A wearable hemofilter for continuous ambulatory ultrafiltration.
Gura V, Ronco C, Nalesso F, Brendolan A, Beizai M, Ezon C, Davenport A, Rambod E.
Ultrafiltration is effective for treating fluid overload, but there are no suitable machines for ambulatory treatment. This study summarizes the use of a light-weight wearable continuous ambulatory ultrafiltration device consisting of a hollow fiber hemofilter, a battery operated pulsatile pump, and two micropumps to control heparin administration and ultrafiltration. Six volume-overloaded patients underwent ultrafiltration for 6 h with treatment discontinued in one patient due to a clotted catheter. Blood flow averaged 116 ml min(-1), the ultrafiltration rate ranged from 120-288 ml h(-1) with about 150 mmol of sodium removed. Blood pressure, pulse, and biochemical parameters remained stable with no significant hemolysis or complications. Our data show that the wearable hemofilter appears to be safe, effective, and practical for patients. This device could have a major impact on the quality of life of fluid-overloaded patients with heart failure. Additional studies will be needed to confirm these initial promising results.
Egalement dans le dernier numéro du Lancet par la meme équipe. Une équipe californienne a testé sur 8 patients (dans l'article du lancet) un dispositif d'hémodialyse portable (débit sanguin 47 ml/min), résultats apparemment prometteur.
RS
12/11/2007
L'anti-CD20 contre le diabète auto-immun ...
Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice.
Hu CY, Rodriguez-Pinto D, Du W, Ahuja A, Henegariu O, Wong FS, Shlomchik MJ, Wen L.
J Clin Invest. 2007 Dec 3;117(12):3857-3867
The precise roles of B cells in promoting the pathogenesis of type 1 diabetes remain undefined. Here, we demonstrate that B cell depletion in mice can prevent or delay diabetes, reverse diabetes after frank hyperglycemia, and lead to the development of cells that suppress disease. To determine the efficacy and potential mechanism of therapeutic B cell depletion, we generated a transgenic NOD mouse expressing human CD20 (hCD20) on B cells. A single cycle of treatment with an antibody specific for hCD20 temporarily depleted B cells and significantly delayed and/or reduced the onset of diabetes. Furthermore, disease established to the point of clinical hyperglycemia could be reversed in over one-third of diabetic mice. Why B cell depletion is therapeutic for a variety of autoimmune diseases is unclear, although effects on antibodies, cytokines, and antigen presentation to T cells are thought to be important. In B cell-depleted NOD mice, we identified what we believe is a novel mechanism by which B cell depletion may lead to long-term remission through expansion of Tregs and regulatory B cells. Our results demonstrate clinical efficacy even in established disease and identify mechanisms for therapeutic action that will guide design and evaluation of parallel studies in patients.
Hu CY, Rodriguez-Pinto D, Du W, Ahuja A, Henegariu O, Wong FS, Shlomchik MJ, Wen L.
J Clin Invest. 2007 Dec 3;117(12):3857-3867
The precise roles of B cells in promoting the pathogenesis of type 1 diabetes remain undefined. Here, we demonstrate that B cell depletion in mice can prevent or delay diabetes, reverse diabetes after frank hyperglycemia, and lead to the development of cells that suppress disease. To determine the efficacy and potential mechanism of therapeutic B cell depletion, we generated a transgenic NOD mouse expressing human CD20 (hCD20) on B cells. A single cycle of treatment with an antibody specific for hCD20 temporarily depleted B cells and significantly delayed and/or reduced the onset of diabetes. Furthermore, disease established to the point of clinical hyperglycemia could be reversed in over one-third of diabetic mice. Why B cell depletion is therapeutic for a variety of autoimmune diseases is unclear, although effects on antibodies, cytokines, and antigen presentation to T cells are thought to be important. In B cell-depleted NOD mice, we identified what we believe is a novel mechanism by which B cell depletion may lead to long-term remission through expansion of Tregs and regulatory B cells. Our results demonstrate clinical efficacy even in established disease and identify mechanisms for therapeutic action that will guide design and evaluation of parallel studies in patients.
Le valsartan protège contre la maladie d'Alzheimer ...
Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease.
Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, Humala N, Seror I, Bartholomew S, Rosendorff C, Pasinetti GM.
J Clin Ivest. 2007 Nov;117(11):3393-402
Recent epidemiological evidence suggests that some antihypertensive medications may reduce the risk for Alzheimer disease (AD). We screened 55 clinically prescribed antihypertensive medications for AD-modifying activity using primary cortico-hippocampal neuron cultures generated from the Tg2576 AD mouse model. These agents represent all drug classes used for hypertension pharmacotherapy. We identified 7 candidate antihypertensive agents that significantly reduced AD-type beta-amyloid protein (Abeta) accumulation. Through in vitro studies, we found that only 1 of the candidate drugs, valsartan, was capable of attenuating oligomerization of Abeta peptides into high-molecular-weight (HMW) oligomeric peptides, known to be involved in cognitive deterioration. We found that preventive treatment of Tg2576 mice with valsartan significantly reduced AD-type neuropathology and the content of soluble HMW extracellular oligomeric Abeta peptides in the brain. Most importantly, valsartan administration also attenuated the development of Abeta-mediated cognitive deterioration, even when delivered at a dose about 2-fold lower than that used for hypertension treatment in humans. These preclinical studies suggest that certain antihypertensive drugs may have AD-modifying activity and may protect against progressive Abeta-related memory deficits in subjects with AD or in those at high risk of developing AD.
A suivre ...
Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, Humala N, Seror I, Bartholomew S, Rosendorff C, Pasinetti GM.
J Clin Ivest. 2007 Nov;117(11):3393-402
Recent epidemiological evidence suggests that some antihypertensive medications may reduce the risk for Alzheimer disease (AD). We screened 55 clinically prescribed antihypertensive medications for AD-modifying activity using primary cortico-hippocampal neuron cultures generated from the Tg2576 AD mouse model. These agents represent all drug classes used for hypertension pharmacotherapy. We identified 7 candidate antihypertensive agents that significantly reduced AD-type beta-amyloid protein (Abeta) accumulation. Through in vitro studies, we found that only 1 of the candidate drugs, valsartan, was capable of attenuating oligomerization of Abeta peptides into high-molecular-weight (HMW) oligomeric peptides, known to be involved in cognitive deterioration. We found that preventive treatment of Tg2576 mice with valsartan significantly reduced AD-type neuropathology and the content of soluble HMW extracellular oligomeric Abeta peptides in the brain. Most importantly, valsartan administration also attenuated the development of Abeta-mediated cognitive deterioration, even when delivered at a dose about 2-fold lower than that used for hypertension treatment in humans. These preclinical studies suggest that certain antihypertensive drugs may have AD-modifying activity and may protect against progressive Abeta-related memory deficits in subjects with AD or in those at high risk of developing AD.
A suivre ...
Le FGF23 agit directement sur la glande parathyroïde pour freiner la sécrétion de PTH
The parathyroid is a target organ for FGF23 in rats.
Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-O M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J.
J Clin Invest. 2007 Dec 3;117(12):4003-4008
Phosphate homeostasis is maintained by a counterbalance between efflux from the kidney and influx from intestine and bone. FGF23 is a bone-derived phosphaturic hormone that acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. FGF23 signals with highest efficacy through several FGF receptors (FGFRs) bound by the transmembrane protein Klotho as a coreceptor. Since most tissues express FGFR, expression of Klotho determines FGF23 target organs. Here we identify the parathyroid as a target organ for FGF23 in rats. We show that the parathyroid gland expressed Klotho and 2 FGFRs. The administration of recombinant FGF23 led to an increase in parathyroid Klotho levels. In addition, FGF23 activated the MAPK pathway in the parathyroid through ERK1/2 phosphorylation and increased early growth response 1 mRNA levels. Using both rats and in vitro rat parathyroid cultures, we show that FGF23 suppressed both parathyroid hormone (PTH) secretion and PTH gene expression. The FGF23-induced decrease in PTH secretion was prevented by a MAPK inhibitor. These data indicate that FGF23 acts directly on the parathyroid through the MAPK pathway to decrease serum PTH. This bone-parathyroid endocrine axis adds a new dimension to the understanding of mineral homeostasis.
Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-O M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J.
J Clin Invest. 2007 Dec 3;117(12):4003-4008
Phosphate homeostasis is maintained by a counterbalance between efflux from the kidney and influx from intestine and bone. FGF23 is a bone-derived phosphaturic hormone that acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. FGF23 signals with highest efficacy through several FGF receptors (FGFRs) bound by the transmembrane protein Klotho as a coreceptor. Since most tissues express FGFR, expression of Klotho determines FGF23 target organs. Here we identify the parathyroid as a target organ for FGF23 in rats. We show that the parathyroid gland expressed Klotho and 2 FGFRs. The administration of recombinant FGF23 led to an increase in parathyroid Klotho levels. In addition, FGF23 activated the MAPK pathway in the parathyroid through ERK1/2 phosphorylation and increased early growth response 1 mRNA levels. Using both rats and in vitro rat parathyroid cultures, we show that FGF23 suppressed both parathyroid hormone (PTH) secretion and PTH gene expression. The FGF23-induced decrease in PTH secretion was prevented by a MAPK inhibitor. These data indicate that FGF23 acts directly on the parathyroid through the MAPK pathway to decrease serum PTH. This bone-parathyroid endocrine axis adds a new dimension to the understanding of mineral homeostasis.
Petit poids de naissance et IRT, un risque augmenté de 70%
Low Birth Weight Increases Risk for End-Stage Renal Disease.
Vikse BE, Irgens LM, Leivestad T, Hallan S, Iversen BM.
J Am Soc Nephrol Publié Online le 5 décembre 2007
Case-control studies have shown an association between low birth weight and risk for renal failure. The Medical Birth Registry of Norway, which comprises data on all births in Norway since 1967, and the Norwegian Renal Registry, which comprises data on all patients who have developed ESRD in Norway since 1980, were used to examine whether birth-related variables were associated with risk for ESRD. Of the 2,183,317 children born between 1967 and 2004, 526 were found in the ESRD registry. Compared with birth weight in the 10th to 90th percentiles, births <10th percentile had a relative risk (RR) for ESRD of 1.7 (95% confidence interval 1.4 to 2.2; P < 0.001). Births with a weight for gestational age <10th percentile had an RR of 1.5 (95% confidence interval 1.2 to 1.9; P = 0.002). These associations were virtually identical after adjustment for birth-related confounders such as congenital malformations, multiple delivery, maternal age at birth, and maternal preeclampsia. Low birth weight was more strongly associated with development of ESRD during the first 14 years of life than after age 15. Low birth weight and low birth weight for gestational age were similarly associated with multiple causes of ESRD. In conclusion, in this cohort study with a maximum follow-up of 38 years, low birth weight and intrauterine growth restriction were associated with increased risk for ESRD.
Une étude très simple (à condition d'avoir des registres) et très démonstrative ! En croisant le registre nationale des naissances en Norvège entre 1967 et 2004 (2 183 317 naissances) avec le registre des insuffisants rénaux au stade terminal entre 1980 et 2005 (526 cas), et en analysant les facteurs de risque de l'IRT les auteurs de ce papier démontrent que un poids de naissance inférieur au 10ème percentile augmente le risque d'IRT de 70% jusqu'à l'âge de 38 ans (l'analyse de va pas au-dela de cet âge).
R Salomon
Vikse BE, Irgens LM, Leivestad T, Hallan S, Iversen BM.
J Am Soc Nephrol Publié Online le 5 décembre 2007
Case-control studies have shown an association between low birth weight and risk for renal failure. The Medical Birth Registry of Norway, which comprises data on all births in Norway since 1967, and the Norwegian Renal Registry, which comprises data on all patients who have developed ESRD in Norway since 1980, were used to examine whether birth-related variables were associated with risk for ESRD. Of the 2,183,317 children born between 1967 and 2004, 526 were found in the ESRD registry. Compared with birth weight in the 10th to 90th percentiles, births <10th percentile had a relative risk (RR) for ESRD of 1.7 (95% confidence interval 1.4 to 2.2; P < 0.001). Births with a weight for gestational age <10th percentile had an RR of 1.5 (95% confidence interval 1.2 to 1.9; P = 0.002). These associations were virtually identical after adjustment for birth-related confounders such as congenital malformations, multiple delivery, maternal age at birth, and maternal preeclampsia. Low birth weight was more strongly associated with development of ESRD during the first 14 years of life than after age 15. Low birth weight and low birth weight for gestational age were similarly associated with multiple causes of ESRD. In conclusion, in this cohort study with a maximum follow-up of 38 years, low birth weight and intrauterine growth restriction were associated with increased risk for ESRD.
Une étude très simple (à condition d'avoir des registres) et très démonstrative ! En croisant le registre nationale des naissances en Norvège entre 1967 et 2004 (2 183 317 naissances) avec le registre des insuffisants rénaux au stade terminal entre 1980 et 2005 (526 cas), et en analysant les facteurs de risque de l'IRT les auteurs de ce papier démontrent que un poids de naissance inférieur au 10ème percentile augmente le risque d'IRT de 70% jusqu'à l'âge de 38 ans (l'analyse de va pas au-dela de cet âge).
R Salomon
L'arginine vasopressine est bien impliquée dans la kystogénèse
Vasopressin Directly Regulates Cyst Growth in Polycystic Kidney Disease.
Wang X, Wu Y, Ward CJ, Harris PC, Torres VE.
Mayo Clinic College of Medicine, Rochester, Minnesota.
J Am Soc nephrol Publié Online le 21 Novembre 2007
The polycystic kidney diseases (PKD) are a group of genetic disorders causing renal failure and death from infancy to adulthood. Arginine vasopressin (AVP) V2 receptor antagonists inhibit cystogenesis in animal models of cystic kidney diseases, presumably by downregulating cAMP signaling, cell proliferation, and chloride-driven fluid secretion. For confirmation that the protective effect of these drugs is due to antagonism of AVP, PCK (Pkhd1(-/-)) and Brattleboro (AVP(-/-)) rats were crossed to generate rats with PKD and varying amounts of AVP. At 10 and 20 weeks of age, PCK AVP(-/-) rats had lower renal cAMP and almost complete inhibition of cystogenesis compared with PCK AVP(+/+) and PCK AVP(+/-) rats. The V2 receptor agonist 1-deamino-8-d-arginine vasopressin increased renal cAMP and recovered the full cystic phenotype of PCK AVP(-/-) rats and aggravated the cystic disease of PCK AVP(+/+) rats but did not induce cystic changes in wild-type rats. These observations indicate that AVP is a powerful modulator of cystogenesis and provide further support for clinical trials of V2 receptor antagonists in PKD.
Le croisement de rat PCK (invalidés pour le gène Pkhd1) avec des rats Brattleboro (dont le gène codant pour l'AVP est absent) démontre que l'AVP est bien un acteur important dans la formation des kystes dans la mesure ou les reins ne sont plus kystiques chez ces rats hybrides (pas de gènes Pkhd1 mais pas de kystes car par d'AVP). L'administration d'un analogue de l'AVP chez ces rats hybrides provoque la formation des kystes. cqfd
L'espoir de pouvoir ralentir la formation des kystes avec des inhibiteurs du récepteur V2 est donc réel, la démonstration de leur efficacité est déjà été faite sur les modèles animaux, des essais chez l'homme sont en cours.
R Salomon
Wang X, Wu Y, Ward CJ, Harris PC, Torres VE.
Mayo Clinic College of Medicine, Rochester, Minnesota.
J Am Soc nephrol Publié Online le 21 Novembre 2007
The polycystic kidney diseases (PKD) are a group of genetic disorders causing renal failure and death from infancy to adulthood. Arginine vasopressin (AVP) V2 receptor antagonists inhibit cystogenesis in animal models of cystic kidney diseases, presumably by downregulating cAMP signaling, cell proliferation, and chloride-driven fluid secretion. For confirmation that the protective effect of these drugs is due to antagonism of AVP, PCK (Pkhd1(-/-)) and Brattleboro (AVP(-/-)) rats were crossed to generate rats with PKD and varying amounts of AVP. At 10 and 20 weeks of age, PCK AVP(-/-) rats had lower renal cAMP and almost complete inhibition of cystogenesis compared with PCK AVP(+/+) and PCK AVP(+/-) rats. The V2 receptor agonist 1-deamino-8-d-arginine vasopressin increased renal cAMP and recovered the full cystic phenotype of PCK AVP(-/-) rats and aggravated the cystic disease of PCK AVP(+/+) rats but did not induce cystic changes in wild-type rats. These observations indicate that AVP is a powerful modulator of cystogenesis and provide further support for clinical trials of V2 receptor antagonists in PKD.
Le croisement de rat PCK (invalidés pour le gène Pkhd1) avec des rats Brattleboro (dont le gène codant pour l'AVP est absent) démontre que l'AVP est bien un acteur important dans la formation des kystes dans la mesure ou les reins ne sont plus kystiques chez ces rats hybrides (pas de gènes Pkhd1 mais pas de kystes car par d'AVP). L'administration d'un analogue de l'AVP chez ces rats hybrides provoque la formation des kystes. cqfd
L'espoir de pouvoir ralentir la formation des kystes avec des inhibiteurs du récepteur V2 est donc réel, la démonstration de leur efficacité est déjà été faite sur les modèles animaux, des essais chez l'homme sont en cours.
R Salomon
12/02/2007
Des variants du gène de la podocine (NPHS2) jouent aussi un rôle dans les formes tardives de syndrome néphrotique idiopathique
Mutations in NPHS2, the gene that encodes podocin, are well-established causes of both familial and sporadic steroid-resistant focal segmental glomerulosclerosis (FSGS) in the pediatric population, but have not been well-characterized in late-onset disease. To investigate the role of NPHS2 polymorphisms in sporadic cases of late-onset FSGS, we studied 377 biopsy-confirmed FSGS cases and 919 controls. We identified 18 single nucleotide polymorphisms (SNPs) by resequencing a subgroup of cases and controls, and subsequently genotyped African-American and European-American cases and controls for five missense SNPs, three SNPs within introns, and four SNPs in the 3' untranslated region. No homozygotes or compound heterozygotes were observed for any missense mutation. R138Q carriers were more frequent among FSGS cases relative to controls (OR = 4.9, P = 0.06), but heterozygosity for the other four missense mutations was equally distributed among FSGS cases and controls. Finally, a common haplotype of noncoding SNPs carried by 20% of African-Americans, but not observed in European-Americans, was strongly associated with a 50% reduction in risk for sporadic FSGS (OR = 0.5, P = 0.001). These results indicate that genetic variation or mutation of NPHS2 may play a role in late-onset sporadic FSGS.
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