Cognitive performance is associated with glomerular filtration rate in patients with chronic kidney disease: results from the CKD-REIN cohort.

BACKGROUND: Chronic kidney disease (CKD) is associated with cognitive impairment in general population. We assessed the association between kidney and cognitive functions in patients with CKD and the influence of cardiovascular (CV) risk factors, and depression on this association. METHODS: The CKD-Renal Epidemiology and Information Network cohort included 3033 patients with CKD stages 3-4, followed for 5 years. Cognitive function was assessed with the Mini-Mental State Examination (MMSE) and estimated glomerular filtration rate (eGFR) with the CKD-Epidemiology Collaboration equation-creatinin formula. Evolution of the MMSE score over time and its association with baseline eGFR were investigated with linear mixed models. We assessed the risk of incident cognitive outcome (hospitalisation or death with relevant International Classification of Disease-10 codes), with a Cox proportional hazard model. RESULTS: The mean age was 66.8, the mean eGFR was 33 mL/min/1.73 m2 and 387 patients (13.0%) had an MMSE score below 24 at baseline. A 10 mL/min/1.73 m2 decrement of baseline eGFR was associated with a mean MMSE decrease of 0.12 (95% CI 0.04 to 0.19) after adjustment for demographic characteristics, depression, CV risk factors and disease; but baseline eGFR was not associated with MMSE temporal evolution. HR for cognitive outcome during follow-up (median 2.01 years) associated with a 10 mL/min/1.73 m2 decrement of baseline eGFR was 1.35 (1.07, 1.70) (p=0.01) after adjustment. CONCLUSIONS: In patients with CKD, lower eGFR was associated with worse cognitive performance and incident cognitive events, independently of demographics, CV risk factors and depression. TRIAL REGISTRATION NUMBER: NCT03381950.

MRI-based kidney radiomic analysis during chronic lithium treatment.

BACKGROUND: Lithium therapy during bipolar disorder is associated with an increased risk of chronic kidney disease (CKD) that is slowly progressive and undetectable at early stages. We aimed at identifying kidney image texture features as possible imaging biomarkers of decreased measured glomerular filtration rate (mGFR) using radiomics of T2-weighted magnetic resonance imaging (MRI). METHODS: One hundred and eight patients treated with lithium were evaluated including mGFR and kidney MRI, with T2-weighted sequence single-shot fast spin-echo. Computed radiomic analysis was performed after kidney segmentation. Significant features were selected to build a radiomic signature using multivariable Cox analysis to detect an mGFR <60 ml/min/1.73 m². The texture index was validated using a training and a validation cohort. RESULTS: Texture analysis index was able to detect an mGFR decrease, with an AUC of 0.85 in the training cohort and 0.71 in the validation cohort. Patients with a texture index below the median were older (59 [42-66] vs. 46 [34-54] years, p = .001), with longer treatment duration (10 [3-22] vs. 6 [2-10] years, p = .02) and a lower mGFR (66 [46-84] vs. 83 [71-94] ml/min/1.73m², p < .001). Texture analysis index was independently and negatively associated with age (ß = -.004 ± 0.001, p < .001), serum vasopressin (-0.005 ± 0.002, p = .02) and lithium treatment duration (-0.01 ± 0.003, p = .001), with a significant interaction between lithium treatment duration and mGFR (p = .02). CONCLUSIONS: A renal texture index was developed among patients treated with lithium associated with a decreased mGFR. This index might be relevant in the diagnosis of lithium-induced renal toxicity.

Higher mortality risk among kidney transplant recipients than among estimated glomerular filtration rate-matched patients with CKD-preliminary results.

BACKGROUND: Although kidney transplantation prolongs survival relative to dialysis, it is associated with a higher death rate than in the general population. The objective of the present study was to assess and compare the risk of mortality and frequency of non-lethal cardiovascular (CV) events in kidney transplant recipients (KTRs) beyond 1 year after successful transplantation versus patients with chronic kidney disease (CKD) using propensity score-matched analysis of estimated glomerular filtration rate (eGFR) and other parameters. METHODS: After propensity score matching, we studied 340 KTRs from the French Données Informatisées et Validées en Transplantation cohort and 605 non-transplant patients with CKD (CKDps) from the French Chronic Kidney Disease-Renal Epidemiology and Information Network cohort. The mean ± standard deviation eGFR was 42 ± 13 and 41 ± 12 mL/min/ 1.73 m2, respectively (P = 0.649). Descriptive data were completed by a survival analysis with Cox regression models. RESULTS: After a median follow-up period of 2.8 years (KTRs 2.0 years, CKDp 2.9 years), 71 deaths were recorded (31 and 40 in the KTR and CKD groups, respectively). Univariate analysis showed that KTRs had a significantly greater risk of mortality than CKDps. In multivariable analysis, KTRs were found to have a 2.7-fold greater risk of mortality [hazard ratio 2.7 (95% confidence interval 1.6-4.7); P = 0.005]. There was no between-group difference concerning the risk of CV events (P = 0.448). CV death rates in KTRs (29.0%) approximated those of CKDps (22.5%), whereas death rates due to infections were higher in KTRs (19.4% versus 10.0%). CONCLUSION: Beyond 1 year after transplantation, KTRs, who possibly had a longer CKD history, had a significantly greater mortality risk than eGFR-matched CKDps. The excess risk was not associated with CV events.

Difference in Profiles of the Gut-Derived Tryptophan Metabolite Indole Acetic Acid between Transplanted and Non-Transplanted Patients with Chronic Kidney Disease.

BACKGROUND: Uremic toxins have emerged as potential mediators of morbidity and mortality in patients with chronic kidney disease (CKD). Indole-3-acetic acid (IAA, a tryptophan-derived uremic toxin) might be a useful biomarker in patients with CKD. The objectives of the present study were to (i) describe IAA concentrations in a cohort of non-transplanted patients with CKD and a cohort of transplanted patients with CKD, and (ii) investigate the possible relationship between IAA levels and adverse outcomes in the two cohorts. METHODS: Levels of free and total IAA were assayed in the two prospective CKD cohorts (140 non-transplanted patients and 311 transplanted patients). Cox multivariate analyses were used to evaluate the association between IAA levels and outcomes (mortality, cardiovascular events, and graft loss). RESULTS: In the non-transplanted CKD cohort, free and total IAA increased progressively with the CKD stage. In the transplanted CKD cohort, free and total IAA levels were elevated at the time of transplantation but had fallen substantially at one-month post-transplantation. Indole acetic acid concentrations were lower in transplanted patients than non-dialysis non-transplanted patients matched for estimated glomerular filtration rate (eGFR), age, and sex. After adjustment for multiple confounders, the free IAA level predicted overall mortality and cardiovascular events in the non-transplanted CKD cohort (hazard ratio [95% confidence interval]: 2.5 [1.2-5.1] and 2.5 [1.3-4.8], respectively). In the transplanted CKD cohort, however, no associations were found between free or total IAA on one hand, and mortality, CV event, or graft survival on the other. CONCLUSION: We demonstrated that levels of IAA increase with the CKD stage, and fall substantially, even normalizing, after kidney transplantation. Free IAA appears to be a valuable outcome-associated biomarker in non-transplanted patients, but-at least in our study setting-not in transplanted patients.

Chronic Lithium Therapy and Urine-Concentrating Ability in Individuals With Bipolar Disorder: Association Between Daily Dose and Resistance to Vasopressin and Polyuria.

Introduction: Lithium treatment can induce nephrogenic diabetes insipidus (NDI), but no consensus intervention is offered to date. We evaluated in these patients patterns of urine concentration and the correlates of 24-hour urine output. Methods: Prospective, single-center, observational study of 217 consecutive lithium-treated individuals, with 24-hour urine collection, desmopressin (1-deamino-arginine vasopressin [DDAVP]) concentrating test, fasting plasma vasopressin measurement (copeptin measurement in n = 119), and measured glomerular filtration rate (mGFR). Maximal urine osmolality (MaxUosm) was the highest level during the DDAVP test. Results: Of the individuals, 21% displayed polyuria (>3 l/d), but 55% displayed elevated fasting vasopressin level (>5 pg/ml). Uosm was significantly lower and urinary output and free water clearance were significantly higher in individuals treated for >10 years. MaxUosm was >600 mOsm/KgH2O in 128 patients (59%), among which vasopressin was increased in 51%, associated with higher lithium dose (950 [750-1200] vs. 800 [500-1000] mg/d, P < 0.001). All patients with lithium daily dose ≥1400 mg/d had high vasopressin levels. In multivariable analysis, 24-hour urine output was associated with higher lithium daily dose (ß 0.49 ± 0.17, P = 0.005), female sex (ß -359 ± 123, P = 0.004), daily osmolar intake (ß 2.21 ± 0.24, P < 0.001), MaxUosm (ß -2.89 ± 0.35, P < 0.001), and plasma vasopressin level (ß 10.17 ± 4.76, P = 0.03). Conclusion: Higher lithium daily dose was associated with higher vasopressin levels and higher urine output, independently of other factors. Daily osmolar intake was also associated with higher 24-hour urine output. These results suggest that controlled salt and protein intake and lithium dose might reduce polyuria in these patients.

[Prevalence of chronic kidney disease in France, Esteban study 2014-2016]. / Prévalence de la maladie rénale chronique en France, Esteban 2014­2016.

BACKGROUND: The epidemiology of chronic kidney disease remains poorly described in France despite its burden. The objective of our study was to provide an estimate of the prevalence of chronic kidney disease stades 3-5 (without replacement therapy) in France. METHOD: The data come from the Esteban study carried out in France between 2014 and 2016 on a representative sample of the French population. This study included 3,021 adults between 18 and 74 years old. Of these, 2422 adults (80.2%) had serum creatinine assay and were included in this analysis. Renal function was estimated by calculating glomerular filtration rate using the Chronic kidney disease epidemiology collaboration (CKD-Epi) and European Kidney function consortium (EKFC) equations. RESULTS: The means glomerular filtration rate in our population were respectively 97.5 and 89.0 mL/min/1.73 m2 with the CKD-EPI and EKFC equations. The prevalence of chronic renal failure, defined by a glomerular filtration rate less than 60 mL/min/1.73 m2 was 1.5% with the CKD-EPI formula and 2.1% with the EKFC formula in adults aged 18 to 74 years. The prevalence was higher in women than in men and increased with age, reaching 6.5% and 9.9% in 65-74 years with the CKD-EPI and EKFC equations, respectively. After extrapolation to the French population, the number of adults with chronic kidney disease stades 3-5 without renal replacement therapy was around 1.6 million. CONCLUSION: In France, the prevalence of chronic kidney disease stades 3-5 without renal replacement therapy was between 1.5 and 2.1% of the adult population aged 18 to 74.

Primary Hyperparathyroidism in Homozygous Sickle Cell Patients: A Hemolysis-Mediated Hypocalciuric Hypercalcemia Phenotype?

Primary hyperparathyroidism (pHPT) has been reported to have a higher prevalence in sickle cell disease (SCD) patients, including a high rate of recurrence following surgery. However, most patients are asymptomatic at the time of diagnosis, with surprisingly infrequent hypercalciuria, raising the issue of renal calcium handling in SCD patients. We conducted a retrospective study including (1) 64 hypercalcemic pHPT non-SCD patients; (2) 177 SCD patients, divided into two groups of 12 hypercalcemic pHPT and 165 non-pHPT; (3) eight patients with a diagnosis of familial hypocalciuric hypercalcemia (FHH). Demographic and biological parameters at the time of diagnosis were collected and compared between the different groups. Determinants of fasting fractional excretion of calcium (FeCa2+) were also analyzed in non-pHPT SCD patients. Compared to non-SCD pHPT patients, our data show a similar ionized calcium and PTH concentration, with a lower plasmatic calcitriol concentration and a lower daily urinary calcium excretion in pHPT SCD patients (p < 0.0001 in both cases). Fasting FeCa2+ is also surprisingly low in pHPT SCD patients, and thus inadequate to be considered hypercalcemia, recalling the FHH phenotype. FeCa2+ is also low in the non-pHPT SCD control group, and negatively associated with PTH and hemolytic biomarkers such as LDH and low hemoglobin. Our data suggest that the pHPT biochemical phenotype in SCD patients resembles the FHH phenotype, and the fasting FeCa2+ association with chronic hemolysis biomarkers strengthens the view of a potential pharmacological link between hemolytic by-products and calcium reabsorption, potentially through a decreased calcium-sensing receptor (CaSR) activity.

Less arterial stiffness in kidney transplant recipients than chronic kidney disease patients matched for renal function.

BACKGROUND: Chronic kidney disease is associated with a high cardiovascular risk. Compared with glomerular filtration rate-matched CKD patients (CKDps), we previously reported a 2.7-fold greater risk of global mortality among kidney transplant recipients (KTRs). We then examined aortic stiffness [evaluated by carotid-femoral pulse wave velocity (CF-PWV)] and cardiovascular risk in KTRs compared with CKDps with comparable measured glomerular filtration rate (mGFR). METHODS: We analysed CF-PWV in two cohorts: TransplanTest (KTRs) and NephroTest (CKDps). Propensity scores were calculated including six variables: mGFR, age, sex, mean blood pressure (MBP), body mass index (BMI) and heart rate. After propensity score matching, we included 137 KTRs and 226 CKDps. Descriptive data were completed by logistic regression for CF-PWV values higher than the median (>10.6 m/s). RESULTS: At 12 months post-transplant, KTRs had significantly lower CF-PWV than CKDps (10.1 versus 11.0 m/s, P = 0.008) despite no difference at 3 months post-transplant (10.5 versus 11.0 m/s, P = 0.242). A lower occurrence of high arterial stiffness was noted among KTRs compared with CKDps (38.0% versus 57.1%, P < 0.001). It was especially associated with lower mGFR, older age, higher BMI, higher MBP, diabetes and higher serum parathyroid hormone levels. After adjustment, the odds ratio for the risk of high arterial stiffness in KTRs was 0.40 (95% confidence interval 0.23-0.68, P < 0.001). CONCLUSIONS: Aortic stiffness was significantly less marked in KTRs 1 year post-transplant than in CKDps matched for GFR and other variables. This observation is compatible with the view that the pathogenesis of post-transplant cardiovascular disease differs, at least in part, from that of CKD per se.

[Sodium metabolism: An update in 2019]. / Métabolisme du sodium : une mise au point en 2019.

The classical theory of sodium metabolism considers mostly its role on the extracellular volume according to a daily response to the variations of salt intake, correlated to the variations of water volume. Recent works consider sodium tissular storage. This non-osmotic pool could play a role in blood pressure regulation and in immunity mechanisms. The regulation modalities could be more complex, organised over the long term, with a modification of the sodium-water relationship. The aim of this article is to give a new insight on sodium metabolism, based on recent works, especially on the role and regulation of non osmotic tissular sodium.

[End stage kidney disease in Maghreb and Africa: Overview of transplant programs in Maghreb and Africa]. / Insuffisance rénale terminale au Maghreb et en Afrique : panorama des programmes de transplantation au Maghreb et en Afrique.

Kidney transplantation is the best treatment for the patient with end stage kidney disease in term of increasing the survival rate, reducing complications, improving quality of live and its lower cost compared to peritoneal dialysis or hemodialysis. However, the number of patients waiting for kidney transplantation is growing day by day and the gap between demand and supply is still huge. This situation is even more complicated in developing countries where the lack of legislation, infrastructure and government involvement is common. Some national transplantation programs have been implemented, with the support of the International Society for Transplantation and the International Society of Nephrology, in order to increase the transplantation activity of these countries in accordance with the Istanbul Declaration on organ trafficking and transplant tourism.

[Middle-molecule uremic toxins: A renewed interest]. / Toxines urémiques de moyen poids moléculaire : un véritable regain d'intérêt.

Cardiovascular mortality in patients with chronic kidney disease remains a major problem. The uremic toxins among which the molecules of middle molecular weight are counted contribute significantly to this high mortality, alongside the traditional risk factors. They generate and maintain a chronic inflammatory state called low-level chronic inflammatory state. A growing interest in these molecules has been noted for some years and the uremic toxins associated with this cardiovascular mortality are currently identified: FGF23, cytokines, pentraxin-3 and recently light chains. The existence of an interaction between uremic toxins, inflammation and/or oxidative stress and cardiovascular mortality is well reported in the various epidemiological studies. While the use of anti-oxidative therapies and/or antibodies against uremic toxins or their site of action have not yet yielded a real benefit, hopes are turning to the use of new hemodialysis membranes medium cut-off (MCO), which have the advantage of purifying the uremic toxin middle molecules without a significant loss of albumin. However, additional works are needed to demonstrate the use of these membranes will lead to modulate the morbi-mortality in the dialysis patients.

Uremic Toxins and Clinical Outcomes: The Impact of Kidney Transplantation.

Non-transplanted and transplanted patients with chronic kidney disease (CKD) differ in terms of mortality and the risk of clinical events. This difference is probably due to the difference of both traditional and non-traditional risk factors. Uremic retention solutes may constitute important non-traditional risk factors in this population. In the present review, we selected a set of uremic toxins that have been associated with harmful effects, and are an appealing target for adjuvant therapy in CKD. For each toxin reviewed here, relevant studies were selected and the relationship with hard clinical outcomes of uremic toxins were compared between non-transplanted CKD patients and transplanted patients taking into account the level of glomerular filtration rate in these two situations.

[Pulmonary ultrasound and dialysis]. / Échographie pulmonaire en dialyse.

Profound deficit of the body fluid composition regulation system is present at the end stage kidney disease, leading to the increase the risk of acute or chronic volume overload, which impacts the morbidity and mortality in these patients. Pulmonary ultrasound by its ability to estimate extrapulmonary water at an infraclinical stage has helped to make progress in this area. Line B is the element of fundamental semiology that reflects the presence of water in the pulmonary alveoli. The alteration of left ventricular function and the increase of pulmonary capillary permeability are the determining factors in the genesis of subclinical pulmonary congestion and are positively correlated with B-lines. Because of its non-invasive nature, its ease of use, its intra- and interoperability reproducibility and its ease of learning, nephrologists can be efficiently and quickly trained to use it to measure pulmonary congestion. Recent data have shown an epidemiological association between B-lines and mortality in end stage kidney disease patients. The causal role of subclinical pulmonary congestion assessed by these B lines in the genesis of detrimental events is being evaluated by a randomized, multicentre, open-label European clinical trial (Lung water by ultra-sound guided treatment [LUST] trial). The clinical usefulness of pulmonary ultrasound in the management of subclinical pulmonary congestion in patients with end stage kidney disease remains to be determined, but it could be considered from now as an additional tool to improve the management of this congestion, possibly by complementing bioimpedancemetry data.

From arterial stiffness to kidney graft microvasculature: Mortality and graft survival within a cohort of 220 kidney transplant recipients.

BACKGROUND: Aortic stiffness assessed by carotid-femoral pulse wave velocity (CF-PWV) is a predictor of mortality in several populations. However, little is known in kidney transplant recipients. Our objectives were to evaluate the ability of CF-PWV measured 3 months following transplantation to predict mortality, graft loss and its potential links to measured Glomerular Filtration Rate (mGFR) or kidney graft microvasculature parameters. METHODS: The study is based on a monocentric retrospective cohort including 220 adult kidney graft recipients evaluated three months after transplantation. CF-PWV measures, clinical, laboratory and histological data performed at 3 (M3) and 12 months (M12) following transplantation were retrospectively collected. The two primary endpoints were all-cause mortality and occurrence of end stage renal disease (ESRD) defined by initiation of dialysis. RESULTS: After a median follow up of 5.5 years [1.9; 8.8], death and graft loss occurred in 10 and 12 patients respectively. M3 CF-PWV was an independent mortality risk factor (HR = 1.29 [1.03; 1.61]; p = 0.03), despite no aortic stiffness variation during the first year of transplantation. Of notice, M3 CF-PWV was not associated with M12 mGFR or ESRD outcome. Graft microcirculation assessed by Banff vascular fibrous intimal thickening score (cv) worsened between M3 and M12 (p = 0.01), but no link was found with CF-PWV, mGFR or ESRD outcome. Surprisingly, acute rejections at M3 were associated after adjustment with mortality (p = 0.03) but not ESRD. CONCLUSION: Aortic stiffness measured 3 months after kidney transplantation is a strong predictor of mortality with no obvious influence on kidney graft microvasculature or graft loss.