Néphroped

La thrombomoduline, un nouvel acteur du SHU atypique

2009-09-04T23:52:00.001+02:00

Thrombomodulin mutations in atypical hemolytic-uremic syndrome.
Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM.
VIB-K.U.Leuven Vesalius Research Center, Leuven, Belgium.
BACKGROUND: The hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The common form of the syndrome is triggered by infection with Shiga toxin-producing bacteria and has a favorable outcome. The less common form of the syndrome, called atypical hemolytic-uremic syndrome, accounts for about 10% of cases, and patients with this form of the syndrome have a poor prognosis. Approximately half of the patients with atypical hemolytic-uremic syndrome have mutations in genes that regulate the complement system. Genetic factors in the remaining cases are unknown. We studied the role of thrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, and cytoprotective properties, in atypical hemolytic-uremic syndrome. METHODS: We sequenced the entire thrombomodulin gene (THBD) in 152 patients with atypical hemolytic-uremic syndrome and in 380 controls. Using purified proteins and cell-expression systems, we investigated whether thrombomodulin regulates the complement system, and we characterized the mechanisms. We evaluated the effects of thrombomodulin missense mutations associated with atypical hemolytic-uremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells. RESULTS: Of 152 patients with atypical hemolytic-uremic syndrome, 7 unrelated patients had six different heterozygous missense THBD mutations. In vitro, thrombomodulin binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I-mediated inactivation of C3b in the presence of cofactors, CFH or C4b binding protein. By promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin variants associated with atypical hemolytic-uremic syndrome had diminished capacity to inactivate C3b and to activate procarboxypeptidase B and were thus less protected from activated complement. CONCLUSIONS: Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic-uremic syndrome. 2009 Massachusetts Medical Society
New Engl J Med Juillet 2009

2009-09-04T23:43:00.002+02:00

Impaired Wnt-beta-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy.
Lancaster MA, Louie CM, Silhavy JL, Sintasath L, Decambre M, Nigam SK, Willert K, Gleeson JG.
Biomedical Sciences Program and Departments of Pediatrics and Medicine, University of California-San Diego (UCSD), La Jolla, California, USA.
Cystic kidney disease represents a major cause of end-stage renal disease, yet the molecular mechanisms of pathogenesis remain largely unclear. Recent emphasis has been placed on a potential role for canonical Wnt signaling, but investigation of this pathway in adult renal homeostasis is lacking. Here we provide evidence of a previously unidentified canonical Wnt activity in adult mammalian kidney homeostasis, the loss of which leads to cystic kidney disease. Loss of the Jouberin (Jbn) protein in mouse leads to the cystic kidney disease nephronophthisis, owing to an unexpected decrease in endogenous Wnt activity. Jbn interacts with and facilitates beta-catenin nuclear accumulation, resulting in positive modulation of downstream transcription. Finally, we show that Jbn is required in vivo for a Wnt response to injury and renal tubule repair, the absence of which triggers cystogenesis.
Nature Medecine Septembre 2009

Devenir à long terme des patients avec une malformation congénital des reins (CAKUT): attention aux biais de recrutement

2009-06-29T10:20:00.001+02:00

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

Des variants dans les gènes du Bartter et du Gitelman font baisser la pression artérielle

2008-05-26T22:15:00.002+02:00

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

Un transporteur des hexoses (GLUT9) se charge aussi de l'acide urique ...

2008-05-25T12:21:00.002+02:00

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

L'hémodialyse portable ! L'avenir ?

2007-12-14T18:55:00.000+01:00

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

L'anti-CD20 contre le diabète auto-immun ...

2007-12-11T10:32:00.000+01:00

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.

Le valsartan protège contre la maladie d'Alzheimer ...

2007-12-11T10:28:00.000+01:00

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 ...

Le FGF23 agit directement sur la glande parathyroïde pour freiner la sécrétion de PTH

2007-12-11T10:16:00.000+01:00

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.

Petit poids de naissance et IRT, un risque augmenté de 70%

2007-12-11T09:45:00.000+01:00

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

L'arginine vasopressine est bien impliquée dans la kystogénèse

2007-12-11T09:27:00.000+01:00

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

Des variants du gène de la podocine (NPHS2) jouent aussi un rôle dans les formes tardives de syndrome néphrotique idiopathique

2007-12-02T17:57:00.000+01:00

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.

Néphrose sous ciclosporine, suivi au long cours chez 117 enfants egyptiens

2005-10-08T11:01:00.000+02:00

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

CD36 et verotoxine, une réaction immunologique croisée à l'origine du SHU ?

2005-10-08T10:51:00.000+02:00

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16197457

Pour faire une SHU: une shigatoxine ET une protéase du facteur Willebrand modifiée, un modèle intéressant chez la souris

2005-10-08T10:47:00.000+02:00

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16200209

Changements ...

2005-09-29T10:12:00.000+02:00

Chers amis,

Je vous propose une petite modification. Les articles sont signalés (voir les quatre articles ci-dessous) avec le lien sur l'abstract PubMed. Les commentaires viennent ensuite. Tout le monde participe bien entendu ! ...

Je rappelle la procédure pour poster un commentaire:

1- cliquer sur le titre du message dans la partie droite de la page sous la rubrique "previous posts"
2- cliquer sur "Post a Comment"

le tout est joué !

Troubles de la déglutition au cours de la cystinose

2005-09-29T09:40:00.000+02:00

Swallowing dysfunction in 101 patients with nephropathic cystinosis: benefit of long-term cysteamine therapy.
Sonies BC, Almajid P, Kleta R, Bernardini I, Gahl WA.
Medicine (Baltimore). 2005 May;84(3):137-46.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15879904&query_hl=10

Examen systématique des urines: que font les pédiatres aux USA ?

2005-09-29T09:36:00.000+02:00

Pediatricians' Screening Urinalysis Practices.
Sox CM, Christakis DA.

J Pediatr. 2005 Sep;147(3):362-365.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16182676&query_hl=8

La mesure ambulatoire de la tension artérielle pour distinguer les HTA secondaires.

2005-09-29T09:34:00.000+02:00

Reduced Nocturnal Blood Pressure dip and Sustained Nighttime Hypertension are Specific Markers of Secondary Hypertension.
Seeman T, Palyzova D, Dusek J, Janda J.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16182677&query_hl=5

Hémodialyse nocturne chez l'enfant

2005-09-29T09:29:00.000+02:00

Home nocturnal hemodialysis in children.Geary DF, Piva E, Tyrrell J, Gajaria MJ, Picone G, Keating LE, Harvey EA.
J Pediatr. 2005 Sep;147(3):383-7.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16182680&query_hl=3

Cystographie: les bonnes pratiques

2005-07-11T17:49:00.000+02:00

How to perform the perfect voiding cystourethrogram.

Agrawalla S, Pearce R, Goodman TR.

Pediatr Radiol. 2004;34:114-9.

The voiding cystourethrogram (VCUG) examination is a difficult investigation toperform and is a stressful experience for patients and their parents, as well asfor the radiologists, technicians and paediatric radiology nurses involved inthe examination. Despite the VCUG being one of the most commonly performedfluoroscopic procedures in paediatric radiology practice, there is no generalconsensus as to the best way to perform this investigation. This is particularlyconcerning when one considers the potentially high gonadal radiation dosechildren may receive. Because of this, we have undertaken a comprehensiveliterature review of various aspects of the test in order to determine the bestway to perform the VCUG in modern paediatric radiology practice.

Premedication during micturating cystourethrogram to achieve sedation and anxiolysis

Akil I, Ozkol M, Ikizoglu OY, Polat M, Tuncyurek OY, Taskin O, Yuksel H.

Pediatr Nephrol. 2005;20:1106-10.

Micturating cystourethrogram (MCUG) is an imaging technique indicated in the diagnosis and follow-up of many diseases. We investigated the reliability and the efficacy of midazolam and chloral hydrate in sedation and anxiolysis during micturating cystourethrogram. Fifty-three children of similar ages (39 girls, 14 boys, mean age of 5.8±3.5 years) were randomized to midazolam (n=17), chloral hydrate (n=18) and control groups (n=18). Oral midazolam 0.6 mg/kg or chloral hydrate 25 mg/kg or saline were administered to the study groups 15–30 min prior to the urinary catheterization. Brietkopf and Buttner, Frankl and Houpt scales and Spielbergers State Anxiety Inventory and parents impressions were used to assess the level of sedation and anxiety. The Brietkopf and Buttner classification of emotional status and Houpt behavior rating scale demonstrated a significantly better emotional status and sedation in the midazolam group when compared to controls (P=0.01 and P=0.018, respectively). The catheterization was described as a more unpleasant and distressing event by the parents of the control and the chloral hydrate groups when compared to the parents of the midazolam group (P<0.05).>0.05). Vital signs did not change significantly in any child. Sedation with midazolam does not have adverse effects on the results of micturating cystourethrogram, while it reduces the discomfort in children undergoing this radiological technique.

Commentaires: quelques suggestions pour améliorer les conditions de cet examen souvent mal vécu par les enfants et leurs parents. Quelles sont les habitudes de vos collègues radiologues ?

Toxicité rénale des AINS

2005-07-11T17:18:00.000+02:00

Acute renal failure, associated with non-steroidal anti-inflammatory drugs in healthy children

Irit Krause1 , Roxana Cleper1, Bella Eisenstein1 and Miriam Davidovits1

Pediatric Nephrology. Juillet 2005, online

Seven patients aged 13 to 17.5 years developed acute renal failure after treatment with a variety of non-steroidal anti-inflammatory drugs (NSAID): naproxen, diclofenac, ibuprofen, dipyrone and paracetamol. Six of the patients used more than one kind of NSAID. None of the patients had previous history of renal disease or concomitant treatment with other drugs. The time interval between NSAID administration to the emergence of symptoms ranged from 1 to 4 days. The most common presenting symptoms were flank pain (4 patients), abdominal pain (3 patients) and vomiting (3 patients). All patients had normal urine output. Microscopic hematuria and proteinuria were found in 5 patients and leukocyturia in 2. Serum creatinine ranged from 1.3 to 8.3 mg% at presentation. Kidney biopsy was performed in 3 patients and showed findings consistent with mild interstitial inflammation in 1 patient, and normal renal tissue in 2. All patients were treated with intravenous fluids, 1 received corticosteroids. Renal function completely normalized in all patients within 7 to 16 days.

Commentaires: Un nouveau témoignage sur les effets des AINS sur le rein ...

Les greffés à donneurs vivants grandiraient mieux: rôles des "cytokines rénales" ?

2005-07-10T17:47:00.000+02:00

Growth in children after kidney transplantation with living related donor graft or cadaveric graft
DrL Pape MDa, , ProfJHH Ehrich MDa, M Zivicnjak PhDa and ProfG Offner MDa

Lancet. 2005;366:151-153

The extent to which growth after renal transplantation differs between children with a living related donor graft (LRD) and those with a cadaveric donor graft (CAD) is unclear. We retrospectively studied growth in the 5 years after transplantation in 30 boys who received LRD and 21 who received CAD. Height was similar in both groups after transplantation but was greater in LRD than in CAD recipients during follow-up. LRD recipients were taller at all ages, and had greater growth velocity in infancy and during puberty. Glomerular filtration rate (GFR) was higher immediately after transplantation in LRD than in CAD recipients, but did not differ between the groups during follow-up. GFR and other factors did not affect height 5 years after transplantation. These findings support use of LRD as the preferred option in children.

Commentaires: Cette étude par le groupe de Hanovre compare la vitesse de croissance après greffe rénale avec donneur vivant ou cadavérique. L'analyse montre une meilleure vitesse de croissance dans le groupe "donneur vivant", qui ne semble pas être le fait d'une meilleure filtration glomérulaitre ni même d'une épargne cortisonique. Les auteurs font l'hypothèse d'une pertubation de l'expression des gènes codant pour certaines cytokines dans les reins après ischémie froide. Cette idée est intéressante mais reste purement spéculative, aucun dosage ou étude d'expression génique n'est ici réalisée. De plus, il faut noter que le nombre de patients étudiés est relativement faible (30 et 21 dans chaque groupe) et la taille des parents n'est pas prise en compte ce qui doit rendre prudent quant à l'interprétation des résutats. Une étude sur un plus grand nombre de greffes s'impose.

Système kallikréine-kinine et paroi artérielle: modulation diététique et génétique

2005-07-07T20:22:00.000+02:00

Arterial and renal consequences of partial genetic deficiency in tissue kallikrein activity in humans.

Azizi M, Boutouyrie P, Bissery A, Agharazii M, Verbeke F, Stern N, Bura-RiviereA, Laurent S, Alhenc-Gelas F, Jeunemaitre X.

J Clin Invest. 2005;115:780-7.

Tissue kallikrein (TK), the major kinin-forming enzyme, is synthesized in several organs, including the kidney and arteries. A loss-of-function polymorphism of the human TK gene (R53H) induces a substantial decrease in enzyme activity. As inactivation of the TK gene in the mouse induces endothelial dysfunction, we investigated the vascular, hormonal, and renal phenotypes of carriers of the 53H allele. In a crossover study, 30 R53R-homozygous and 10 R53H-heterozygous young normotensive white males were randomly assigned to receive both a low sodium-high potassium diet to stimulate TK synthesis and a high sodium-low potassium diet to suppress TK synthesis, each for 1 week. Urinary kallikrein activity was 50-60% lower in R53H subjects than in R53R subjects. Acute flow-dependent vasodilatation and endothelium-independent vasodilatation of the brachial artery were both unaffected in R53H subjects. In contrast, R53H subjects consistently exhibited an increase in wall shear stress and a paradoxical reduction in artery diameter and lumen compared with R53R subjects. Renal and hormonal adaptation to diets was unaffected in R53H subjects. The partial genetic deficiency in TK activity is associated with an inward remodeling of the brachial artery, which is not adapted to a chronic increase in wall shear stress, indicating a new form of arterial dysfunction affecting 5-7% of white people.

Commentaires: Ce travail fort intéressant de l'équipe de Xavier Jeunemaitre montre qu'un polymorphisme dans le gène codant pour la kallikréine présent dans 5 à 7% de la population à peau blanche est associé à une réduction de l'activité de cette enzyme et à une modification des propriétés mécaniques de la paroi artérielle. A coté des facteurs diététiques (Na et K) qui modulent le système kallikréine-kinine, un facteur génétique est donc clairement identifié qui pourrait rendre compte d'une part de l'héritabilité de l'hypertension artérielle.

Spironolactone: utilisation en pédiatrie

2005-06-29T11:04:00.000+02:00

Clinical experience with spironolactone in pediatrics.

Buck ML.

Ann Pharmacother. 2005; 39:823-8.

BACKGROUND: In 2003, the Food and Drug Administration placedspironolactone on its list of drugs needing pediatric studies.OBJECTIVE: To describe the use of spironolactone in a large group ofchildren and evaluate its safety, focusing on its effects on potassium. METHODS: A prospective observational study was conducted. Patient demographic information was collected, as well as dosing regimens, useof other medications, and potassium concentrations. Patients were grouped by diagnosis. Comparisons were made with unpaired t-tests. RESULTS: One hundred consecutive patients were evaluated. The average age was 20.8 months and weight was 9.5 kg. Sixty-two patients had heart disease (HD), 29 had chronic lung disease (CLD), and 9 had other conditions. The initial dose was 1.8 +/- 0.7 mg/kg/day. Patients with CLD received a higher dose than those with HD (2 +/- 0.8 vs 1.7 +/- 0.5mg/kg/day; p = 0.04). Sixty-six patients received furosemide and 37 received thiazides (12 received both). The average potassium concentration after initiation was 4.3 +/- 0.8 mEq/L, with higher values in patients with CLD versus HD (4.7 +/- 0.7 vs 4.2 +/- 0.7 mEq/L; p =0.007). Twenty-six patients required potassium supplementation,including 16 with CLD and 8 with HD; no other adverse effects were noted. Average length of treatment was 16 days, with a length of stay of 38 days. Of the 92 patients surviving to discharge, 66 continued on spironolactone. CONCLUSIONS: This sample demonstrates that spironolactone is a common component of diuretic regimens in pediatric patients. The only adverse effects were alterations in potassium. Whilehyperkalemia was more common initially, hypokalemia was more frequent with long-term use. Potassium concentrations should be carefully monitored, particularly in children receiving multiple diuretics. Additional research is needed to define the pharmacokinetics and optimal dosing interval of spironolactone, as well as determine its long-term effects on potassium.

Quels examens radiologiques après une infection urinaire ?

2005-06-27T22:46:00.000+02:00

The presence of vesicoureteric reflux does not identify a population at risk for renal scarring following a first urinary tract infection.
Moorthy I, Easty M, McHugh K, Ridout D, Biassoni L, Gordon I.

Arch Dis Child. 2005 Jul;90(7):733-6.
BACKGROUND: Childhood urinary tract infection (UTI) with or without vesicoureteric reflux (VUR) may predispose to renal scarring. There is no clear consensus in the literature regarding imaging following UTI in infancy. AIMS: To define the role of cystography following a first UTI in children aged under 1 year, when urinary tract ultrasonography (US) is normal. METHODS: Retrospective data collection of 108 children (216 renal units) aged under 1 year at the time of a bacteriologically proven UTI. All had a normal US and underwent both catheter cystogram and DMSA test. Sensitivity, specificity, likelihood ratios positive and negative, and diagnostic odds ratio were calculated for VUR on cystography versus scarring on DMSA. RESULTS: VUR was shown in 25 (11.6%) renal units. Scarring on DMSA was seen in 8 (3.7 %) kidneys. Only 16% of kidneys with VUR had associated scarring; 50% of scarred kidneys were not associated with VUR. The likelihood ratio positive was 4.95 (95% CI 2.22 to 11.05) and the likelihood ratio negative was 0.56 (95% CI 0.28 to 1.11). The diagnostic odds ratio was 8.9, suggesting that cystography provided little additional information. CONCLUSION: Since only 16% of children with VUR had an abnormal kidney, the presence of VUR does not identify a susceptible population with an abnormal kidney on DMSA. In the context of a normal ultrasound examination, cystography contributes little to the management of children under the age of 1 year with a UTI. In this context, a normal DMSA study reinforces the redundancy of cystography.

Urinary tract infection: is there a need for routine renal ultrasonography?

Zamir G, Sakran W, Horowitz Y, Koren A, Miron D.

Arch Dis Child. 2004;89:466-8.
AIMS: To assess the yield of routine renal ultrasound (RUS) in the management of young children hospitalised with first uncomplicated febrile urinary tract infection (UTI). METHODS: All children aged 0-5 years who had been hospitalised over a two year period with first uncomplicated febrile UTI in a medium size institutional regional medical centre were included. Children with known urinary abnormalities and/or who had been treated with antibacterial agents within seven days before admission were excluded. All included children underwent renal ultrasonography during hospitalisation and voiding cystouretrography (VCUG) within 2-6 months. The yield of RUS was measured by its ability to detect renal abnormalities, its sensitivity, specificity, and positive and negative predictive values for detecting vesicoureteral reflux (VUR), and by its impact on UTI management. RESULTS: Of 255 children that were included in the study, 33 children had mild to moderate renal pelvis dilatation on RUS suggesting VUR, of whom only nine had VUR on VCUG. On the other hand, in 36 children with VUR on VCUG the RUS was normal. The sensitivity, specificity, positive predictive value, and negative predictive value of abnormal RUS for detecting VUR were 17.7%, 87.6%, 23.5%, and 83.2% respectively. In none of the patients with abnormal RUS was a change in the management at or following hospitalisation needed. CONCLUSION: Results show that the yield of RUS to the management of children with first uncomplicated UTI is questionable.

Commentaires: Ces deux articles bousculent un peu les dogmes en posant la question de la pertinence de l'échographie et de la cystographie après un épisode d'infection urinaire chez le nourrisson. Ils font suite à un article de l'équipe d'Hoberman publié il y plus de deux ans dans le New England Journal of Medicine (voir ci-dessous) et qui concluait que l'échographie n'était pas inispensable ! Dans le premier papier les auteurs ont revu les cystographies (conventionnelle chez les garçons et isotopiques chez les filles) de tout les enfants âgés de 0 à 12 mois ayant eu une première infection urinaire. Sur les 108 nourrissons, 25 reflux était mis en evidence dont un seul de haut grade (l'écho était normale). Les corrélations entre la présence d'un RVU et celle de cicatrices ne sont pas bonnes. Les auteurs rappellent que des études récentes sur le long terme ont montré qu'il n'y avait pas de bonnes corrélations entre la présence de cicatrices et l'apparition d'une HTA. La vraie question reste donc celle de savoir s'il faut une antibioprophylaxie en cas de RVU de bas grade.

Dans le deuxième article qui est plus un commentaire de l'article d'Hoberman, l'analyse prospective de 255 cas (0 à 5 ans) montre qu'il n'y a pas de bonne corrélation entre l'écho et la cystographie en terme de prédiction de la présence d'un RVU. Chez les 14.1% des enfants ayant une écho anormale, l'attitude n'a pas été modifiée par le résultat de cet examen. Les auteurs arrivent aux mêmes conclusions qu'Hoberman: si l'écho anténatale est normale il n'est pas nécessaire de faire une écho après une infection urinaire. Encore faut-il être sur de la qualité de l'échographie anténatale ce qui n'est peut-être pas toujours si évident ...

Imaging studies after a first febrile urinary tract infection in young children.

Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER.
N Engl J Med. 2003;348:195-202.

BACKGROUND: Guidelines from the American Academy of Pediatrics recommend obtaining a voiding cystourethrogram and a renal ultrasonogram for young children after a first urinary tract infection; renal scanning with technetium-99m-labeled dimercaptosuccinic acid has also been endorsed by other authorities. We investigated whether imaging studies altered management or improved outcomes in young children with a first febrile urinary tract infection. METHODS: In a prospective trial involving 309 children (1 to 24 months old), an ultrasonogram and an initial renal scan were obtained within 72 hours after diagnosis, contrast voiding cystourethrography was performed one month later, and renal scanning was repeated six months later. RESULTS: The ultrasonographic results were normal in 88 percent of the children (272 of 309); the identified abnormalities did not modify management. Acute pyelonephritis was diagnosed in 61 percent of the children (190 of 309). Thirty-nine percent of the children who underwent cystourethrography (117 of 302) had vesicoureteral reflux; 96 percent of these children (112 of 117) had grade I, II, or III vesicoureteral reflux. Repeated scans were obtained for 89 percent of the children (275 of 309); renal scarring was noted in 9.5 percent of these children (26 of 275). CONCLUSIONS: An ultrasonogram performed at the time of acute illness is of limited value. A voiding cystourethrogram for the identification of reflux is useful only if antimicrobial prophylaxis is effective in reducing reinfections and renal scarring. Renal scans obtained at presentation identify children with acute pyelonephritis, and scans obtained six months later identify those with renal scarring. The routine performance of urinalysis, urine culture, or both during subsequent febrile illnesses in all children with a previous febrile urinary tract infection will probably obviate the need to obtain either early or late scans. Copyright 2003 Massachusetts Medical Society

Petit poids de naissance: dernières publications ...

2005-06-21T17:27:00.000+02:00

Blood pressure in the small-for-gestational age newborn.

Strambi M, Vezzosi P, Buoni S, Berni S, Longini M.

Minerva Pediatr. 2004; 56:603-10.

AIM: The aim of the paper is to verify the existence of an inversecorrelation between birth weight and blood pressure (BP) in neonates,infants and adolescents. METHODS: BP was measured at 7 days, 3, 6, 9, 12months and 7-18 years in 432 subjects born at term at the Department ofPediatrics, Obstetrics and Reproductive Medicine, University of Siena;228 of these subjects were small for gestational age (SGA) and 204appropriate for gestational age (AGA). For small babies, BP was measuredwith a DYNAMAP oscillometer which provides digital visualisation ofsystolic, diastolic and mean arterial pressure and heart rate. In olderchildren, a mercury sphygmomanometer was used. Statistical analysis wascarried out with SPSS 8.01 software using the Kolmogorov-Smirnov testfor normality of populations. RESULTS: Statistical analysis did notreveal any significant differences between SGA and AGA subjects in thevarious age classes of the first 12 months of life. Significantcorrelation was found between 7 and 18 years with differences in thevarious age classes for systolic pressure. Subjects with normalbirthweight had lower systolic and diastolic BP. SGA males had higherrisk of high systolic and diastolic pressure, whereas SGA females wereonly at higher risk for elevated diastolic pressure. CONCLUSIONS: SGAsubjects should be monitored for BP and life-style between 7 and 18years to risk of cardiovascular disease.

Aortic wall thickness in newborns with intrauterine growth restriction.Skilton MR, Evans N, Griffiths KA, Harmer JA, Celermajer DS.

Lancet. 2005;365:1484-6

Much epidemiological evidence has linked low birthweight with late cardiovascular risk. We measured aortic wall thickness (a marker of early atherosclerosis) by ultrasonography in 25 newborn babies with intrauterine growth restriction and 25 with normal birthweight. Maximum aortic thicknesses were significantly higher in the babies with intrauterine growth restriction (810 microm [SD 113]) than in those without (743 microm [76], p=0.02), more so after adjustment for birthweight (300 microm/kg [45] vs 199 microm/kg [29], p<0.0001).>

Long-term renal follow-up of extremely low birth weight infants.

Rodriguez-Soriano J, Aguirre M, Oliveros R, Vallo A.

Pediatr Nephrol. 2005 May;20(5):579-84

There is evidence that low birth weight caused by intrauterine growth retardation adversely affects normal renal development. Very little information on this issue is available on children born very prematurely. This investigation examined clinical and functional renal parameters in 40 children (23 boys, 17 girls) ranging in age between 6.1 and 12.4 years and weighing less than 1000 g at birth. Results were compared to those obtained in 43 healthy children of similar age and gender. Study subjects were significantly smaller and thinner than control subjects (mean height SDS: -0.36 vs. +0.70; and mean BMI SDS: -0.56 vs. +1.18). Systolic, diastolic, and mean blood pressures did not differ from those of controls. Renal sonography revealed no abnormality, and mean percentiles for renal length and volume appeared normal. In comparison with controls, plasma creatinine concentration (0.62+/-0.1 vs. 0.53+/-0.1 mg/dl) and estimated creatinine clearance (117+/-17 vs. 131+/-17 ml min(-1) 1.73 m(-2)) differed significantly. No significant differences were observed in microalbuminuria values, but five study subjects (12.5%) presented values above the upper limit of normality. A defect in tubular phosphate transport was also evident: TmP/GFR (3.6+/-0.4 vs. 4.2+/-0.8 mg/dl) and TRP (83+/-5% vs. 90+/-4%) were significantly lower, and urinary P excretion, estimated by the ratio UP/UCr, was significantly higher (1.2+/-0.4 vs. 0.9+/-0.4 mg/mg) than controls. Urinary calcium excretion, estimated by the UCa/UCr ratio, was also significantly higher (0.15+/-0.07 vs. 0.12+/-0.09 mg/mg). These data clearly demonstrate that both GFR and tubular phosphate transport are significantly diminished in school-age children born with extreme prematurity, probably as a consequence of impaired postnatal nephrogenesis.

Commentaires: Trois publications récentes qui s'ajoutent à la littérature déjà prolixe depuis les premières publications de Barker à propos des conséquences sur la pression artérielle (PA) et la fonction rénale du retard de croissance intra-utérin.

L'étude italienne confirme ce qui a déjà été largement démontré à savoir que chez les enfants nés avec un petit poids de naissance (PPN) la PA est plus élevée à l'adolescence ou à l'âge adulte.

L'étude australienne publiée dans Lancet montre que l'épaisseur de l'intima aortique est plus importante chez les nouveaux-nés avec PPN. Ce marqueur précoce de la maladie athéromateuse est donc visible dès la naissance !

Enfin l'étude espagnole nous montre à partir du suivi de 40 enfants nés avec PN ... (suite ci-dessous)

Syndrome de Gitelman: pourquoi la calciurie est basse ?

2005-06-21T09:59:00.000+02:00

Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia

Tom Nijenhuis1, Volker Vallon2, Annemiete W.C.M. van der Kemp1, Johannes Loffing3, Joost G.J. Hoenderop1 and René J.M. Bindels1

J. Clin. Invest. 115:1651-1658 (2005).

Thiazide diuretics enhance renal Na+ excretion by blocking the Na+-Cl– cotransporter (NCC), and mutations in NCC result in Gitelman syndrome. The mechanisms underlying the accompanying hypocalciuria and hypomagnesemia remain debated. Here, we show that enhanced passive Ca2+ transport in the proximal tubule rather than active Ca2+ transport in distal convolution explains thiazide-induced hypocalciuria. First, micropuncture experiments in mice demonstrated increased reabsorption of Na+ and Ca2+ in the proximal tubule during chronic hydrochlorothiazide (HCTZ) treatment, whereas Ca2+ reabsorption in distal convolution appeared unaffected. Second, HCTZ administration still induced hypocalciuria in transient receptor potential channel subfamily V, member 5–knockout (Trpv5-knockout) mice, in which active distal Ca2+ reabsorption is abolished due to inactivation of the epithelial Ca2+ channel Trpv5. Third, HCTZ upregulated the Na+/H+ exchanger, responsible for the majority of Na+ and, consequently, Ca2+ reabsorption in the proximal tubule, while the expression of proteins involved in active Ca2+ transport was unaltered. Fourth, experiments addressing the time-dependent effect of a single dose of HCTZ showed that the development of hypocalciuria parallels a compensatory increase in Na+ reabsorption secondary to an initial natriuresis. Hypomagnesemia developed during chronic HCTZ administration and in NCC-knockout mice, an animal model of Gitelman syndrome, accompanied by downregulation of the epithelial Mg2+ channel transient receptor potential channel subfamily M, member 6 (Trpm6). Thus, Trpm6 downregulation may represent a general mechanism involved in the pathogenesis of hypomagnesemia accompanying NCC inhibition or inactivation.

Commentaires : cet article propose une explication cohérente, basée sur des expériences solides avec modèles animaux, explication à l’hypocalciurie du syndrome de Gitelman : le syndrome de G est dû à une anomalie du cotransporteur Na Cl dans le tube contourné distal entraînant une perte de sel le plus souvent infraclinique et des signes biologiques nets : hypokaliémie et hypomagnésémie. Il paraissait logique (bien que le mécanisme ne soit pas compris) que l’hypocalciurie constamment associée soit due à une réabsorption accrue du calcium par un mécanisme en cascade situé également dans le tube distal. Cet article propose en fait que la réabsorption du calcium soit accrue dans le tube proximal. (vieille hypothèse classique de la diminution de la réabsorption du calcium dans le TP lorsque les volumes extra cellulaires sont diminués ), la réabsorption du calcium dans le tube distal étant normale.
Quant à l’hypomagnésémie, son mécanisme n’est pas encore très clair…….

Michèle Dechaux

Calcinose tumorale familiale : GALNT3 aussi !

2005-06-21T09:19:00.000+02:00

Identification of a recurrent mutation in GALNT3 demonstrates that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders.

Frishberg Y, Topaz O, Bergman R, Behar D, Fisher D, Gordon D, Richard G, Sprecher E.

J Mol Med. 2005;83:33-8.

Hyperphosphatemia-hyperostosis syndrome (HHS) is a rare autosomal recessive metabolic disorder characterized by elevated serum phosphate levels and repeated attacks of acute, painful swellings of the long bones with radiological evidence of periosteal reaction and cortical hyperostosis. HHS shares several clinical and metabolic features with hyperphosphatemic familial tumoral calcinosis (HFTC), which is caused by mutations in GALNT3 encoding a glycosyltransferase responsible for initiating O-glycosylation. To determine whether GALNT3 is involved in the pathogenesis of HHS we screened two unrelated Arab-Israeli HHS families for pathogenic mutations in this gene. All affected individuals harbored a homozygous splice site mutation (1524+1G-->A) in GALNT3. This mutation was previously described in a large Druze HFTC kindred and has been shown to alter GALNT3 expression and result in ppGalNAc-T3 deficiency. Genotype analysis of six microsatellite markers across the GALNT3 region on 2q24-q31 revealed that the HHS and HFTC families share a common haplotype spanning approximately 0.14 Mb. Our results demonstrate that HHS and HFTC are allelic disorders despite their phenotypic differences and suggest a common origin of the 1524+1G-->A mutation in the Middle East (founder effect). The heterogeneous phenotypic expression of the identified splice site mutation implies the existence of inherited or epigenetic modifying factors of importance in the regulation of ppGalNAc-T3 activity.

Commentaire : Un gène peut en cacher un second ! On apprend dans cet article que les mutations de GALNT3 donnent un tableau identique à celui entrainé par une mutation inhibitrice de FGF23 : la calcinose familiale tumorale... mais également les mutations de GALNT3 se retrouvent aussi dans le syndrome hyperostose hyperphosphatémie. GALNT3 codant pour une glycosyltransferase, et FGF23 étant glycosylé, l'hypothèse (non encore prouvée) reliant toutes ces anomalies est élégante et vient complêter les connaissances sur le métabolisme phosphocalcique.

Vincent Guigonis

La calcinose tumorale familiale: une mutation inactivatrice de FGF23

2005-06-21T09:14:00.000+02:00

An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia.

Benet-Pages A, Orlik P, Strom TM, Lorenz-Depiereux B.

Hum Mol Genet. 2005;14:385-90.

Familial tumoral calcinosis (FTC) is an autosomal recessive disorder characterized by ectopic calcifications and elevated serum phosphate levels. Recently, mutations in the GALNT3 gene have been described to cause FTC. The FTC phenotype is regarded as the metabolic mirror image of hypophosphatemic conditions, where causal mutations are known in genes FGF23 or PHEX. We investigated an individual with FTC who was negative for GALNT3 mutations. Sequencing revealed a homozygous missense mutation in the FGF23 gene (p.S71G) at an amino acid position which is conserved from fish to man. Wild-type FGF23 is secreted as intact protein and processed N-terminal and C-terminal fragments. Expression of the mutated protein in HEK293 cells showed that only the C-terminal fragment is secreted, whereas the intact protein is retained in the Golgi complex. In addition, determination of circulating FGF23 in the affected individual showed a marked increase in the C-terminal fragment. These results suggest that the FGF23 function is decreased by absent or extremely reduced secretion of intact FGF23. We conclude that FGF23 mutations in hypophosphatemic rickets and FTC have opposite effects on phosphate homeostasis.

Commentaire : Le premier d'une série d'articles décrivant le tableau clinique inverse du rachitisme hypophosphorémique secondaire à une mutation inhibitrice de FGF 23 : la calcinose tumorale familiale. A retenir pour les cas d'hyperphosphorémies inexpliquées.

Vincent Guigonis

Présentation initiale du lupus chez l'enfant: une étude multicentrique française

2005-06-17T18:34:00.000+02:00

Initial presentation of childhood-onset systemic lupus erythematosus: a French multicenter study.
Bader-Meunier B, Armengaud JB, Haddad E, Salomon R, Deschenes G, Kone-Paut I, Leblanc T, Loirat C, Niaudet P, Piette JC, Prieur AM, Quartier P, Bouissou F, Foulard M, Leverger G, Lemelle I, Pilet P, Rodiere M, Sirvent N, Cochat P.

J Pediatr. 2005;146:648-53.

OBJECTIVE: To describe the clinical and laboratory manifestations of childhood-onset systemic lupus erythematosus (SLE) at presentation. STUDY DESIGN: This retrospective French multicenter study involved 155 patients in whom SLE developed before the age of 16 years. Mean patient age at onset was 11.5 +/- 2.5 years (range, 1.5-16 years). The female to male ratio was 4.5. RESULTS: The most common initial manifestations were hematologic (72%), cutaneous (70%), musculoskeletal (64%), renal (50%), and fever (58%). Thirty-two percent of children had atypical symptoms, mainly including abdominal involvement in 26 patients, which lead to negative laparotomy results for presumed appendicitis. Severe renal, neurologic, hematologic, abdominal, cardiac, pulmonary, thrombotic, and/or cutaneous manifestations occurred within the first month after the diagnosis in 40% of patients. The mean erythrocyte sedimentation rate was 72 +/- 29 mm/h, and the mean C-reactive protein value 22 +/- 21 mg/L. Antinuclear antibodies an, anti-double stranded DNA antibodies, and low C3 or C4 level were retrieved in 97%, 93%, and 78 % of patients, respectively. CONCLUSION: Initial manifestations of childhood-onset SLE are diverse and often severe. The diagnosis of SLE should be promptly considered in any febrile adolescent with unexplained organ involvement, especially when associated with an increased erythrocyte sedimentation rate.

Commentaires: Cette série rétrospective de 155 enfants atteints d'un lupus à partir d'un questionnaire envoyé aux cliniciens. 65 des 89 services contactés ont répondu dont 13 unités de néphrologie pédiatrique, 10 de rhumatologie, 8 de pédiatrie générale et 2 d'hématologie. Malgré les biais de recrutement inhérents à ce type de d'étude les résultast sont riches d'enseignements. On voit que dans 50% des cas il existe une atteinte rénale dès le début de la maladie, que les manifestations digestives ne sont pas si rares, qu'il existe des antécédents familiaux d'auto-immunité dans 26% des cas, que même dans les cas de lupus "incomplet" selon les critères de l'ACR il peut y avoir une atteinte rénale dans un tiers des cas dès le début, etc ... A lire !

Rappel: Les Archives Françaises de Pédiatrie ont publié l'année dernière un article récapitulant les examens utiles pour le bilan initial et pour le suivi des enfants atteints de lupus. Pratique.

Arch Pediatr. 2004 Aug;11(8):941-4.

SIADH par mutations activatrices du récepteur de la vasopressine

2005-06-16T14:09:00.000+02:00

Nephrogenic syndrome of inappropriate antidiuresis.

Feldman BJ, Rosenthal SM, Vargas GA, Fenwick RG, Huang EA, Matsuda-Abedini M, Lustig RH, Mathias RS, Portale AA, Miller WL, Gitelman SE.

N Engl J Med. 2005 May 5;352(18):1884-90.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. We describe two infants whose clinical and laboratory evaluations were consistent with the presence of SIADH, yet who had undetectable arginine vasopressin (AVP) levels. We hypothesized that they had gain-of-function mutations in the V2 vasopressin receptor (V2R). DNA sequencing of each patient's V2R gene (AVPR2) identified missense mutations in both, with resultant changes in codon 137 from arginine to cysteine or leucine. These novel mutations cause constitutive activation of the receptor and are the likely cause of the patients' SIADH-like clinical picture, which we have termed "nephrogenic syndrome of inappropriate antidiuresis."

Commentaires: A partir de l'analyse de deux cas de syndrome inapproprié de sécrétion d'ADH (SIADH) avec un taux d'AVP bas, les auteurs ont émis l'hypothèse qu'il pouvait y avoir une activation constitutive du récepteur de la vasopressine. L'étude du gène AVPR2 a permi de mettre en évidence une mutation impliquant l'arginine en position 137 chez chacun des patients(R137C et R137L). Curieusement, cette même arginine est remplacée dans certains diabète insipide néphrogénique (R137H), il s'agit alors bien sur d'une mutation inactivatrice.

Les auteurs suggèrent que cette pathologie n'est pas si rare et recommandent d'étudier le gène AVPR2 si l'AVP est basse chez un enfant ayant un SIADH.

Un partenaire inattendu dans le réseau des protéines du diaphragme de fente.

2005-06-13T23:28:00.000+02:00

TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function

Reiser J, Polu KR, Moller CC, Kenlan P, Altintas MM, Wei C, Faul C, Herbert S, Villegas I, Avila-Casado C, McGee M, Sugimoto H, Brown D, Kalluri R, Mundel P, Smith PL, Clapham DE, Pollak MR.

Nat Genet. 2005 May 27

Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.Commentaire: Le groupe de Martin Pollack (Boston) publie dans Nature Genetics du mois de Mai un article montrant la présence de mutation dans le gène TRPC6 codant pour un canal dont le rôle semble essentiel pour le bon fonctionnement de la barrière de filtration glomérulaire. Ce canal est localisé au même endroit dans le podocyte que la néphrine et la podocine avec lesquelles il interagit directement. Des mutations sont retrouvées dans 5 familles avec une HSF tardive se transmettant sur le mode autosomique dominant. Deux de ces mutations entrainnent%

Analyse du poids de naissance chez les jumeaux

2005-06-13T16:56:00.000+02:00

Birth Weight and Creatinine Clearance in Young Adult Twins: Influence of Genetic, Prenatal, and Maternal Factors.
J Am Soc Nephrol. 2005 Jun 8

Previous studies have shown that low birth weight (LBW) is a risk factor for renal impairment in adult life. The effects of LBW and renal function were studied by using twins, which allows distinguishing among fetoplacental, maternal, and genetic influences. Perinatal data were obtained at birth, and absolute creatinine clearance (not corrected for body surface area) was measured at a mean age of 25.6 yr in 653 individuals. Twins were considered both as individuals and as members of twin pairs. Statistical analyses were performed with and without adjusting for gestational age, zygosity, gender, age, body mass index, glucose level, BP, and smoking status. Creatinine clearance was 4 ml/min lower in twins with LBW (<2500 g) than in twins with a high birth weight (P < 0.04, adjusted). Intrapair birth weight difference correlated positively with the intrapair difference in creatinine clearance equally in monozygotic and dizygotic twins (r = 0.35, P < 0.0001; r = 0.43, P < 0.0001, respectively). This suggests that fetoplacental factors are related to renal function and that genetic factors are less important. There was no significant difference in creatinine clearance between twins who both had LBW as compared with twins who both had a high birth weight. This may suggest that maternal factors, which influence the relation between LBW and renal function, are less important. LBW is related to a lower creatinine clearance at adult age. This relationship is probably due to fetoplacental factors. Surprising, genetic and maternal factors seem less important.

Commentaire: la première étude à ma connaissance de ce type qui indique assez clairement même si les différences de clairance ne sont pas énormes que le poids de naissance influe la filtration glomérulaire à long terme. L'effet "maternel" et les facteurs génétiques n'interviennent à priori pas ici.

Création du Blog Nephroped

2005-06-12T22:44:00.000+02:00

Chers amis,

Nous avions émis l'idée de partager au sein de notre groupe nos lectures en créant une sorte de "journal club" par l'intermédiaire d' internet. Le blog pourrait bien être une solution simple et efficace pour réaliser ce projet. Je vous propose d'essayer. Je n'ai personnellement aucune expérience en la matière, nous faisons nos premiers pas ensemble !

Ce blog ne remplace en aucune façon le site web de la SNP mené de mains de maitre par Vincent Guigonis, par contre il pourrait peut-être compléter avantageusement notre liste de diffusion par e-mail (à voir).

Dans un premier temps je vous propose de nous limiter à signaler des articles qui nous ont semblé intéressants en transmettant sur le blog l'abstract tel qu'il apparait dans PubMed et en y ajoutant un commentaire personnel de quelques lignes. Bien entendu l'article est alors ouvert à discussion et chacun peut y aller de son commentaire.

Rémi Salomon