Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers for Advanced Chronic Kidney Disease : A Systematic Review and Retrospective Individual Participant-Level Meta-analysis of Clinical Trials.

BACKGROUND: In patients with advanced chronic kidney disease (CKD), the effects of initiating treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) on the risk for kidney failure with replacement therapy (KFRT) and death remain unclear. PURPOSE: To examine the association of ACEi or ARB treatment initiation, relative to a non-ACEi or ARB comparator, with rates of KFRT and death. DATA SOURCES: Ovid Medline and the Chronic Kidney Disease Epidemiology Collaboration Clinical Trials Consortium from 1946 through 31 December 2023. STUDY SELECTION: Completed randomized controlled trials testing either an ACEi or an ARB versus a comparator (placebo or antihypertensive drugs other than ACEi or ARB) that included patients with a baseline estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. DATA EXTRACTION: The primary outcome was KFRT, and the secondary outcome was death before KFRT. Analyses were done using Cox proportional hazards models according to the intention-to-treat principle. Prespecified subgroup analyses were done according to baseline age (<65 vs. ≥65 years), eGFR (<20 vs. ≥20 mL/min/1.73 m2), albuminuria (urine albumin-creatinine ratio <300 vs. ≥300 mg/g), and history of diabetes. DATA SYNTHESIS: A total of 1739 participants from 18 trials were included, with a mean age of 54.9 years and mean eGFR of 22.2 mL/min/1.73 m2, of whom 624 (35.9%) developed KFRT and 133 (7.6%) died during a median follow-up of 34 months (IQR, 19 to 40 months). Overall, ACEi or ARB treatment initiation led to lower risk for KFRT (adjusted hazard ratio, 0.66 [95% CI, 0.55 to 0.79]) but not death (hazard ratio, 0.86 [CI, 0.58 to 1.28]). There was no statistically significant interaction between ACEi or ARB treatment and age, eGFR, albuminuria, or diabetes (P for interaction > 0.05 for all). LIMITATION: Individual participant-level data for hyperkalemia or acute kidney injury were not available. CONCLUSION: Initiation of ACEi or ARB therapy protects against KFRT, but not death, in people with advanced CKD. PRIMARY FUNDING SOURCE: National Institutes of Health. (PROSPERO: CRD42022307589).

A meta-analysis of randomized controlled clinical trials for implications of acute treatment effects on glomerular filtration rate for long-term kidney protection.

Pharmacologic interventions to slow chronic kidney disease progression, such as ACE-inhibitors, angiotensin receptor blockers, or sodium glucose co-transporter 2 inhibitors, often produce acute treatment effects on glomerular filtration rate (GFR) that differ from their long-term chronic treatment effects. Observational studies assessing the implications of acute effects cannot distinguish acute effects from GFR changes unrelated to the treatment. Here, we performed meta-regression analysis of multiple trials to isolate acute effects to determine their long-term implications. In 64 randomized controlled trials (RCTs), enrolling 154,045 participants, we estimated acute effects as the mean between-group difference in GFR slope from baseline to three months, effects on chronic GFR slope (starting at three months after randomization), and effects on three composite kidney endpoints defined by kidney failure (GFR 15 ml/min/1.73m2 or less, chronic dialysis, or kidney transplantation) or sustained GFR declines of 30%, 40% or 57% decline, respectively. We used Bayesian meta-regression to relate acute effects with treatment effects on chronic slope and the composite kidney endpoints. Overall, acute effects were not associated with treatment effects on chronic slope. Acute effects were associated with the treatment effects on composite kidney outcomes such that larger negative acute effects were associated with lesser beneficial effects on the composite kidney endpoints. Associations were stronger when the kidney composite endpoints were defined by smaller thresholds of GFR decline (30% or 40%). Results were similar in a subgroup of interventions with supposedly hemodynamic effects that acutely reduce GFR. For studies with GFR 60 mL/min/1.73m2 or under, negative acute effects were associated with larger beneficial effects on chronic GFR slope. Thus, our data from a large and diverse set of RCTs suggests that acute effects of interventions may influence the treatment effect on clinical kidney outcomes.

Determinants of protective humoral response to mRNA-1273 and BNT162b2 vaccines in peritoneal dialysis patients: a prospective cohort study.

Patients with chronic kidney disease (CKD) on dialysis have a higher mortality rate associated with SARS-CoV-2 infection. Although vaccines are now available, the protective response rates and determinants of humoral response to the vaccine are poorly described in patients on peritoneal dialysis. This was a prospective observational study describing the response rates of detectable and standardized protective antibody titers one month after each mRNA vaccine dose in a cohort of 88 patients on peritoneal dialysis. We found that the vast majority of patients produced protective levels of antibodies (73%) one month after the second vaccine dose. In the multivariate analysis, the single determinant for an adequate humoral response was the weekly Kt/V, a surrogate of dialysis dose. The response rate was higher, but not significantly, with the mRNA-1273 than with the BNT162b2 vaccine one month after the second dose (78.7 vs. 46.2%, respectively, p = 0.02). We found that patients on peritoneal dialysis had a satisfactory humoral response rate, which was much higher than in transplant recipients. PD patients with a poor humoral response, particularly those with a low wKT/V, may benefit from an additional dose of vaccine.

A randomized multicenter trial on a lung ultrasound-guided treatment strategy in patients on chronic hemodialysis with high cardiovascular risk.

Lung congestion is a risk factor for all-cause and cardiovascular mortality in patients on chronic hemodialysis, and its estimation by ultrasound may be useful to guide ultrafiltration and drug therapy in this population. In an international, multi-center randomized controlled trial (NCT02310061) we investigated whether a lung ultrasound-guided treatment strategy improved a composite end point (all-cause death, non-fatal myocardial infarction, decompensated heart failure) vs usual care in patients receiving chronic hemodialysis with high cardiovascular risk. Patient-Reported Outcomes (Depression and the Standard Form 36 Quality of Life Questionnaire, SF36) were assessed as secondary outcomes. A total of 367 patients were enrolled: 183 in the active arm and 180 in the control arm. In the active arm, the pre-dialysis lung scan was used to titrate ultrafiltration during dialysis and drug treatment. Three hundred and seven patients completed the study: 152 in the active arm and 155 in the control arm. During a mean follow-up of 1.49 years, lung congestion was significantly more frequently relieved in the active (78%) than in the control (56%) arm and the intervention was safe. The primary composite end point did not significantly differ between the two study arms (Hazard Ratio 0.88; 95% Confidence Interval: 0.63-1.24). The risk for all-cause and cardiovascular hospitalization and the changes of left ventricular mass and function did not differ among the two groups. A post hoc analysis for recurrent episodes of decompensated heart failure (0.37; 0.15-0.93) and cardiovascular events (0.63; 0.41-0.97) showed a risk reduction for these outcomes in the active arm. There were no differences in patient-reported outcomes between groups. Thus, in patients on chronic hemodialysis with high cardiovascular risk, a treatment strategy guided by lung ultrasound effectively relieved lung congestion but was not more effective than usual care in improving the primary or secondary end points of the trial.

Dialysis dose and mortality in haemodialysis: is higher better?

BACKGROUND: The effect of dialysis dose on mortality remains unsettled. Current guidelines recommend targeting a single-pool Kt/V (spKt/V) at 1.20-1.40 per thrice-weekly dialysis session. However, the optimal dialysis dose remains mostly disputed. METHODS: In a nationwide registry of all incident patients receiving thrice-weekly haemodialysis, 32 283 patients had available data on dialysis dose, estimated by Kt/V and its variants epuration volume per session (Kt) and Kt indexed to body surface area (Kt/A). Survival was analysed with a multivariate Cox model and a concurrent risk model accounting for renal transplantation. A predictive model of Kt in the upper quartile was developed. RESULTS: Regardless of the indicator, a higher dose of dialysis was consistently associated with better survival. The survival differential of Kt was the most discriminating, but marginally, compared with the survival differential according to Kt/V and Kt/A. Patient survival was higher in the upper quartile of Kt (>69 L/session) then deteriorated as the Kt decreased, with a difference in survival between the upper and lower quartile of 23.6% at 5 years. Survival differences across Kt distribution were similar after accounting for kidney transplantation as a competing risk. Predictive factors for Kt in the upper quartile were arteriovenous fistula versus catheters and graft, haemodiafiltration versus haemodialysis, scheduled dialysis start versus emergency start, long weekly dialysis duration and spKt/V measurement versus double-pool equilibrated Kt/V. CONCLUSIONS: Our data confirm the existence of a relationship between dialysis dose and survival that persisted despite correcting for known confounders. A model for predicting a high dose of dialysis is proposed with practical relevance.

Impact of the dialysate acid component on haemodialysis mortality rates.

BACKGROUND: No prospective study has evaluated the long-term effect on mortality of the new acid concentrates added to bicarbonate dialysate. The aim of this pharmacoepidemiological study was to evaluate the association between hydrochloric or citric acid-based dialysate and mortality on haemodialysis (HD). METHODS: This study included 117 796 patients with 3 723 887 months on HD recorded in the national French Renal Epidemiology and Information Network registry. Dialysate acid components were retrospectively reconstructed for each facility. All patients on HD were associated each month with an exposure based on that at their facility of treatment. We took each patient's time-varying exposure into account to calculate the monthly mortality rates for each exposure. Incidence rate ratios (IRRs) for mortality were calculated with a Poisson regression, with acetic acid as the reference. Regressions were adjusted for initial clinical characteristics (age, gender, previous cardiovascular events, active malignancy, diabetes, pulmonary disease, mobility), dialysis technique and location (in-centre, outpatient centre, self-care unit) and ESRD vintage, updated monthly. RESULTS: The crude mortality rate per 1000 patient-months with citric acid {11.5 [95% confidence interval (CI) 11.1-12.0]} was lower than with either acetic acid [12.9 (95% CI 12.8-13.1)] or hydrochloric acid [12.8 (95% CI 12.2-13.5)]. For the 2014-17 period, the IRR for mortality with citric acid [adjusted IRR 0.94 (95% CI 0.90-0.99)] and with hydrochloric acid [adjusted IRR 0.86 (95% CI 0.79-0.94)] were significantly lower than with acetic acid. CONCLUSION: This post-marketing study of long-term exposure to dialysate acidifiers at the patient level found the use of citric and hydrochloric acid-based dialysates, compared with acetic acid, was associated with lower mortality.

Effect of adding vildagliptin to insulin in haemodialysed patients with type 2 diabetes: The VILDDIAL study, a randomized, multicentre, prospective study.

AIM: To evaluate the effect of adding the dipeptidyl-peptidase-4 inhibitor vildagliptin to insulin on the glycaemic control of patients with type 2 diabetes undergoing haemodialysis. METHODS: Overall, 65 insulin-treated patients with type 2 diabetes undergoing haemodialysis (HbA1c: 7.3% ± 1.1%; age: 70.5 ± 8.5 years) were randomized (1:1) either to receive vildagliptin 50 mg/day in addition to insulin (vildagliptin-insulin group) or to pursue their usual insulin regimen (insulin-only group). Continuous glucose monitoring (CGM) was performed for 48 ± 6 hours at baseline and at week 12. The primary study endpoint was change from baseline in mean interstitial glucose using CGM. The secondary endpoints included other CGM variables and glucose control markers. RESULTS: After 12 weeks, a greater reduction in mean CGM glucose from baseline was observed in the vildagliptin-insulin group compared with the insulin-only group, although the between-treatment difference was not statistically significant (mean difference [CI 95%]: -0.96 mmol/L [-2.09; 0.18] vs. -0.29 mmol/L [-1.29; 0.76], P = 0.32). However, a significant decrease from baseline in HbA1c, glycated albumin and insulin daily doses was observed in the vildagliptin-insulin group versus the insulin-only group (-0.6% [-1.19; -0.1], P < 0.01), in the vildagliptin-insulin group versus no change in the insulin-only group (-130.6 µmol/L [-271; 10.7] vs. +36.2 µmol/L [-164.4; 236.9], P = 0.04 and - 5.9 IU/day [-1.8; 7.1] vs. +1.1 IU/day [-14.5; 16.6], P = 0.01, respectively). There was no significant difference in the percentage of time spent in hypoglycaemia using CGM, occurrence of severe hypoglycaemia or number of adverse events. CONCLUSION: In this study, vildagliptin added to insulin improved glycaemic control with an associated insulin-sparing effect in patients with type 2 diabetes undergoing haemodialysis and was well tolerated.

Metabolic syndrome in haemodialysis patients: prevalence, determinants and association to cardiovascular outcomes.

BACKGROUND: In the general population, metabolic syndrome (MetS) is predictive of major adverse cardiovascular events (MACE). Waist circumference (WC), a component of the MetS criteria, is linked to visceral obesity, which in turn is associated with MACE. However, in haemodialysis (HD) patients, the association between MetS, WC and MACE is unclear. METHODS: In a cross-sectional study of 1000 HD patients, we evaluated the prevalence and characterised the clinical predictors of MetS. The relationship between MetS and its components, alone or in combination, and MACE (coronary diseases, peripheral arteriopathy, stroke or cardiac failure), was studied using receiver operating characteristics (ROC) curves and logistic regression. RESULTS: A total of 753 patients were included between October 2011 and April 2013. The prevalence of MetS was 68.5%. Waist circumference (> 88 cm in women, 102 cm in men) was the best predictor of MetS (sensitivity 80.2; specificity 82.3; AUC 0.80; p <  0.05). In multivariate analysis, MetS was associated with MACE (OR: 1.85; 95CI 1.24-2.75; p <  0.01), but not WC alone. There was a stronger association between the combination of abdominal obesity, hypertriglyceridaemia and low high-density lipoprotein cholesterol with MACE after exclusion of impaired fasting glucose and hypertension. CONCLUSIONS: MetS is frequent and significantly associated with MACE in our haemodialysis cohort and probably in other European dialysis populations as well. In HD patients, a new simplified definition could be proposed in keeping with the concept of the "hypertriglyceridaemic waist".

Relative prognostic impact of nutrition, anaemia, bone metabolism and cardiovascular comorbidities in elderly haemodialysis patients.

BACKGROUND: The prognostic impact of nutrition and chronic kidney disease (CKD) complications has already been described in elderly haemodialysis patients but their relative weights on risk of death remain uncertain. Using structural equation models (SEMs), we aimed to model a single variable for nutrition, each CKD complication and cardiovascular comorbidities to compare their relative impact on elderly haemodialysis patients' survival. METHODS: This prospective study recruited 3165 incident haemodialysis patients ≥75 years of age from 178 French dialysis units. Using SEMs, the following variables were computed: nutritional status, anaemia, mineral and bone disorder and cardiovascular comorbidities. Systolic blood pressure was also used in the analysis. Survival analyses used Poisson models. RESULTS: The population average age was 81.9 years (median follow-up 1.51 years, 35.5% deaths). All variables were significantly associated with mortality by univariate analysis. Nutritional status was the variable most strongly associated with mortality in the multivariate analysis, with a negative prognostic impact of low nutritional markers {incidence rate ratio [IRR] 1.42 per 1 standard deviation [SD] decrement [95% confidence interval (CI) 1.32-1.53]}. The 'cardiovascular comorbidities' variable was the second variable associated with mortality [IRR 1.19 per 1 SD increment (95% CI 1.11-1.27)]. A trend towards low intact parathyroid hormone and high serum calcium and low values of systolic blood pressure were also associated with poor survival. The variable 'anaemia' was not associated with survival. CONCLUSIONS: These findings should help physicians prioritize care in elderly haemodialysis patients with CKD complications, with special focus on nutritional status.

Outcomes of acute kidney injury depend on initial clinical features: a national French cohort study.

Background: Acute kidney injury (AKI) is a common condition that is associated with poor short- and long-term outcomes. The aim of this nationwide cohort study was to profile the long-term outcome of patients admitted for AKI in France. Methods: Based on the comprehensive French hospital discharge database, all hospitalizations for an AKI episode were categorized in four groups according to the presence of at least one dialysis session [renal replacement therapy (RRT)] and according to the coding of AKI as the principal or associated diagnosis (PRINC_DIAG or ASS_DIAG). Results: In this nationwide cohort of 989 974 patients (median age 77 years) hospitalized with AKI during the 2009-16 period, 422 739 (43%) patients died (235 572 during the first hospitalization) and 40 015 (4%) patients reached end-stage renal disease (ESRD) (5962 during first hospitalization) up to 31 December 2016. Patients without RRT and discharged from hospital had a cumulative incidence of ESRD that ranged from 5.3% (5.2-5.4) in the ASS_DIAG group to 28.7% (27.9-29.5) in the RRT-PRINC_DIAG group at 60 months. The cumulative incidence of death ranged from 31.0% (30.2-32.2) in the RRT-ASS_DIAG group to 45.5% (45.3-45.7) in the ASS_DIAG group. Initial clinical features were associated with outcome independent of comorbidities and age. Conclusions: The death penalty of AKI is abysmal and AKI was an important predisposing factor to chronic ESRD. Our study strengthens the current recommendations for long-term follow-up of patients with AKI. The novelty of this study is to propose a clinical classification of AKI episodes that is easy to detect in administrative medical databases and that is strongly associated with immediate and long-term outcomes.

Survival advantage of planned haemodialysis over peritoneal dialysis: a cohort study.

Background: Previous studies comparing the outcomes in haemodialysis (HD) with those in peritoneal dialysis (PD) have yielded conflicting results. Methods: The aim of the study was to compare the survival of planned HD versus PD patients in a cohort of adult incident patients who started renal replacement therapy (RRT) between 2006 and 2008 in the nationwide REIN registry (Réseau Epidémiologie et Information en Néphrologie). Patients who started RRT in emergency or stopped RRT within 2 months were excluded. Adjusted Cox models, propensity score matching and marginal structural models (MSMs) were used to compensate for the lack of randomization and provide causal inference from longitudinal data with time-dependent treatments and confounders including transplant censorship, modality change over time and time-varying covariates. Results: Among a total of 13 767 dialysis patients, 13% were on PD at initiation of RRT and 87% were on HD. The median survival times were 53.5 months or 4.45 years and 38.6 months or 3.21 years for patients starting on HD and PD, respectively. Regardless of the model used, there was a consistent advantage in terms of survival for HD patients: hazard ratio (HR) 0.76 [95% confidence interval (95% CI) 0.69-0.84] with the Cox model using propensity score; HR 0.67 (95% CI 0.62-0.73) in the Cox model with censorship for each treatment change; and HR 0.82 (95% CI 0.69-0.97) with MSMs. However, MSMs tended to reduce the survival gap between PD and HD patients. Conclusion: This large cohort study using various statistical methods to minimize the bias appears to demonstrate a better survival in planned HD than in PD.

Deleterious effects of dialysis emergency start, insights from the French REIN registry.

BACKGROUND: Emergency start (ES) of dialysis has been associated with worse outcome, but remains poorly documented. This study aims to compare the profile and outcome of a large cohort of patients starting dialysis as an emergency or as a planned step in France. METHODS: Data on all patients aged 18 years or older who started dialysis in mainland France in 2012 or in 2006 were collected from the Renal Epidemiology and Information Network and compared, depending on the dialysis initiation condition: ES or Planned Start (PS). ES was defined as a first dialysis within 24 h after a nephrology visit due to a life-threatening event. Three-year survival were compared, and a multivariate model was performed after multiple imputation of missing data, to determine the parameters independently associated with three-year survival. RESULTS: In 2012, 30.3% of all included patients (n = 8839) had ES. Comorbidities were more frequent in the ES than PS group (≥ 2 cardiovascular diseases: 39.2% vs 28.8%, p < 0.001). ES was independently associated with worse three-year survival (57% vs. 68.2%, p = 0.029, HR 1.10, 95% CI 1.01-1.19) in multivariate analysis. Among ES group, a large part had a consistent previous follow-up: 36.4% of them had ≥3 nephrology consultations in the previous year. This subgroup of patients had a particularly high comorbidity burden. ES rate was stable between 2006 and 2012, but some proactive regions succeeded in reducing markedly the ES rate. CONCLUSION: ES remains frequent and is independently associated with worse three-year survival, demonstrating that ES deleterious impact is never overcome. This study shows that a large part of patients with ES had a previous follow-up, but high comorbidity burden that could favor acute decompensation with life-threatening conditions before uremic symptoms appearance. This suggests the need of closer end-stage renal disease follow-up or early dialysis initiation in these high-risk patients.

Correction to: Deleterious effects of dialysis emergency start, insights from the French REIN registry.

Following publication of the original article [1], the authors reported that all of the authors' names were processed incorrectly so that their given and family names were interchanged.

Multiphasic effects of blood pressure on survival in hemodialysis patients.

Dialysis patients exhibit an inverse, L- or U-shaped association between blood pressure and mortality risk, in contrast to the linear association in the general population. We prospectively studied 9333 hemodialysis patients in France, aiming to analyze associations between predialysis systolic, diastolic, and pulse pressure with all-cause mortality, cardiovascular mortality, and nonfatal cardiovascular endpoints for a median follow-up of 548 days. Blood pressure components were tested against outcomes in time-varying covariate linear and fractional polynomial Cox models. Changes throughout follow-up were analyzed with a joint model including both the time-varying covariate of sequential blood pressure and its slope over time. A U-shaped association of systolic blood pressure was found with all-cause mortality and of both systolic and diastolic blood pressure with cardiovascular mortality. There was an L-shaped association of diastolic blood pressure with all-cause mortality. The lowest hazard ratio of all-cause mortality was observed for a systolic blood pressure of 165 mm Hg, and of cardiovascular mortality for systolic/diastolic pressures of 157/90 mm Hg, substantially higher than currently recommended values for the general population. The 95% lower confidence interval was approximately 135/70 mm Hg. We found no significant correlation for either systolic, diastolic, or pulse pressure with myocardial infarction or nontraumatic amputations, but there were significant positive associations between systolic and pulse pressure with stroke (per 10-mm Hg increase: hazard ratios 1.15, 95% confidence interval 1.07 and 1.23; and 1.20, 1.11 and 1.31, respectively). Thus, whereas high pre-dialysis blood pressure is associated with stroke risk, low pre-dialysis blood pressure may be both harmful and a proxy for comorbid conditions leading to premature death.

Low parathyroid hormone status induced by high dialysate calcium is an independent risk factor for cardiovascular death in hemodialysis patients.

Here we studied a possible association between low parathyroid hormone (PTH) status and mortality in incident patients undergoing hemodialysis . A total of 1983 patients were included at baseline and prospectively followed for 24 months. Patients were classified according to their Kidney Disease: Improving Global Outcomes PTH status at baseline and at 12 months, and mortality evaluated at 12 to 24 months using adjusted Cox analysis. Factors potentially involved in PTH status variability between baseline and 12 months were analyzed. A decrease in serum PTH from normal or high to low values between baseline and 12 months was associated with significantly increased cardiovascular mortality at 12 to 24 months (hazard ratio, 2.03; 95% confidence interval, 1.22-3.36). For patients with high or normal baseline PTH levels, the main independent factor at 6 months for a decrease to low PTH levels at 12 months was high dialysate calcium (1.75 mmol/L), whereas prescription of non-calcium-based phosphate binders was associated with a lower risk of PTH decrease. In the high cardiovascular (CV) mortality risk subgroup of patients who acquired a low PTH status at 12 months, the main independent factor at 12 months associated with significant 12- to 24-month CV mortality was high dialysate calcium (odds ratio, 5.44; 95% CI, 2.52-11.75). Thus, patients with a serum PTH decrease to low values after 1 year of hemodialysis treatment are at high risk of short-term CV death. High dialysate calcium was an important contributor to PTH oversuppression, and continued use was associated with increased CV mortality.

Efficacy of a remote web-based lung ultrasound training for nephrologists and cardiologists: a LUST trial sub-project.

Within the framework of the LUST trial (LUng water by Ultra-Sound guided Treatment to prevent death and cardiovascular events in high-risk end-stage renal disease patients), the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis Transplant Association established a central core lab aimed at training and certifying nephrologists and cardiologists participating in this trial. All participants were trained by an expert trainer with an entirely web-based programme. Thirty nephrologists and 14 cardiologists successfully completed the training. At the end of training, a set of 47 lung ultrasound (US) videos was provided to trainees who were asked to estimate the number of B-lines in each video. The intraclass correlation coefficient (ICC) for the whole series of 47 videos between each trainee and the expert trainer was high (average 0.81 ± 0.21) and >0.70 in all but five cases. After further training, the five underperforming trainees achieved satisfactory agreement with the expert trainer (average post-retraining ICC 0.74 ± 0.14). The Bland-Altman plot showed virtually no bias (difference between the mean 0.03) and strict 95% limits of agreement lines (-1.52 and 1.45 US B-lines). Only four cases overlapped but did not exceed the same limits. Likewise, the Spearman correlation coefficient applied to the same data series was very high (r = 0.979, P < 0.0001). Nephrologists and cardiologists can be effectively trained to measure lung congestion by an entirely web-based programme. This web-based training programme ensures high-quality standardization of US B-line measurements and represents a simple, costless and effective preparatory step for clinical trials targeting lung congestion.

Prognosis of patients with severe hyponatraemia is related not only to hyponatraemia but also to comorbidities and to medical management: results of an observational retrospective study.

BACKGROUND: The true cause of death in severe hyponatraemic patients remains controversial. The present study aimed to analyse the relationship between comorbidity, medical management and prognosis in severe hyponatraemic patients. METHODS: Medical records of all patients hospitalised in our institution in 2012 with a plasma sodium ≤120 mmol/l were retrospectively analysed. RESULTS: One hundred forty-seven of 64 723 adult patients (0.2 %) were identified with severe hyponatraemia. In-hospital mortality rate was 24.5 and 50.3 % after a median follow-up of 431 days. Patients with plasma sodium <110 mmol/l had less comorbidity (Charlson Comorbidity Index 2.2 ± 1.9 vs. 4.0 ± 3.1 (plasma sodium 110-115 mmol/l) and 4.2 ± 3.1 (plasma sodium 116-120 mmol/l); P = .02)) and a small trend for less mortality, respectively 40.0, 51.2 and 52.3 % (P = .64). At discharge, nonsurvivors and survivors had similar plasma sodium with 58.3 % of nonsurvivors being normonatraemic. Urine analysis was performed in 74.2 % of cases and associated with lower in-hospital mortality (20.2 % vs. 36.8 %, P = .05). In multivariate Cox analysis, mortality was significantly associated with plasma sodium normalisation (HR 0.35, P < 0.001), urine analysis (HR 0.48, P = .01), Charlson Comorbidity Index (HR 1.23, P < .001) and serum albumin (HR 0.88, P < .001). CONCLUSION: Mortality in severe hyponatraemia appears mainly due to comorbidities although the latter are potentiated by hyponatraemia itself and its management thereby exacerbating the risk of death.

Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1.

Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.