CKD Increases Carbonylation of HDL and Is Associated with Impaired Antiaggregant Properties.

BACKGROUND: CKD is associated with increased oxidative stress that correlates with occurrence of cardiovascular events. Modifications induced by increased oxidative stress particularly affect circulating lipoproteins such as HDL that exhibit antiatheromatous and antithrombotic properties in vitro. METHODS: To explore the specific role of oxidative modifications of HDL in CKD and their effect on the platelet-targeting antiaggregant properties of HDL, we used a CKD (5/6 nephrectomy) rabbit model. For ex vivo assessment of the antiaggregant properties of HDL, we collected blood samples from 15 healthy volunteers, 25 patients on hemodialysis, and 20 on peritoneal dialysis. We analyzed malondialdehyde, 4-hydroxynonenal (HNE), and 4-hydroxy-2-hexenal protein adduct levels. Platelet aggregation and activation were assessed by aggregometry, thromboxane B2 assay, or FACS. We modified HDL from controls by incubating it overnight at 37°C with 100 µM of HNE. RESULTS: HDL from CKD rabbits and patients on hemodialysis had HNE adducts. The percentage of platelet aggregation or activation induced by collagen was significantly higher when platelets were incubated with HDL from CKD rabbit and hemodialysis groups than with HDL from the control group. In both rabbits and humans, platelet aggregation and activation were significantly higher in the presence of HNE-modified HDL than with HDL from their respective controls. Incubation of platelets with a blocking antibody directed against CD36 or with a pharmacologic inhibitor of SRC kinases restored the antiaggregative phenotype in the presence of HDL from CKD rabbits, patients on hemodialysis and peritoneal dialysis, and HNE-modified HDL. CONCLUSIONS: HDL from CKD rabbits and patients on hemodialysis exhibited an impaired ability to inhibit platelet aggregation, suggesting that altered HDL properties may contribute to the increased cardiovascular risk in this population.

[Access to kidney transplantation's waiting list: Setting up a clinical pathway]. / Accès à la liste d'attente de transplantation rénale : mise en place d'un chemin clinique.

Early information about the kidney transplant is recommended to begin quickly the process of registration on the kidney transplantation waiting list, even for the patients not dialyzed at stage V of the renal insufficiency. It is a strategic choice for the patient care. From the arrival of all the patients in our center of dialysis, a systematic evaluation of the access to the kidney transplant waiting list is organized thanks to a clinical pathway. The impact of this new organization was estimated at 18 months with regard to the information about the kidney transplant transmitted to the patient, of the time required for the assessment of pre-kidney transplant evaluation, and of putting in contraindication. On 78 incident patients, 64 received the information concerning the kidney transplant. After 18 months, 50 clinical pathways are finalized at the time of the analysis among which 25 with a period lower than 6 days and 25 with a median of 169 days. A significant difference of age exists between both groups. The main causes of definitive medical contraindications were estimated. Twenty-two percent of the clinical pathway finalized is awaiting lifting of temporary contraindication. The management of the patient is improved, due to motivation of all the medical teams and a considerable work of coordination between the secretarial department and the department of transplantation in teaching hospital.

[Thrice-weekly warfarin administration: results in 12 hemodialysis patients]. / Administration tri-hebdomadaire de la warfarine en hémodialyse chronique. Résultats chez 12 patients.

We report our experience of thrice-weekly warfarin administration, at the end of the dialysis session, in 12 patients (average age: 79 ± 5 years). In 10 cases, indication for anticoagulation therapy was atrial fibrillation, in one case a mechanical heart valve, in another case axillo femoral bypass. The International Normalized Ratio (INR) therapeutic goal was between 2 and 3, except for the patient with a mechanical aortic heart valve, whose goal was between 2.5 and 3.5. The INR was determined during the first dialysis session of the week. The thrice-weekly warfarin dose was based on this result. INR stability was assessed for each patient over an uninterrupted period of treatment of at least 6 months. The average duration of warfarin treatment was 20 ± 5 months. One in two patients had hypertensive nephropathy. The average Charlson co-morbidity score was 9 ± 1. Four patients were also taking aspirin or clopidogrel. The 10 patients with atrial fibrillation had an average CHA(2)DS(2)-VASc score of 4.4 ± 0.8. The average haemorrage risk HAS-BLED score was 3.3 ± 0.6. The average weekly warfarin dose was 23 ± 5 mg. No thrombotic events were observed. The side effects of warfarin were minor in most cases: (1) INR more than 6 in two cases without associated bleeding; (2) minor bleeding (nose, bladder) in three cases. One case of skin necrosis was observed. No cases of major bleeding (requiring blood transfusion) were observed. Only one patient was admitted into hospital as a result of warfarin treatment (the case of skin necrosis). Five hundred and forty-seven INR results were analyzed: 65% of these results were within the therapeutic goal, only 3% were either beneath 1.5 or over 4. To conclude, warfarin administration at the end of the dialysis session is efficient and associated with remarkable INR stability in the goal. It enables precise dose adaptation and optimum therapeutic observance, which in turn reduces the risk of bleeding.

The clinical status and survival in elderly dialysis: example of the oldest region of France.

BACKGROUND: The number of elderly (≥75 years) patients with end-stage renal disease (ESRD) has increased markedly, including in the Limousin region, which has the oldest population in France. We retrospectively compared outcomes in elderly and non-elderly ESRD patients who started dialysis during two time periods. METHODS: Baseline clinical characteristics, care, and survival rates were assessed in 557 ESRD patients aged ≥75 and <75 years who started dialysis in 2002-2004 and 2005-2007. Survival curves and Cox proportional hazards model were used to assess survival and factors associated with survival. RESULTS: Of the 557 patients, 343 and 214 were <75 years and ≥75 years, respectively. Dialysis was started in 2002-2004 and 2005-2007 by 197 and 146 patients <75 years, respectively, and by 96 and 118 patients ≥75 years, respectively. Median age (73.4 years [interquartile range [IQR] 61.7-79.5 years] vs 69.5 years [IQR 57.4-77.4 years] p = 0.001) and the proportion aged ≥75 years (44.7% vs 32.8%, p = 0.004) were significantly higher in 2005-2007 than in 2002-2004. Improved initial status during 2005-2007 was observed only in patients ≥75 years, with a decrease in some co-morbidities, improved walking and better preparation for dialysis. Mortality rates were significantly lower in 2005-2007 than in 2002-2004 (hazard ratio 0.81, 95% confidence interval 0.69-0.95; p = 0.008), with the difference due to factors associated with clinical status and care. CONCLUSIONS: Improved initial clinical status and better preparation for dialysis, accompanied by increased survival, were observed for patients ≥75 years who started dialysis more recently, perhaps because of early referral to a nephrologist.

A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin.

Familial juvenile hyperuricemic nephropathy (FJHN [MIM 162000]) is an autosomal-dominant disorder characterized by abnormal tubular handling of urate and late development of chronic interstitial nephritis leading to progressive renal failure. A locus for FJHN was previously identified on chromosome 16p12 close to the MCKD2 locus, which is responsible for a variety of autosomal-dominant medullary cystic kidney disease (MCKD2). UMOD, the gene encoding the Tamm-Horsfall/uromodulin protein, maps within the FJHN/MCKD2 critical region. Mutations in UMOD were recently reported in nine families with FJHN/MCKD2 disease. A mutation in UMOD has been identified in 11 FJHN families (10 missense and one in-frame deletion)-10 of which are novel-clustering in the highly conserved exon 4. The consequences of UMOD mutations on uromodulin expression were investigated in urine samples and renal biopsies from nine patients in four families. There was a markedly increased expression of uromodulin in a cluster of tubule profiles, suggesting an accumulation of the protein in tubular cells. Consistent with this observation, urinary excretion of wild-type uromodulin was significantly decreased. The latter findings were not observed in patients with FJHN without UMOD mutations. In conclusion, this study points to a mutation clustering in exon 4 of UMOD as a major genetic defect in FJHN. Mutations in UMOD may critically affect the function of uromodulin, resulting in abnormal accumulation within tubular cells and reduced urinary excretion.