinal evaluations of bone mineral density (BMD) in 70 KTR with a mean posttransplantation time of 8.1 years. BMD was determined by dual-energy X-ray absorptiometry and was repeated in 55 of the patients after a mean follow-up period of 22 +/- 5 months. Lumbar and femoral osteopenia, defined as a BMD lower than 2 standard deviations from mean value of sex- and age-matched controls, was present in 28.6% and 10.5% of patients, respectively. There was a significant negative correlation between cumulative prednisone dose and adjusted lumbar as well as femoral BMD (R = 0.45, P0.001 and R = 0.29, P0.05, respectively). Five patients had a vertebral BMD below a fracture threshold of 0.777 g/cm2. Vertebral fractures (VF) were found in four men and were associated with higher prednisone dosage (P0.05), larger cumulative prednisone dose (P0.05), and significantly lower BMD values. According to World Health Organization recent criteria for women, prevalences of lumbar and femoral osteopenia and lumbar and femoral osteoporosis in female patients reach 75%, 65%, 33%, and 10%, respectively. The longitudinal part of the study showed a persistent pathological lumbar demineralization process. Over the study period, BMD, expressed as a percentage of that of controls, decreased from 89 +/- 14% to 86 +/- 14% (P0.001). Annual change of bone mass was -1.7 +/- 2.8% per year. Accelerated vertebral bone loss (defined as a decrease of BMD, expressed as a percentage of that of controls, of more than 1% per year) was present in 56% of patients and was associated with higher prednisone dosage (P0.01). In conclusion, although VF are relatively infrequent in long-term survivors of renal transplantation, osteopenia is a frequent finding, and a substantial proportion of women present lumbar osteoporosis. An ongoing demineralization process of the spine is also demonstrated and probably contributes to long-term spinal osteoporosis incidence. Prednisone dosage remains the most constantly isolated risk factor.

Intermittent hemodialysis is considered the modality of choice when enhanced lithium removal is indicated. However, postdialysis rebound in serum lithium concentration is frequently observed after the dialysis sessions and results from incomplete intracellular removal. Continuous renal replacement therapy could provide a more gradual and complete lithium removal since it is performed over longer time periods, thus avoiding rebound following therapy. Seven patients presenting with symptomatic lithium intoxication were treated by continuous renal replacement therapy (continuous arteriovenous and venovenous hemodiafiltration [CAVHDF and CVVHDF]). For CAVHDF, the dialysate flow rate was increased to 4 L/hr to optimize solute clearances. Five intoxicated patients (four acute and one chronic) were treated by high dialysate flow rate (HDFR) (4 L/hr) CAVHDF and two patients with chronic poisoning were treated by CVVHDF, one with a dialysate flow rate of 1 L/hr and one with a dialysate flow rate of 2 L/hr. Serum lithium concentrations for the four acute poisoning cases were 4.0, 4.6, 4.4, and 3.2 mEq/L, at initiation of HDFR CAVHDF, and decreased respectively to 1.2, 0.8, 1.2, and 1.1 mEq/L after 15, 19, 35, and 21 hours of treatment. No lithium rebound was observed over 24 to 36 hours following CAVHDF. For the three chronic intoxication cases, serum lithium concentrations dropped from 1.7, 2.2, and 3.8 mEq/L to 0.7, 0.17, and 0.4 mEq/L, respectively, after 18, 42, and 44 hours of HDFR CAVHDF or CVVHDF. The chronic case treated for only 18 hours presented a slight rebound in lithium level (0.3 mEq/L), whereas no significant rebound was observed for the two other cases treated for longer periods. Mean +/- SEM dialyser urea, lithium, and creatinine clearance during HDFR CAVHDF were 50.5 +/- 5.0, 41.4 +/- 4.6, and 37.6 +/- 3.7 mL/min, respectively (number of measurements = 41). Dialyser lithium clearance during CVVHDF was 48.4 +/- 1.4 mL/min (n = 10) and 61.9 +/- 2.3 mL/min (n = 7), with dialysate flow rates of 1 and 2 L/hr, respectively. Mean dialyzer lithium removal for the seven cases was 106.4 mEq, while mean renal lithium removal was 21.5 mEq during the same period. We conclude that HDFR CAVHDF and CVVHDF are effective alternatives to intermittent hemodialysis for treatment of lithium poisoning. They provide excellent lithium clearances (60 to 85 L/d); in addition, because of their continuous nature, they prevent posttherapy lithium rebound by allowing a more gradual and complete removal from intracellular compartments, and they may be particularly useful in chronic poisoning in which intracellular lithium accumulation is more extensive.