Beneficial effect of insulin-like growth factor-1 on hypoxemic renal dysfunction in the newborn rabbit

Acute normocapnic hypoxemia can cause functional renal insufficiency by increasing renal vascular resistance (RVR), leading to renal hypoperfusion and decreased glomerular filtration rate (GFR). Insulin-like growth factor 1 (IGF-1) activity is low in fetuses and newborns and further decreases during hypoxia. IGF-1 administration to humans and adult animals induces pre- and postglomerular vasodilation, thereby increasing GFR and renal blood flow (RBF). A potential protective effect of IGF-1 on renal function was evaluated in newborn rabbits with hypoxemia-induced renal insufficiency. Renal function and hemodynamic parameters were assessed in 17 anesthetized and mechanically ventilated newborn rabbits. After hypoxemia stabilization, saline solution (time control) or IGF-1 (1mg/kg) was given as an intravenous (i.v.) bolus, and renal function was determined for six 30-min periods. Normocapnic hypoxemia significantly increased RVR (+16%), leading to decreased GFR (−14%), RBF (−19%) and diuresis (−12%), with an increased filtration fraction (FF). Saline solution resulted in a worsening of parameters affected by hypoxemia. Contrarily, although mean blood pressure decreased slightly but significantly, IGF-1 prevented a further increase in RVR, with subsequent improvement of GFR, RBF and diuresis. FF indicated relative postglomerular vasodilation. Although hypoxemia-induced acute renal failure was not completely prevented, IGF-1 elicited efferent vasodilation, thereby precluding a further decline in renal functio

Microalbuminuria and hyperfiltration in subjects with nephro-urological disorders

Background Microalbuminuria (MA) has been shown to be an early biomarker of renal damage. It is postulated that MA is the early result of hyperfiltration, which could evolve into glomerular sclerosis and renal failure if hyperfiltration is left untreated. We hypothesized that MA is a good indicator of hyperfiltration in children with kidney disorders, obviating the need to calculate the filtration fraction (FF). Methods A total of 155 children or young adults were prospectively included [42 single kidney (SK), 61 vesico-ureteral reflux, 23 obstructive uropathies, 29 other kidney diseases]. We measured inulin, para-aminohippuric acid clearances, FF and MA. Prediction of hyperfiltration was explored by studying the association between the FF and other variables such as urinary albumin (Alb), urinary albumin-creatinine ratio (ACR) and creatinine clearance. Results A significant but weak association between urinary Alb or ACR and FF was found in subjects with an SK (Spearman correlation coefficients 0.32 and 0.19, respectively). Multivariate analysis also showed that urinary Alb and ACR significantly predict FF only in subjects with an SK (r2 = 0.17, P = 0.01 and r2 = 0.13, P = 0.02, respectively). This holds true only in subjects with an SK and inulin clearance >90 mL/min/1.73 m2 (r2 = 0.41, P < 0.001). There was no association between creatinine clearance and FF. Conclusions MA is not associated with FF in our subjects with nephro-urological disorders, except in those with an SK, where the association is weak, indicating that MA is due to other mechanisms than high FF and cannot predict hyperfiltration in such group

Assessment of adult formulas for glomerular filtration rate estimation in children

Background: Estimated glomerular filtration rate (eGFR) is an important diagnostic instrument in clinical practice. The National Kidney Foundation-Kidney Disease Quality Initiative (NKF-KDOQI) guidelines do not recommend using formulas developed for adults to estimate GFR in children; however, studies confirming these recommendations are scarce. The aim of our study was to evaluate the accuracy of the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, the Modification of Diet in Renal Disease (MDRD) formula, and the Cockcroft-Gault formula in children with various stages of chronic kidney disease (CKD). Methods: A total of 550 inulin clearance (iGFR) measurements for 391 children were analyzed. The cohort was divided into three groups: group 1, with iGFR >90ml/min/1.73m2; group 2, with iGFR between 60 and 90 ml/min/1.73m2; group 3, with iGFR of <60 ml/min/1.73m2. Results: All formulas overestimate iGFR with a significant bias (p < 0.001), present poor accuracies, and have poor Spearman correlations. For an accuracy of 10%, only 11, 6, and 27% of the eGFRs are accurate when using the MDRD, CKD-EPI, and Cockcroft-Gault formulas, respectively. For an accuracy of 30%, these formulas do not reach the NKF-KDOQI guidelines for validation, with only 25, 20, and 70% of the eGFRs, respectively, being accurate. Conclusions: Based on our results, the performances of all of these formulas are unreliable for eGFR in children across all CKD stages and cannot therefore be applied in the pediatric population grou

Urinary low-molecular-weight protein excretion in pediatric idiopathic nephrotic syndrome

Background: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the most common causes of idiopathic nephrotic syndrome (INS). We have evaluated the reliability of urinary neutrophil-gelatinase-associated lipocalin (uNGAL), urinary alpha1-microglobulin (uα1M) and urinary N-acetyl-beta-D-glucosaminidase (uβNAG) as markers for differentiating MCD from FSGS. We have also evaluated whether these proteins are associated to INS relapses or to glomerular filtration rate (GFR). Methods: The patient cohort comprised 35 children with MCD and nine with FSGS; 19 healthy age-matched children were included in the study as controls. Of the 35 patients, 28 were in remission (21 MCD, 7 FSGS) and 16 were in relapse (14 MCD, 2 FSGS). The prognostic accuracies of these proteins were assessed by receiver operating characteristic (ROC) curve analyses. Results: The level of uNGAL, indexed or not to urinary creatinine (uCreat), was significantly different between children with INS and healthy children (p = 0.02), between healthy children and those with FSGS (p = 0.007) and between children with MCD and those with FSGS (p = 0.01). It was not significantly correlated to proteinuria or GFR levels. The ROC curve analysis showed that a cut-off value of 17ng/mg for the uNGAL/uCreat ratio could be used to distinguish MCD from FSGS with a sensitivity of 0.77 and specificity of 0.78. uβNAG was not significantly different in patients with MCD and those with FSGS (p = 0.86). Only uα1M, indexed or not to uCreat, was significantly (p < 0.001) higher for patients in relapse compared to those in remission. Conclusions: Our results indicate that in our patient cohort uNGAL was a reliable biomarker for differentiating MCD from FSGS independently of proteinuria or GFR level

Transport of the Organic Cation N1-Methylnicotinamide by the Rabbit Proximal Tubule. I. Accumulation in the Isolated Nonperfused Tubule1&apos;2

Prinffii in U.S.A. ABBREVIATIONS: TEA, tetraethylammonium; NMN, N1-methylnicotinamide; PAH, p-aminohippurate; T/M, tubular cell water over medium concentration ratio; HPLC, high performance liquid chromatography

New combined serum creatinine and cystatin C quadratic formula for GFR assessment in children.

BACKGROUND AND OBJECTIVES: The estimated GFR (eGFR) is important in clinical practice. To find the best formula for eGFR, this study assessed the best model of correlation between sinistrin clearance (iGFR) and the solely or combined cystatin C (CysC)- and serum creatinine (SCreat)-derived models. It also evaluated the accuracy of the combined Schwartz formula across all GFR levels. DESIGN, SETTING, PARTICIPANTS, &amp; MEASUREMENTS: Two hundred thirty-eight iGFRs performed between January 2012 and April 2013 for 238 children were analyzed. Regression techniques were used to fit the different equations used for eGFR (i.e., logarithmic, inverse, linear, and quadratic). The performance of each model was evaluated using the Cohen κ correlation coefficient and the percentage reaching 30% accuracy was calculated. RESULTS: The best model of correlation between iGFRs and CysC is linear; however, it presents a low κ coefficient (0.24) and is far below the Kidney Disease Outcomes Quality Initiative targets to be validated, with only 84% of eGFRs reaching accuracy of 30%. SCreat and iGFRs showed the best correlation in a fitted quadratic model with a κ coefficient of 0.53 and 93% accuracy. Adding CysC significantly (P&lt;0.001) increased the κ coefficient to 0.56 and the quadratic model accuracy to 97%. Therefore, a combined SCreat and CysC quadratic formula was derived and internally validated using the cross-validation technique. This quadratic formula significantly outperformed the combined Schwartz formula, which was biased for an iGFR≥91 ml/min per 1.73 m(2). CONCLUSIONS: This study allowed deriving a new combined SCreat and CysC quadratic formula that could replace the combined Schwartz formula, which is accurate only for children with moderate chronic kidney disease

Transient postnatal overfeeding causes liver stress-induced premature senescence in adult mice

International audienceUnbalanced nutrition early in life is increasingly recognized as an important factor in the development of chronic, non-communicable diseases at adulthood, including metabolic diseases. We aimed to determine whether transient postnatal overfeeding (OF) leads to liver stress-induced premature senescence (SIPS) of hepatocytes in association with liver structure and hepatic function alterations. Litters sizes of male C57BL/6 mice were adjusted to 9 pups (normal feeding, NF) or reduced to 3 pups during the lactation period to induce transient postnatal OF. Compared to the NF group, seven-monthold adult mice transiently overfed during the postnatal period were overweight and developed glucose intolerance and insulin resistance. Their livers showed microsteatosis and fibrosis, while hepatic insulin signaling and glucose transporter protein expressions were altered. Increased hepatic oxidative stress (OS) was observed, with increased superoxide anion production, glucose-6-phosphate dehydrogenase protein expression, oxidative DNA damage and decreased levels of antioxidant defense markers, such as superoxide dismutase and catalase proteins. Hepatocyte senescence was characterized by increased p21 WAF , p53, Acp53, p16 INK4a and decreased pRb/Rb and Sirtuin-1 (SIRT-1) protein expression levels. Transient postnatal OF induces liver OS at adulthood, associated with hepatocyte SIPS and alterations in liver structure and hepatic functions, which could be mediated by a SIRT-1 deficiency