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Background: Earlier work on adults undergoing surgery with cardiopulmonary bypass suggests that there is a close relationship between the lower limit of the cerebral and renal autoregulation pressures. Although cerebral autoregulation during bypass in infants has been extensively investigated, the impact of bypass on kidney function is not well known. It is, nevertheless, acknowledged that the main pathophysiological process involved in cardiac surgery-related kidney damage is tubular injury, and that urine neutrophil gelatinase-associated lipocaline (uNGAL) is a reliable biomarker of injury., Objective: To identify the most predictive bypass variable for the measurement of renal injury, its threshold value and the most predictive time below that threshold., Design: Observational study linking electronically recorded bypass perfusion pressure and oxygen delivery rate with intra-operative uNGAL excretion. Variations in bypass variables were accounted for by their excursions below several thresholds., Setting: French tertiary referral paediatric cardiac centre., Patients: A total of 72 infants in whom uNGAL was measured within 1 h of bypass., Interventions: None., Main Outcome Measure: Renal injury, identified by a high creatinine normalised uNGAL concentration (>21.2 μg mmol)., Results: At the end of bypass, 43.75% of infants had high uNGAL. A more than 40% pressure drop below the normal age-standardised mean arterial pressure was associated with high uNGAL. Receiver operating curve [interquartile range] areas were 0.626 [0.501 to 0.752] for a more than 40% drop, and 0.679 [0.555 to 0.804] for a more than 50% drop. A more than 40% pressure drop for 19.5 min provided a 0.65 negative predictive value for high uNGAL, and a more than 50% pressure drop for 5.4 min provided a 0.67 negative predictive value. The link between uNGAL and oxygen delivery rate was negligible., Conclusion: Maintaining the perfusion pressure above 60% of the normal age-standardised mean arterial pressure may provide an effective renal protective strategy., Trial Registration: Registered on October 11, 2010, ClinicalTrials.gov Identifier: NCT01219998.

Background: Vitamin D (25 hydroxyvitamin D [25(OH)D]) deficiency is common in patients with chronic kidney disease (CKD). Neither the relation of this deficiency to the decrease in glomerular filtration rate (GFR) nor the effects on CKD mineral and bone disorders (MBD) are clearly established., Study Design: Cross-sectional analysis of baseline data from a prospective cohort, the NephroTest Study., Setting & Participants: 1,026 adult patients with all-stage CKD not on dialysis therapy or receiving vitamin D supplementation., Predictors: For part 1, measured GFR (mGFR) using (51)Cr-EDTA renal clearance; for part 2, 25(OH)D deficiency at <15 ng/mL., Outcomes & Measurements: For part 1, 25(OH)D deficiency and several circulating MBD markers; for part 2, circulating MBD markers., Results: For part 1, the prevalence of 25(OH)D deficiency was associated inversely with mGFR, ranging from 28%-51% for mGFR ≥60-<15 mL/min/1.73 m(2). It was higher in patients of African origin; those with obesity, diabetes, hypertension, macroalbuminuria, and hypoalbuminemia; and during winter. After adjusting for these factors, ORs for 25(OH)D deficiency increased from 1.4 (95% CI, 0.9-2.3) to 1.4 (95% CI, 0.9-2.1), 1.7 (95% CI, 1.1-2.7), and 1.9 (95% CI, 1.1-3.6) as mGFR decreased from 45-59 to 30-44, 15-29, and <15 (reference, ≥60) mL/min/1.73 m(2) (P for trend = 0.02). For part 2, 25(OH)D deficiency was associated with higher age-, sex-, and mGFR-adjusted ORs of ionized calcium level <1.10 mmol/L (2.6; 95% CI, 1.2-5.9), 1,25 dihydroxyvitamin D concentration <16.7 pg/mL (1.8; 95% CI, 1.3-2.4), hyperparathyroidism (1.8; 95% CI, 1.3-2.4), and serum C-terminal cross-linked collagen type I telopeptides concentration >1,000 pg/mL (1.6; 95% CI, 1.0-2.6). It was not associated with hyperphosphatemia (phosphate >1.38 mmol/L)., Limitations: Cross-sectional analysis of the data prevents causal inferences., Conclusions: 25(OH)D deficiency is related independently to impaired mGFR. Both mGFR decrease and 25(OH)D deficiency are associated with abnormal levels of circulating MBD biomarkers., (Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Glomerular filtration rate (GFR) decline with age increases the risk of inappropriate dosing of drugs. We investigated the determinants and the mortality associated with the use of drugs that are contraindicated or require dose adjustment according to kidney function among the community-dwelling elderly., Methods: The Three-City population-based study included 8701 participants ≥65 years from 1999 to 2001. Exposure to the risk of inappropriate drug dosage was defined as reported use of either a contraindicated drug or one requiring dose adjustment according to the individual baseline glomerular filtration rate estimated (eGFR) with the Modification of Diet in Renal disease study equation. Six-year mortality was analysed using Cox models adjusted for several sociodemographic, biologic and clinical risk factors., Results: The overall percentage of exposure to the risk of inappropriate drug use was 13.3% (contraindication, 0.8%): it was 52.5% (4.5%) in those with an eGFR of 30-59 and 96% (48%) in those <30 mL/min/1.73 m(2). Antihypertensive agents, fibrates and psycholeptics accounted for most of the drugs with dosing recommendations and antidiabetic agents and antihistamines for those contraindicated. Individuals at risk were more likely to be men, older, and under treatment for hypertension or hypercholesterolemia. Exposure to either risk was independently related to higher all-cause mortality (hazard ratio 1.4, 95% confidence interval 1.0-1.9) in participants with eGFR <60 mL/min/1.73 m(2)., Conclusions: Contraindicated drug prescription was uncommon but >10% of the population took drugs requiring renal dosing adjustments. Regular monitoring of eGFR may prevent excess mortality associated with inappropriate drug prescription in the elderly.

We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m² lower eGFR below a threshold of 45 ml/min per 1.73 m² was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD.

Background: The objective of this study was to use information from a donor to establish the lowest possible serum creatinine (SCr) of the recipient as a means of identifying early graft dysfunction., Methods: We analyzed retrospectively 58 pairs of living donors and recipients. The lowest possible SCr was calculated from four different formulae derived from Cockcroft-Gault formula: Ax(140-recipient age)xrecipient weight/donor GFR (A, women: 1.04, men: 1.23). Donor GFR was represented by the following values (a) mSCrD0: measured pretransplant GFR for both kidneys, (b) mSCrSKD0: single transplanted kidney GFR on day 0, (c) eSCrD0: estimated GFR based on SCr at day 0, or (d) eSCrD30: on day 30. These resulting estimated SCr were tested for correlation coefficient, bias, precision, and accuracy in predicting the lowest observed recipient SCr during the first year posttransplant., Results: The lowest possible SCr was 80+/-22 micromol/L for mSCrD0, 79.1+/-23 micromol/L for mSCrSKD0, 83+/-27 micromol/L for eSCrD0, and 115+/-22 micromol/L for eSCrD30. Mean values for lowest possible SCr correlated significantly with the lowest observed SCr for all four formulae. The eSCrD0 formula showed the best correlation (r=0.47), the smallest positive bias (20.5 micromol/L), the highest precision (21.9 micromol/L), and the second highest percentage of predicted values that fell within 30% of the observed SCr (69%)., Conclusion: The use of the Cockcroft-Gault derived formula with eSCrD0 may be a useful tool to detect early discrepancy between observed and lowest possible SCr value. This could help to identify patients who may require invasive investigations.

Apical bumetanide-sensitive Na(+)-K(+)-2Cl(-) co-transporter, termed NKCC2, is the major salt transport pathway in kidney thick ascending limb. NKCC2 surface expression is subject to regulation by intracellular protein trafficking. However, the protein partners involved in the intracellular trafficking of NKCC2 remain unknown. Moreover, studies aimed at under-standing the post-translational regulation of NKCC2 have been hampered by the difficulty to express NKCC2 protein in mammalian cells. Here we were able to express NKCC2 protein in renal epithelial cells by tagging its N-terminal domain. To gain insights into the regulation of NKCC2 trafficking, we screened for interaction partners of NKCC2 with the yeast two-hybrid system, using the C-terminal tail of NKCC2 as bait. Aldolase B was identified as a dominant and novel interacting protein. Real time PCR on renal microdissected tubules demonstrated the expression of aldolase B in the thick ascending limb. Co-immunoprecipitation and co-immunolocalization experiments confirmed NKCC2-aldolase interaction in renal cells. Biotinylation assays showed that aldolase co-expression reduces NKCC2 surface expression. In the presence of aldolase substrate, fructose 1,6-bisphosphate, aldolase binding was disrupted, and aldolase co-expression had no further effect on the cell surface level of NKCC2. Finally, functional studies demonstrated that aldolase-induced down-regulation of NKCC2 at the plasma membrane was associated with a decrease in its transport activity. In summary, we identified aldolase B as a novel NKCC2 binding partner that plays a key role in the modulation of NKCC2 surface expression, thereby revealing a new regulatory mechanism governing the co-transporter intracellular trafficking. Furthermore, NKCC2 protein expression in mammalian cells and its regulation by protein-protein interactions, described here, may open new and important avenues in studying the cell biology and post-transcriptional regulation of the co-transporter.