Renal outcome in patients with congenital anomalies of the kidney and urinary tract.
Sanna-Cherchi S, Ravani P, Corbani V, Parodi S, Haupt R, Piaggio G, Innocenti ML, Somenzi D, Trivelli A, Caridi G, Izzi C, Scolari F, Mattioli G, Allegri L, Ghiggeri GM.
[1] Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA [2] Department of Clinical Medicine, Nephrology and Health Sciences, University of Parma, Italy.
Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are a major cause of morbidity in children. We measured the risk of progression to end-stage renal disease in 312 patients with CAKUT preselected for the presence of anomalies in kidney number or size. A model of dialysis-free survival from birth was established as a function of the renal CAKUT categories of solitary kidney; unilateral and bilateral hypodysplasia; renal hypodysplasia associated with posterior urethral valves; and multicystic and horseshoe kidney. Cox regression analysis took into account the concomitant presence of vesicoureteral reflux, year of diagnosis, and time-varying values of serum creatinine, proteinuria, and hypertension. By 30 years of age, 58 patients had started dialysis, giving a yearly incidence of 0.023 over a combined 2474 patient risk years. The risk for dialysis was significantly higher for patients with a solitary kidney or with renal hypodysplasia associated with posterior urethral valves (hazard ratios of 2.43 and 5.1, respectively) compared to patients with unilateral or bilateral renal hypodysplasia, or multicystic or horseshoe kidney, and was independent of other prognostic factors. Our study shows that sub-clinical defects of the solitary kidney may be responsible for a poorer prognosis compared to more benign forms of CAKUT. Prospective studies are needed to validate these results.
Kidney International advance online publication, 17 June 2009; doi:10.1038/ki.2009.220.
Cette étude rétrospective analyse le devenir à long terme de patients ayant une anomalie congénitale de l'appareil urinaire. 312 patients ont été inclus dans un seul centre (Gènes, Italie). Le critère d'inclusion était la réduction de la taille de l'un ou des deux reins. Cette cohorte est très hétérogène incluant aussi bien des reins uniques, des dysplasies multikystiques, des hypodysplasies rénales (HDR) uni ou bilatérales et des valves de l'urêthre postérieur. Une des conclusionn des auteurs est que le pronostic des reins uniques et des valves de l'urêthre postérieur (VUP) est moins bon que celui des HDR avec un risque de dialyse augmenté ("hazard ratio") de 2.43 et 5.1 respectivement (1.79 pour les HDR bilatérales). Cela peut se comprendre pour les VUP mais moins facilement pour les reins uniques. Ainsi 21 des 79 reins uniques sont en dialyse à un âge moyen de 21+/-13 ans. Il est fortement probable qu'il y ait eu un biais de recrutement des reins uniques qui sont pour la plupart diagnostiqués après la naissance à un âge moyen de 15 ans. Il n'en demeure pas moins que les reins uniques doivent être suivis longtemps (ad vitam), mais de cela nous somme tous convaincus...
Rémi Salomon
6/29/2009
Devenir à long terme des patients avec une malformation congénital des reins (CAKUT): attention aux biais de recrutement
5/26/2008
Des variants dans les gènes du Bartter et du Gitelman font baisser la pression artérielle
Rare independent mutations in renal salt handling genes contribute to blood pressure variation.
Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP.
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
Nat Genet. 2008 May;40(5):592-9
The effects of alleles in many genes are believed to contribute to common complex diseases such as hypertension. Whether risk alleles comprise a small number of common variants or many rare independent mutations at trait loci is largely unknown. We screened members of the Framingham Heart Study (FHS) for variation in three genes-SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1 (ROMK)-causing rare recessive diseases featuring large reductions in blood pressure. Using comparative genomics, genetics and biochemistry, we identified subjects with mutations proven or inferred to be functional. These mutations, all heterozygous and rare, produce clinically significant blood pressure reduction and protect from development of hypertension. Our findings implicate many rare alleles that alter renal salt handling in blood pressure variation in the general population, and identify alleles with health benefit that are nonetheless under purifying selection. These findings have implications for the genetic architecture of hypertension and other common complex traits.
Exemple du rôle de la balance sodée dans le contrôle de la pression artérielle. Les sujets de la cohorte de Framingham (étude des risques cardiovasculaires avec un suivi de 35 ans), hétérozygotes pour une mutation d’un de 3 des gènes responsables du syndrome de Bartter/Gitelman, ont des chiffres de pression artérielle systolique et diastolique significativement plus bas pour toutes les tranches d’âge. Cet effet avait été montré pour de petits groupes, en particulier pour le cotransporteur Na-Cl. Cet article en fait une élégante démonstration dans la durée.
Rosa Vargas Poussou
Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP.
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
Nat Genet. 2008 May;40(5):592-9
The effects of alleles in many genes are believed to contribute to common complex diseases such as hypertension. Whether risk alleles comprise a small number of common variants or many rare independent mutations at trait loci is largely unknown. We screened members of the Framingham Heart Study (FHS) for variation in three genes-SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1 (ROMK)-causing rare recessive diseases featuring large reductions in blood pressure. Using comparative genomics, genetics and biochemistry, we identified subjects with mutations proven or inferred to be functional. These mutations, all heterozygous and rare, produce clinically significant blood pressure reduction and protect from development of hypertension. Our findings implicate many rare alleles that alter renal salt handling in blood pressure variation in the general population, and identify alleles with health benefit that are nonetheless under purifying selection. These findings have implications for the genetic architecture of hypertension and other common complex traits.
Exemple du rôle de la balance sodée dans le contrôle de la pression artérielle. Les sujets de la cohorte de Framingham (étude des risques cardiovasculaires avec un suivi de 35 ans), hétérozygotes pour une mutation d’un de 3 des gènes responsables du syndrome de Bartter/Gitelman, ont des chiffres de pression artérielle systolique et diastolique significativement plus bas pour toutes les tranches d’âge. Cet effet avait été montré pour de petits groupes, en particulier pour le cotransporteur Na-Cl. Cet article en fait une élégante démonstration dans la durée.
Rosa Vargas Poussou
5/25/2008
Un transporteur des hexoses (GLUT9) se charge aussi de l'acide urique ...
SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.
Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CN, Knott SA, Kolcic I, Polasek O, Graessler J, Wilson JF, Marinaki A, Riches PL, Shu X, Janicijevic B, Smolej-Narancic N, Gorgoni B, Morgan J, Campbell S, Biloglav Z, Barac-Lauc L, Pericic M, Klaric IM, Zgaga L, Skaric-Juric T, Wild SH, Richardson WA, Hohenstein P, Kimber CH, Tenesa A, Donnelly LA, Fairbanks LD, Aringer M, McKeigue PM, Ralston SH, Morris AD, Rudan P, Hastie ND, Campbell H, Wright AF.MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK.
Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.
SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.Döring A, Gieger C, Mehta D, Gohlke H, Prokisch H, Coassin S, Fischer G, Henke K, Klopp N, Kronenberg F, Paulweber B, Pfeufer A, Rosskopf D, Völzke H, Illig T, Meitinger T, Wichmann HE, Meisinger C.Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Serum uric acid concentrations are correlated with gout and clinical entities such as cardiovascular disease and diabetes. In the genome-wide association study KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K (n = 1,644), the most significant SNPs associated with uric acid concentrations mapped within introns 4 and 6 of SLC2A9, a gene encoding a putative hexose transporter (effects: -0.23 to -0.36 mg/dl per copy of the minor allele). We replicated these findings in three independent samples from Germany (KORA S4 and SHIP (Study of Health in Pomerania)) and Austria (SAPHIR; Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk), with P values ranging from 1.2 x 10(-8) to 1.0 x 10(-32). Analysis of whole blood RNA expression profiles from a KORA F3 500K subgroup (n = 117) showed a significant association between the SLC2A9 isoform 2 and urate concentrations. The SLC2A9 genotypes also showed significant association with self-reported gout. The proportion of the variance of serum uric acid concentrations explained by genotypes was about 1.2% in men and 6% in women, and the percentage accounted for by expression levels was 3.5% in men and 15% in women.
Un bel exemple de ce que peuvent apporter les études d’association sur génome entier pour comprendre la physiopathologie. En utilisant cette approche, ces deux équipes ont mis en évidence une association entre des polymorphismes introniques ou exoniques du gène SLC2A9 et la concentration d’acide urique. Cette association fortement significative est confirmée sur d’autres populations; l’haplotype moins fréquent est associé à des concentrations d’acide urique plus basses, avec un effet plus fort chez la femme que chez l’homme.
Le gène SLC2A9 code pour GLUT9 qui appartient à la famille de transporteurs des hexoses. GLUT9 participe au transport du fructose et celui-ci était connu pour induire une hyperuricémie (augmentation de la synthèse hépatique). Une de deux équipes montre que GLUT9, exprimé dans l’ovocyte de Xenopus, transporte également de l’acide urique.
Peu-être une piste pour cibler les enfants susceptibles de faire des hyperuricémies par exemple au cours des syndromes de lyse tumorale.
Rosa Vargas-Poussou
Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CN, Knott SA, Kolcic I, Polasek O, Graessler J, Wilson JF, Marinaki A, Riches PL, Shu X, Janicijevic B, Smolej-Narancic N, Gorgoni B, Morgan J, Campbell S, Biloglav Z, Barac-Lauc L, Pericic M, Klaric IM, Zgaga L, Skaric-Juric T, Wild SH, Richardson WA, Hohenstein P, Kimber CH, Tenesa A, Donnelly LA, Fairbanks LD, Aringer M, McKeigue PM, Ralston SH, Morris AD, Rudan P, Hastie ND, Campbell H, Wright AF.MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK.
Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.
SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.Döring A, Gieger C, Mehta D, Gohlke H, Prokisch H, Coassin S, Fischer G, Henke K, Klopp N, Kronenberg F, Paulweber B, Pfeufer A, Rosskopf D, Völzke H, Illig T, Meitinger T, Wichmann HE, Meisinger C.Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Serum uric acid concentrations are correlated with gout and clinical entities such as cardiovascular disease and diabetes. In the genome-wide association study KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K (n = 1,644), the most significant SNPs associated with uric acid concentrations mapped within introns 4 and 6 of SLC2A9, a gene encoding a putative hexose transporter (effects: -0.23 to -0.36 mg/dl per copy of the minor allele). We replicated these findings in three independent samples from Germany (KORA S4 and SHIP (Study of Health in Pomerania)) and Austria (SAPHIR; Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk), with P values ranging from 1.2 x 10(-8) to 1.0 x 10(-32). Analysis of whole blood RNA expression profiles from a KORA F3 500K subgroup (n = 117) showed a significant association between the SLC2A9 isoform 2 and urate concentrations. The SLC2A9 genotypes also showed significant association with self-reported gout. The proportion of the variance of serum uric acid concentrations explained by genotypes was about 1.2% in men and 6% in women, and the percentage accounted for by expression levels was 3.5% in men and 15% in women.
Un bel exemple de ce que peuvent apporter les études d’association sur génome entier pour comprendre la physiopathologie. En utilisant cette approche, ces deux équipes ont mis en évidence une association entre des polymorphismes introniques ou exoniques du gène SLC2A9 et la concentration d’acide urique. Cette association fortement significative est confirmée sur d’autres populations; l’haplotype moins fréquent est associé à des concentrations d’acide urique plus basses, avec un effet plus fort chez la femme que chez l’homme.
Le gène SLC2A9 code pour GLUT9 qui appartient à la famille de transporteurs des hexoses. GLUT9 participe au transport du fructose et celui-ci était connu pour induire une hyperuricémie (augmentation de la synthèse hépatique). Une de deux équipes montre que GLUT9, exprimé dans l’ovocyte de Xenopus, transporte également de l’acide urique.
Peu-être une piste pour cibler les enfants susceptibles de faire des hyperuricémies par exemple au cours des syndromes de lyse tumorale.
Rosa Vargas-Poussou
12/14/2007
L'hémodialyse portable ! L'avenir ?
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
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.
10/08/2005
Néphrose sous ciclosporine, suivi au long cours chez 117 enfants egyptiens
BACKGROUND: Because of its potential nephrotoxicity, the long-term use of cyclosporine (CsA) as treatment for nephrotic syndrome (NS) is controversial. The clinical outcome of the patients with NS treated with CsA is unclear. METHODS: This study reports the results of long-term CsA treatment in 117 children with idiopathic NS, who received CsA therapy for more than 2 years (median, 34 months). The mean age of children at initiation of CsA therapy was 11+/-4 years. The starting dose of CsA was 5 mg/kg/day, adjusted to maintain a trough level of 100-150 ng/ml in the first 2 months, 50-100 ng/ml thereafter. Later, a level as low as 30 ng/ml was accepted so long as it maintained remission. All patients received CsA between 1993 and 2003. Indications for treatment included steroid-dependent nephrotic syndrome (SDNS) in 74 patients and steroid-resistant nephrotic syndrome (SRNS) in 43 patients. Initial renal histology showed minimal change disease (MCD) in 38 patients and focal segmental glomerulosclerosis (FSGS) in 79 patients. Most patients were receiving moderate doses of prednisone. Sixty patients received cyclophosphamide prior to CsA. The observation periods were 5.8+/-3 years and 6.1+/-1.9 years before and after CsA treatment, respectively. RESULTS: Complete remission [proteinuria <4> or = 45 mg/h/m2/BSA) were observed in 82.1, 5.1 and 12.8%, respectively. Hypertension, renal impairment (>30% rise of serum creatinine), gingival hyperplasia and hypertrichosis occurred in 10.3, 6.0, 32.5 and 70.1%, respectively. Steroids were stopped in 102 patients, of which 31 relapsed. Out of 29 patients for whom CsA was intentionally discontinued while in remission, 22 relapsed. Of these, six patients were resistant to a second course of CsA. Post-therapy biopsies, performed in 45 patients (33 with SDNS and 12 with SRNS), showed mild stripped interstitial fibrosis and tubular atrophy in two SDNS patients (4.4%). At the last follow-up, one child had developed end-stage renal failure and two had chronic renal insufficiency. CONCLUSIONS: Long-term CsA therapy in low doses is effective in the treatment of children with idiopathic NS, but the rate of relapse is high after drug withdrawal. Hypertension developed in 10% of patients and renal insufficiency in 6% (most patients with FSGS).
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16204303
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16204303
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