Is there an age cutoff to apply adult formulas for GFR estimation in children?

BACKGROUND: Estimation of glomerular filtration rate (eGFR) using a common formula for both adult and pediatric populations is challenging. Using inulin clearances (iGFRs), this study aims to investigate the existence of a precise age cutoff beyond which the Modification of Diet in Renal Disease (MDRD), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), or the Cockroft-Gault (CG) formulas, can be applied with acceptable precision. Performance of the new Schwartz formula according to age is also evaluated. METHOD: We compared 503 iGFRs for 503 children aged between 33 months and 18 years to eGFRs. To define the most precise age cutoff value for each formula, a circular binary segmentation method analyzing the formulas' bias values according to the children's ages was performed. Bias was defined by the difference between iGFRs and eGFRs. To validate the identified cutoff, 30% accuracy was calculated. RESULTS: For MDRD, CKD-EPI and CG, the best age cutoff was ≥14.3, ≥14.2 and ≤10.8 years, respectively. The lowest mean bias and highest accuracy were -17.11 and 64.7% for MDRD, 27.4 and 51% for CKD-EPI, and 8.31 and 77.2% for CG. The Schwartz formula showed the best performance below the age of 10.9 years. CONCLUSION: For the MDRD and CKD-EPI formulas, the mean bias values decreased with increasing child age and these formulas were more accurate beyond an age cutoff of 14.3 and 14.2 years, respectively. For the CG and Schwartz formulas, the lowest mean bias values and the best accuracies were below an age cutoff of 10.8 and 10.9 years, respectively. Nevertheless, the accuracies of the formulas were still below the National Kidney Foundation Kidney Disease Outcomes Quality Initiative target to be validated in these age groups and, therefore, none of these formulas can be used to estimate GFR in children and adolescent populations.

A prospective observational study comparing a non-operator dependent automatic PWV analyser to pulse pressure, in assessing arterial stiffness in hemodialysis.

BACKGROUND: Chronic kidney disease (CKD) accelerates vascular stiffening related to age. Arterial stiffness may be evaluated measuring the carotid-femoral pulse wave velocity (PWV) or more simply, as recommended by KDOQI, monitoring pulse pressure (PP). Both correlate to survival and incidence of cardiovascular disease. PWV can also be estimated on the brachial artery using a Mobil-O-Graph; a non-operator dependent automatic device. The aim was to analyse whether, in a dialysis population, PWV obtained by Mobil-O-Graph (MogPWV) is more sensitive for vascular aging than PP. METHODS: A cohort of 143 patients from 4 dialysis units has been followed measuring MogPWV and PP every 3 to 6 months and compared to a control group with the same risk factors but an eGFR > 30 ml/min. RESULTS: MogPWV contrarily to PP did discriminate the dialysis population from the control group. The mean difference translated in age between the two populations was 8.4 years. The increase in MogPWV, as a function of age, was more rapid in the dialysis group. 13.3% of the dialysis patients but only 3.0% of the control group were outliers for MogPWV. The mortality rate (16 out of 143) was similar in outliers and inliers (7.4 and 8.0%/year). Stratifying patients according to MogPWV, a significant difference in survival was seen. A high parathormone (PTH) and to be dialysed for a hypertensive nephropathy were associated to a higher baseline MogPWV. CONCLUSIONS: Assessing PWV on the brachial artery using a Mobil-O-Graph is a valid and simple alternative, which, in the dialysis population, is more sensitive for vascular aging than PP. As demonstrated in previous studies PWV correlates to mortality. Among specific CKD risk factors only PTH is associated with a higher baseline PWV. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02327962.

Preclinical Pharmacokinetics, Pharmacodynamics and Safety of Sucroferric Oxyhydroxide.

Sucroferric oxyhydroxide (VELPHORO(®)) is a polynuclear iron-based phosphate binder recently approved for the treatment of hyperphosphataemia in patients with chronic kidney disease (CKD). As a number of the available phosphate binders do not provide the optimal combination of good efficacy, adequate tolerability and low pill burden, sucroferric oxyhydroxide constitutes a promising alternative. Among the attributes of an ideal phosphate binder is minimal absorption and, hence, low risk of systemic toxicity. Accordingly, the iron-releasing properties and absorption, distribution, metabolism and excretion (ADME) profile of sucroferric oxyhydroxide, as well as the possibility of iron accumulation and toxicity, were investigated in a series of preclinical studies. The effect of sucroferric oxyhydroxide on the progression of vascular calcification was also investigated. Sucroferric oxyhydroxide exhibited a high phosphate-binding capacity and low iron-releasing properties across the physiological pH range found in the gastrointestinal tract. In the ADME studies, uptake of (59)Fe-radiolabelled sucroferric oxyhydroxide was low in rats and dogs (<1% from a 50 mg Fe/kg bodyweight dose), with the majority of absorbed iron located in red blood cells. Long-term (up to 2 years) administration of sucroferric oxyhydroxide in rats and dogs was associated with modest increases in tissue iron levels and no iron toxicity. Moreoever, in uraemic rats, sucroferric oxyhydroxide was associated with reduced progression of vascular calcification compared with calcium carbonate. In conclusion, sucroferric oxyhydroxide offers a new option for the treatment of hyperphosphataemia, with a high phosphate-binding capacity, minimal iron release, and low potential for iron accumulation and toxicity.

L'insuffisance rénale chronique: quelle est la diète optimale

The optimal diet for chronic kidney disease (CKD) is an issue frequently brought up by patients and/or their relatives during outpatient visits. For patients without malnutrition who are motivated and supported by an experienced multidisciplinary team, the optimal protein intake of 0,6 g/kg of ideal body weight/day is recommended to halt the progression of CKD. A calorie intake of 30 to 35 kcal/kg of ideal body weight/day is necessary to reduce the risk of malnutrition from a low protein diet and to maintain a neutral nitrogen balance. A low-salt diet, namely 5 to 6 g/d, is useful to optimize the treatment of hypertension associated with CKD and to limit fluid overload. At the advanced stage of CKD, it is also necessary to restrict the intake of phosphorus and sometimes potassium. Given the complexity of optimal renal diet, coordination between general practitioners, nephrologists and dietitians is essential to foster optimal care.

Eligibility to treatment and economic effect of the implementation of the new U.S. or European Society of Hypertension/European Society of Cardiology hypertension guidelines.

OBJECTIVE: To evaluate the population and economic impact of implementing the new Joint National Committee (JNC) or European Society of Hypertension (ESH)/European Society of Cardiology (ESC) hypertension guidelines in the Swiss population. METHODS: Cross-sectional, population-based sample (6708 participants) collected between 2003 and 2006 in the city of Lausanne, Switzerland. Blood pressure categories were defined according to both the JNC (JNC-7 and JNC-8) and the ESH/ESC (2007 and 2013) guidelines. RESULTS: The proportion of participants aged 35-60 years eligible for drug treatment was 25.6% [95% confidence interval (CI) 24.4-26.9%] and 24.8% (95% CI 23.6-26.0%) for the JNC-7 and the JNC-8 guidelines, respectively; for participants aged 60-75 years, the values were 62.3% (95% CI 60.1-64.5%) and 46.8% (95% CI 44.5-49.0%), respectively. Shifting from the JNC-7 to the JNC-8 guidelines would lead to an annual saving of 163.6 million Swiss francs (187.7 million US dollars or 134.5 million European euro). The proportion of participants aged 35-75 years without chronic kidney disease, diabetes mellitus or reported history of cardiovascular disease and eligible for treatment was 30.2% (95% CI 29.0-31.4%) for the ESH/ESC 2007 and 2013 guidelines. For participants with chronic kidney disease, diabetes mellitus or reported history of cardiovascular disease, the values were 73.6% (95% CI 70.8-76.3%) and 55.6% (95% CI 52.5-58.8%), respectively. Shifting from the ESH/ESC 2007 to the ESH/ESC 2013 guidelines would lead to an annual saving of 86.9 million Swiss francs (99.5 million US dollars or 71.4 million European euro). CONCLUSION: In Switzerland, shifting from the JNC-7 to the JNC-8 guidelines or from the ESH/ESC 2007 to the ESH/ESC 2013 guidelines would decrease the prevalence of patients eligible for treatment and increase the percentage of treated patients within blood pressure goals. Both strategies lead to potential savings in antihypertensive drug treatment.

N-WASP is required for B-cell-mediated autoimmunity in Wiskott-Aldrich syndrome.

Mutations of the Wiskott-Aldrich syndrome gene (WAS) are responsible for Wiskott-Aldrich syndrome (WAS), a disease characterized by thrombocytopenia, eczema, immunodeficiency, and autoimmunity. Mice with conditional deficiency of Was in B lymphocytes (B/WcKO) have revealed a critical role for WAS protein (WASP) expression in B lymphocytes in the maintenance of immune homeostasis. Neural WASP (N-WASP) is a broadly expressed homolog of WASP, and regulates B-cell signaling by modulating B-cell receptor (BCR) clustering and internalization. We have generated a double conditional mouse lacking both WASP and N-WASP selectively in B lymphocytes (B/DcKO). Compared with B/WcKO mice, B/DcKO mice showed defective B-lymphocyte proliferation and impaired antibody responses to T-cell-dependent antigens, associated with decreased autoantibody production and lack of autoimmune kidney disease. These results demonstrate that N-WASP expression in B lymphocytes is required for the development of autoimmunity of WAS and may represent a novel therapeutic target in WAS.

Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes.

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10(-7)) and 13% for RAB38/CTSC (P = 5.8 × 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.

Ganciclovir Exposure under a 450 mg Daily Dosage of Valganciclovir for the Prevention of Cytomegalovirus Disease in Kidney Transplant Recipients.

Background: It is suggested that a low dose of valganciclovir can be equally effective than a standard dose for cytomegalovirus (CMV) prophylaxis after kidney transplantation. The aim of our study was to determine the ganciclovir exposure observed under a routine daily dosage of 450 mg valganciclovir in kidney transplant recipients with a wide range of renal function. Methods: In this prospective study, kidney transplant recipients with a GFR MDRD above 25 mL/min at risk for CMV (donor or recipient seropositive for CMV) received a dose of valganciclovir (450 mg daily) prophylaxis for 3 months. Ganciclovir levels at trough (Ctrough) and at peak (C3h) were measured monthly. Ganciclovir exposure (AUC0-24) was estimated using Bayesian non-linear mixed-effect modelling (NONMEM) and compared between 3 groups of patients according to their kidney function: GFRMDRD 26-39 mL/min (Group 1), GFRMDRD 40-59 mL/min (Group 2) and GFRMDRD 60-90 mL/min (Group 3). CMV DNAemia was assessed during and after prophylaxis using PCR. Results: Thirty-six patients received 450 mg daily of valganciclovir for 3 months. Median ganciclovir C3h was 3.9 mg/L (range: 1.3-7.1) and Ctrough was 0.4 mg/L (range 0.1-2.7). Median (range) AUC0-24 of ganciclovir was 59.3 mg.h/L (39.0-85.3) in Group 1 patients, 35.8 mg.h/L (24.9-55.8) in Group 2 patients and 29.6 mg.h/L (22.0- 43.2) in Group 3 patients (p<0.001). Anemia was more common in Group 1 patients compared to patients on the other groups (p=0.01). No differences in other adverse events according to ganciclovir exposure were observed. CMV DNAemia was not detected during prophylaxis. After discontinuing prophylaxis, CMV DNAemia was seen in 8/34 patients (23.5%) and 4/36 patients (11%) developed CMV disease. Conclusion: A routine dosage of valganciclovir achieved plasma levels of ganciclovir in patients with GFR>60 mL/min similar to those previously reported using oral ganciclovir. A daily dose of 450 mg valganciclovir appears to be acceptable for CMV prophylaxis in most kidney transplant recipients.

Kidney transplantation in patients with Fabry disease

Introduction and Aims: Fabry disease is an X-linked lysosomal storage disorder caused by absence or deficient activity of the lysosomal enzyme alpha-galactosidase A. Renal manifestations occur early in life in a significant proportion of children, in many women and in almost all men with Fabry disease. These manifestations ultimately progress to end-stage renal disease in nearly all males and in some female patients. Data on kidney transplantation in patients with Fabry disease who are receiving enzyme replacement therapy (ERT), however, are scarce. Methods: We examined the clinical characteristics of kidney transplant recipients (KTRs) in the Fabry Outcome Survey (FOS) - a European database of patients with Fabry disease that was established to monitor the safety and outcome of ERT. Results: Of the 752 patients enrolled in FOS up to October 2005, 34 (4.5%) were reported to be KTRs. The mean age of these 32 male and 2 female patients was 45 ± 9 years, the median time since the transplant was 9 years, the median estimated glomerular filtration rate (eGFR) was 46 mL/min/1.73 m2 and the median level of proteinuria was 180 mg/24 hours. ERT was well tolerated, with mild infusion-related reactions reported in only one patient. Amongst these patients, 53% were reported to have hypertension, 71% left ventricular hypertrophy, 27% cardiac valve disease and 27% arrhythmia. A total of 23 (68%) of the patients (1 female, 22 males) were receiving ERT with agalsidase alfa (Replagal; Shire Human Genetic Therapies, UK), with a median duration of treatment of 2.5 years. There were no differences in age or time since transplantation between treated and untreated patients. The median eGFRs were 46 and 49 mL/min/1.73 m2 and the median levels of proteinuria were 200 and 160 mg/24 hours, respectively. Conclusions: KTRs represent a significant minority of individuals enrolled in a large international registry of patients with Fabry disease (FOS). Approximately two-thirds of KTRs with Fabry disease enrolled in FOS receive ERT with agalsidase alfa, which is well tolerated. Comparison of treated and untreated patients has the potential to examine effects of ERT on the progression of renal and cardiovascular disease.

Antinucleosome antibodies as a marker of active proliferative lupus nephritis.

BACKGROUND: Antinucleosome autoantibodies were previously described to be a marker of active lupus nephritis. However, the true prevalence of antinucleosome antibodies at the time of active proliferative lupus nephritis has not been well established. Therefore, the aim of this study is to define the prevalence and diagnostic value of autoantibodies against nucleosomes as a marker for active proliferative lupus nephritis. STUDY DESIGN: Prospective multicenter diagnostic test study. SETTING & PARTICIPANTS: 35 adult patients with systemic lupus erythematosus (SLE) at the time of the renal biopsy showing active class III or IV lupus nephritis compared with 59 control patients with SLE. INDEX TEST: Levels of antinucleosome antibodies and anti-double-stranded DNA (anti-dsDNA) antibodies. REFERENCE TEST: Kidney biopsy findings of class III or IV lupus nephritis at the time of sampling in a study population versus clinically inactive or no nephritis in a control population. RESULTS: Increased concentrations of antinucleosome antibodies were found in 31 of 35 patients (89%) with active proliferative lupus nephritis compared with 47 of 59 control patients (80%) with SLE. No significant difference between the 2 groups with regard to number of positive patients (P = 0.2) or antibody concentrations (P = 0.2) could be found. The area under the receiver operating characteristic curve as a marker of the accuracy of the test in discriminating between proliferative lupus nephritis and inactive/no nephritis in patients with SLE was 0.581 (95% confidence interval, 0.47 to 0.70; P = 0.2). Increased concentrations of anti-dsDNA antibodies were found in 33 of 35 patients (94.3%) with active proliferative lupus nephritis compared with 49 of 58 control patients (84.5%) with SLE (P = 0.2). In patients with proliferative lupus nephritis, significantly higher titers of anti-dsDNA antibodies were detected compared with control patients with SLE (P < 0.001). The area under the receiver operating characteristic curve in discriminating between proliferative lupus nephritis and inactive/no nephritis in patients with SLE was 0.710 (95% confidence interval, 0.60 to 0.82; P < 0.001). CONCLUSIONS: Antinucleosome antibodies have a high prevalence in patients with severe lupus nephritis. However, our data suggest that determining antinucleosome antibodies is of limited help in the distinction of patients with active proliferative lupus nephritis from patients with SLE without active renal disease.

Meningococcal disease in a kidney transplant recipient with mannose-binding lectin (MBL) deficiency

Background: There is an increasing amount of data associating MBL deficiency with a higher susceptibility to meningococca[ disease. In addition, meningococca[ disease has been reported in patients with various immunosuppressive conditions. However, to our knowledge, only three cases of meningococca[ disease have been reported in solid organ recipients (SOT). Methods & Results: A 32 year-old male patient underwent cadaveric kidney transplantation for endstage renal disease of unknown origin. On day 71 post-transplantation he developed fever (39.6°C), shaking chilis, and tachycardia without hypotension. At this time, immunosuppression consisted of tacro[imus, prednisone 10mg daily and mycopheno[ ate mofeti[ 2 g daily. Physical examination on admission was normal, except for two small petechia[ lesions on the forearm. No meningeal signs were present. Three sets of blood cultures grew Neisseria meningitidis group C susceptible to ceftriaxone (MIC=0.003mg/[). Antibiotic therapy consisted in intravenous ceftriaxone 2 g per day for a total duration of 7 days. Serum immunog[obu[in levels, C3, C4 and CHS0 were normal However, using a method to screen for the functional activity of a[[ three pathways of complement (Wies[ab, Lund, Sweden), no activation via the MBL pathway could be detected (0%). A subsequent quantification of MBL pathway components revealed normal levels of MASP 2 but undetectab[e amounts of MBL (below 10 ng/m[, normal range: >500 ng/m[). Conclusion: Since the exact incidence and the possible relationship between meningococca[ disease and organ transplantation is not we[[ understood, we strongly encourage transplantation centers to report additional cases. The potential clinical usefu[ ness of screening SOT candidates for MBL deficiency in relation to infectious complications after transplantation remains to be determined.