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Resume Introduction L’etat des lieux de la prise en charge de la maladie renale chronique avant le deploiement du forfait-parcours des patients est important a connaitre pour permettre d’en mesurer l’impact a terme. Patients et methodes Nous avons decrit la prise en charge en nephrologie sur 3 ans de 2835 patients ayant une maladie renale chronique moderee a severe, suivis dans la cohorte CKD-REIN entre 2013 et 2019, et son adequation au referentiel de la Haute Autorite de Sante en vigueur sur la periode. Resultats Le nombre moyen de consultations nephrologiques des patients (âge moyen 67 ans ; 65 % d’hommes ; 43 % de MRC stade 4 ou 5) augmentait de 1,1 a 2,7 par an, du stade 3A au stade 5 de la maladie renale chronique. Aux stades 3B, 4 et 5, respectivement 84, 63 et 33 % des patients avaient le nombre minimum de consultations de nephrologie recommande par la Haute Autorite de Sante. Au stade 4 ou 5 de la maladie renale chronique, seuls 34 et 40 % des patients, respectivement, avaient beneficie de consultation dietetique, et 33 et 54 % avaient recu des informations sur les options de traitement. Le delai moyen d’attente pour une premiere consultation de nephrologie etait plus long (60 vs 45 jours), et leur duree moyenne plus courte (30 vs 38 a 40 minutes) en CHU compare aux centres hospitaliers et aux etablissements prives. Conclusion L’ecart important constate entre les pratiques reelles et les recommandations temoigne des limites des ressources humaines et des organisations dans la prise en charge de la maladie renale chronique en nephrologie, pour lesquelles des avancees sont attendues avec le financement au forfait.

Chronic kidney disease is defined as an inability of the kidney to perform its normal functions and which persists beyond three months. Nowadays, the estimated glomerular filtration rate based on plasmatic creatinine level remains the gold standard to assess renal function. In Madagascar, we miss national data concerning the epidemiology of chronic kidney disease probably due to the complexity of carrying out the serum creatinine assays. The recent availability of creatinometer using a creatinine strip test with capillary creatinine facilitated the determination of the creatinine level in epidemiological study.This simple technique allowed us to plan a pilot study in Antananarivo, the capital of Madagascar. The main objective was to assess the prevalence of chronic kidney disease determined from capillary creatinine level. The secondary objective was to determine the factors associated with chronic kidney disease in Madagascar. It is an analytical cross-sectional study over a period of three months. Chronic kidney disease is defined as a decrease of the glomerular filtration rate of capillary creatinine less than 60mL/min/1.73mAt the end of the study, 210 people were randomized for screening. The average age was 40 years old with 14.9 as standard deviation. The sex ratio (male/female) was 1.76. The prevalence of chronic kidney disease was 13.8% with extreme values of 9,1 and 18.5. With chronic kidney disease, high blood pressure (hypertension) and diabetes were found respectively in 41.3 and 17.2%. Chronic kidney disease affected mainly in 72.4% of population aged 25 to 54 years old.This is the first study in Africa to screen chronic kidney disease using a creatinine strip test. This prevalence is relatively different compared to other African countries. The limits of the study are the absence of a subsequent control and/or double control of the creatinine, which definitively confirms the chronicity of kidney disease, the absence evaluation of the urinary sediments to determine proteinuria. Nevertheless, the results of our study can be used as data awaiting the results of a multicenter studies. To determine the national prevalence of chronic kidney disease, screening in the six provinces is currently in progress.

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.

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.

We present the case of a family whose members have high levels of serum calcium (hypercalcaemia) by loss of function of the enzyme vitamin D 24-hydroxylase due to bi-allelic mutations in the CYP24A1 gene: c.443 TC (p.Leu148Pro) and c.1187 GA (p.Arg396Gln). 24-VITD hydroxylase is a key player in regulating the circulating calcitriol, its tissue concentration and its biological effects. Transmission is recessive. The estimated prevalence of stones in the affected subjects is estimated between 10 and 15%. The loss of peripheral catabolism of vitamin D metabolites in patients with an inactivating mutation of CYP24A1 is responsible for persistent high levels of 1,25-dihydroxyvitamin D especially after sun exposure and a charge of native vitamin D. Although there are currently no recommendations (French review) on this subject, this disease should be suspected in association with recurrent calcium stones with nephrocalcinosis, and a calcitriol-dependent hypercalcaemia with adapted low parathyroid hormone levels. Resistance to corticosteroid therapy distinguishes it from other calcitriol-dependent hypercalcemia. A ratio of 25-hydroxyvitamin D/24.25 hydroxyvitamin D50, is in favor of hypercalcemia with vitamin D deficiency 24-hydroxylase. Genetic analysis of CYP24A1 should be performed at the second step. The current therapeutic management includes the restriction native vitamin D supplementation and the limitation of sun exposure. Biological monitoring will be based on serum calcium control and modulation of parathyroid hormone concentrations.

Preserving kidney function and improving the transition from chronic kidney disease to end stage is a research and healthcare challenge. The national Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort was established to identify the determinants, biomarkers and practice patterns associated with chronic kidney disease outcomes.The study will include more than 3000 adult patients with moderate to advanced chronic kidney disease from a representative sample of 40 nephrology clinics with respect to regions and legal status, public or private. Patients are recruited during a routine visit and followed for 5 years, before and after starting renal replacement therapy. Patient-level clinical, biological, and lifestyle data are collected annually, as well as provider-level data on clinical practices, coordinated with the International Chronic Kidney Disease Outcomes and Practice Pattern Study. Blood and urine samples are stored in a biobank. Major studied outcomes include survival, patient-reported outcomes, disease progression and hospitalizations.More than 13,000 eligible patients with chronic kidney disease were identified, 60% with stage 3 and 40% with stage 4. Their median age is 72 years [interquartile range, 62-80 years], 60% are men and 38% have diabetes. By the end of December 2015, 2885 patients were included.The CKD-REIN cohort will serve to improve our understanding of chronic kidney disease and provide evidence to improve patient survival and quality of life as well as health care system performances.

Resume Introduction Preserver la fonction renale et ameliorer la transition de la maladie renale chronique vers le stade terminal constituent un defi pour la nephrologie. La cohorte nationale Chronic Kidney Disease–Reseau Epidemiologie et Information en Nephrologie (CKD-REIN) a ete mise en place pour identifier les determinants, les biomarqueurs et les profils de pratiques associes au pronostic de la maladie renale chronique. Methodes L’etude vise a inclure plus de 3000 patients adultes avec une maladie renale chronique moderee ou avancee suivis dans 40 consultations de nephrologie representatives du point de vue des regions et du statut public ou prive des etablissements. Les patients sont inclus a l’occasion d’une consultation de routine et suivis pendant 5 ans, avant et apres l’initiation eventuelle d’un traitement de suppleance renale. Des donnees cliniques, biologiques, sur la sante percue et le mode de vie des patients sont recueillies annuellement, ainsi que sur les pratiques, en coordination avec l’etude internationale Chronic Kidney Disease Outcome and Practice Pattern Study. Une biotheque d’echantillons de sang et d’urine est constituee. Les principaux evenements etudies sont la survie, la qualite de vie, la progression de la maladie et les hospitalisations. Resultats Plus de 13 000 patients eligibles ont ete identifies, 60 % au stade 3 et 40 % au stade 4 de la maladie renale, d’âge median 72 ans [interquartile, 62–80 ans], dont 60 % sont de sexe masculin et 38 % ont un diabete. Fin decembre 2015, 2885 patients etaient inclus. Conclusion La cohorte CKD-REIN servira a mieux connaitre la maladie renale chronique et a apporter des donnees probantes pour ameliorer la sante et la qualite de vie des patients ainsi que les performances du systeme de sante dans ce domaine.

Vascular calcification is a marker of cardiovascular risk increase. Age and specific disease such as diabetes or chronic kidney disease are important factors for calcification genesis. Vascular calcification process is a complex phenomenon, involving several activators and inhibitors factors. Indeed, recent works related to in vitro and in vivo experimental studies have led to a better understanding of calcification process and identification of molecules able to modulate this system. This revue will summarize some of these molecules with a particular interest of those with therapeutic relevance. We will present: i) calcium sensing receptor and its modulation by cinacalcet; ii) pyrophosphate supplementation; iii) fetuin A and overall propensity serum test for calcification and finally; iv) matrix-Gla-protein and the use of vitamin K to prevent vascular calcification progression.

Matrix-gla-protein (MGP) is mainly secreted by chondrocytes and smooth vascular muscle cells. This potent inhibitor of vascular calcification need to undergo 2 post-transcriptional steps to be fully active: one phosphorylation of 3 serine residues (on 5) and a carboxylation of 5 glutamate residues (on 9). Like other "Gla" proteins, this carboxylation is vitamin K dependant. Several forms of MGP thus circulate in the plasma, some of them being totally inactive (the unphosphorylated and uncarboxylated MGP), some others being partially or fully active, according to the number of phosphorylated or carboxylated sites. A theoretical link exists between MGP, vitamin K, vascular calcifications and cardiovascular diseases. This link is even more evident in patients suffering from chronic kidney diseases (CKD), and notably hemodialysis patients. If this link has been demonstrated in different experimental studies, clinical studies are mainly observational and their results must be interpreted accordingly. MGP concentrations are definitely not yet a surrogate to estimate the levels of vascular calcification, but could allow the monitoring of vitamin K treatment. Modulation of MGP concentrations may reduce vascular calcification in hemodialyzed patients, if the large ongoing trials show an efficiency of this treatment. In this review, we will summarize the role of MGP in the vascular calcifications process, describe the problems linked to the analytical determination of MGP in plasma and finally describe the different clinical studies on MGP and vascular calcifications in the general population and in CKD patients.

The number of patients with chronic kidney disease (CKD) with its associated complications has increased dramatically worldwide in recent years. Therefore, many experimental and clinical studies have examined over the last decade the mechanisms involved, in order to explain the sharp increase in cardiovascular mortality. Hyperphosphatemia is a major problem in these patients especially at advanced stages of CKD, and it is associated with cardiovascular and mineral complications in these patients. Sevelamer is a phosphate binder that allows a better control of hyperphosphatemia, like other phosphate binder agents, but it has additional pleiotropic effects such as correcting certain abnormalities of lipid metabolism and clearance of several uremic toxins. These effects of sevelamer, restricted to the intestinal lumen, underline the importance of intestinal pathway in CKD and open the way to new therapeutic strategies for the management of the CKD and its complications.

The emergence of new effective therapeutic strategies for the treatment of resistant hypertension such as renal sympathetic denervation technique has lead to a renewed interest in the screening and assessment of prognosis of this specific entity which constitutes a subset of uncontrolled hypertension. Its prevalence is unknown, but estimated between 12 and 15% among hypertensive subjects from the general population. Several factors have been associated with the development of resistant hypertension, four of which are essential: age, diabetes, chronic kidney disease and vascular structural alteration. Excessive salt intake is also a risk factor for poorly controlled hypertension in patients with salt-dependent hypertension, and may participate to the genesis of resistant hypertension. Because of population ageing and increasing prevalence of diabetes, obesity and chronic kidney disease, the prevalence of resistant hypertension is expected to rise. A better understanding of its determinants and associated risks (such as chronic kidney disease) would identify high-risk groups that may benefit from extensive diagnosis work up and more specific treatments.

The role of oxidative stress in patients with chronic kidney disease (CKD) as a potential marker of morbidity and mortality remains poorly evaluated. The aim of the present study aims was thus: to determine plasma levels of malondialdehyde (MDA), end product of lipid peroxidation in patients at different CKD stages (predialysis and dialysis); to evaluate the association between plasma MDA levels and vascular disease or overall and cardiovascular mortality. Plasma MDA levels evaluated by HPLC, pulse wave velocity, aortic calcification score were evaluated in 94 CKD patients (67±13 years, 54% males, 29% at CKD stages 2-3, 32% at stages 4-5, 39% at stage 5D) prospectively followed for mortality. We observed that the plasma MDA levels were increased in patient with CKD and augmented progressively with CKD stages. However, we did not find any independent association between plasma levels of MDA and pulse wave velocity, aortic calcification score, or overall and cardiovascular mortality. Our results suggest that plasma MDA is not a useful biomarker in CKD patients.

Numerous clinical and experimental studies have been performed on endothelial progenitor cells since their discovery in 1997. However, the lack of consensus on both their definition and study method is confusing. The purpose of this review is to describe the usual in vitro protocols, and the links with chronic renal insufficiency.

Vascular calcifications are feature of late stages of atherosclerosis and are associated with cardiovascular disease. Numerous pathologies like diabetes or chronic renal insufficiency were also associated with the development of vascular calcification, particularly in the artery media. In the past, vascular calcifications were considered like a passive and degenerative event. Several studies have allowed demonstrating that they are the results of an active and inflammatory regulated process. A new idea emerges related to the role of calcifications as a cause of inflammation resulting in a vicious circle between inflammation and vascular calcification. This revue proposes to present an update on these different phenomenons.

The vitamin D hormonal system is involved in the regulation of more than 800 genes. Vitamin D deficiency, which is evaluated on the basis of the serum level of 25-hydroxycholecalciferol (25[OH]D), is frequently observed in the general population, particularly in patients with chronic kidney disease (CKD). Vitamin D deficiency is associated with an increased risk of falls and fracture and also with diabetes, malignancies, autoimmune diseases, depression and mortality. Furthermore, CKD is accompanied by a decrease in the renal production of 1,25 dihydroxycholecalciferol (1,25[OH](2)D). Such deficiencies have also been implicated in the pathophysiology of secondary hyperparathyroidism. Currently, vitamin D supplementation is not recommended in stage 5 CKD. However, since there is also significant extra-renal production of 1,25(OH)(2)D this would appear to be in favour of vitamin D treatment. We describe the disturbances of vitamin D metabolism occurring in CKD and discuss the advantages and the potential toxicity risk of vitamin D supplementation as well as the optimal serum 25[OH]D level. We then present the pharmacological properties of the various medicinal forms of vitamin D derivates and suggest therapeutic guidelines for supplementation with 25(OH)D(3) or cholecalciferol. We also examine existing guidelines for the administration of active 1-alpha-hydroxylated vitamin D. Despite the absence of strong scientific support by randomized controlled intervention studies, vitamin D supplementation should be considered in patients with CKD stages 4-5D having vitamin D insufficiency or deficiency, for the prevention of secondary hyperparathyroidism and for other potential benefits owing to its pleiotropic effects.

Diabetic nephropathy is a frequent complication in type 2 diabetic. Patients with diabetic nephropathy have a characteristic dyslipidemia profile associated increased concentrations of triglycerides, reduced levels of HDL cholesterol, and qualitative abnormalities of LDL. The dyslipidemia management in patients with diabetic nephropathy not yet in dialysis includes diet, insulin sensitizers (glitazones, metformin?), and hypolipemic agents, with statins as a first choice.

Nephrologists should be aware the fact that the angioedema is a common side effect not only under angiotensin-converting enzyme (ACE) inhibitors treatment but also under sartans therapy. The frequency of angioedema under ACE inhibitors is estimated at 1 to 7 per thousand. The physiopathology of ACE angioedema implicates the lack of degradation of kinines due to the inhibition of multiple enzymes activity including ACE. Angioedema under sartans seems less frequent than this observed under ACE inhibitors. Its mechanism remains poorly defined, but implicates the increase of kinine production via the stimulation of angiotensin receptor type II, and/or the lack of degradation of kinines via multiple enzymes other than ACE. The frequency of the apparition of angioedema under sartans in patients who had have angioedema under ACE inhibitors is inconsistent and varied from 7.7% to 50%. Reports indicated that angioedema under ACE or sartans could have a spontaneous regression. However, the relapse of angioedema under these drugs should lead to the diagnosis of iatrogenic etiology, and to the drugs withdrawal. ACE inhibitors/Sartans-associated angioedema episodes need to be reported to the French Adverse Event Reporting System database to evaluate their frequency and to avoid severe consequences.

In this editorial review on the optimal antihypertensive treatment for chronic kidney disease (CKD) patients, we start with the controversy triggered by Casas et al., for proposing a bitherapy optimal not only for nephroprotection, but also for global cardiovascular protection. The incidence of cardiovascular complications are indeed much greater than the occurrence of end stage renal disease (ESRD) in these patients, so that their prevention has at least the same priority. We explain the huge amount of discordant papers, on the basis of methodology deficiencies in the studies aiming at evidencing the truth of 2 antinomic concepts underlying this controversy: 1) "The correction by antihypertensive drugs of the cardiovascular risk excess in hypertensive patients is exclusively related to their blood pressure lowering effect, the optimal blood pressure (BP) level being defined by epidemiologists at 115/75 mmHg"; 2) "Independently of BP lowering effect, antihypertensive drugs may have intrinsic, protective or deleterious, renal and cardiovascular effects which may be variable according to the target organ". We think that truth is conciliating and that both mechanisms should not be exclusive. However more rigorous studies are still needed to evidence it. Meanwhile we propose the optimal therapy by hypokaliemic diuretics (thiazides+/-loop diuretics according to glomerular filtration decline)+inhibitors of the angiotensin AT1-receptor (ACE inhibitors or AT1RB), in preference to the association of dihydropyridines with diuretics. This recommendation is strong however, only for CKD patients with macroproteinuria. The priority that we give to diuretic therapy is based on the evidence that this class confers good prevention against both heart failure and strokes, which is not the case for all AT1-inhibitors and dihydropyridines. Furthermore the diuretics are the drugs with the longest antihypertensive effect (many weeks) and their efficiency in CKD patients is proportional to the sodium depletion they initially induce and therefore to the dose (specially of the loop diuretics). Indeed volemia control is an incontrovertible factor for optimal BP control in renal insufficiency. As regards the use of betablockers, they should no more be considered as first drug for hypertension because they have the strongest diabetogenic effect. They should be used selectively for their specific cardiologic indications such as angina, heart failure, arythmia and as substitute for ACEI or AT1RB when general anesthesia is considered. Regarding the choice between ACEI and AT(1)RB, on the basis of indirect comparisons, we think that the latter may grant a comparable cardiac protection while giving a better cerebral protection. We shall have to wait the results of ONTARGET study to have or not the evidence for this preference. Finally, we want to stress the necessity to individualize the treatment by taking into account coexistence of cardiovascular complications and of other diseases, as well as the tolerance of the treatment (which may be influenced by seasons, in particular the canicula one), and the cost of the drugs.

STATINS IN THE CASE OF CHRONIC RENAL DISEASE: Data of several large clinical trials in the general population demonstrated that hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) are effective in cardiovascular disease prevention with a relatively safe profile. Patients with chronic kidney disease (CKD) are at high risk for developing premature cardiovascular disease, so the benefits of statin therapy might be expected to be substantial in this population. Adjusted dose of statins to calcinurine inhibitors and renal function seem to exhibit a favorable risk/benefit ratio in CKD patients.Statin use is CKD patients has been associated with a certain efficacy of cardiovascular disease prevention in several uncontrolled trials, and one randomized trial in renal transplant recipients. Several other large-scale randomized trials in CKD patients [4D (atorvastatin), AURORA (rosuvastatin) and SHARP (simvastatin/ezetimib) are currently underway. The results of these trials will permit evidence-based medicinal arguments justifying life-long clinical use of statins for cardiovascular prevention in CKD patients with progressive renal dysfunction, but data are inconclusive.Clinically relevant plethoric effects associated with statin therapy in CKD patients might be restricted to the decrease of inflammation and oxidative stress.

To determine the degree of anaemia corresponding to the decreasing levels of renal function in patients with chronic renal failure (CRF) and not yet on dialysis, and to assess the indications for treatment with recombinant erythropoeitin (epoetin).We studied the relationship between haemoglobin (Hb) concentration and creatinine clearance (Ccr) in 403 consecutive patients with CRF regularly monitored in nephrology consultations between January 1 and June 30, 1999, and who received appropriate iron and vitamin supplementation. These patients were then followed-up until June 30, 2000 or until maintenance dialysis was initiated.There was a significant and close correlation between the degree of anaemia and renal dysfunction. An Hb value11 g/dl (corresponding to the present threshold for the indication of epoetin) was observed in 62% of patients with creatinine levels400 micromol/l and in 58% when Ccr was20 ml/mn/1.73 m2. Whatever the level of CRF, the degree of anaemia was higher in the women than in the men. Among the 123 patients who had to start maintenance dialysis during the observation period, 85 (69%) were treated with epoetin before dialysis was started.In patients with CRF, clinically symptomatic anaemia is more frequent than imagined, and early treatment is required. Regular monitoring of Hb and iron levels is mandatory in order to allow patients to benefit from timely initiation of epoetin and thus prevent the development of disabling asthenia and other deleterious consequences of anaemia.