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Background Posterior urethral valves (PUVs) account for 17% of pediatric renal failure. The management of pregnancies involving fetuses with PUV is hampered by the fact that current clinical parameters obtained from fetal ultrasound and/or fetal urine biochemistry are insufficient to predict postnatal renal function. We previously have developed a fetal urine peptide signature (12PUV) that predicted with high precision postnatal renal failure at 2 years of age in fetuses with PUV. Here, we evaluated the accuracy of this signature to predict postnatal renal outcome in fetuses with PUV in an independent single-center study. Methods Thirty-three women carrying fetuses with suspected PUV were included. Twenty-five fetuses received vesicoamniotic shunts during pregnancy. PUV was confirmed postnatally in 23 patients. Of those 23 fetuses, 2 were lost in follow-up. Four and 3 patients died in the pre- and perinatal periods, respectively. Follow-up renal function at 6 months of age was obtained for the remaining 14 patients. The primary outcome was early renal failure, defined by an eGFR < 60 mL/min/1.73 m.sup.2 before 6 months of age or pre- or perinatal death. Results The peptide signature predicted postnatal renal outcome in postnatally confirmed PUV fetuses with an AUC of 0.94 (95%CI 0.74-1.0) and an accuracy of 90% (95%CI 78-100). The signature predicted postnatal renal outcome for the suspected PUV cases with an AUC of 0.89 (95%CI 0.72-0.97) and an accuracy of 84% (95%CI 71-97). Conclusions This single-center study confirms the predictive power of the previously identified 12PUV fetal urinary peptide signature., Author(s): Bénédicte Buffin-Meyer [sup.1] [sup.2] , Marcin Tkaczyk [sup.3] , Malgorzata Stanczyk [sup.3] , Benjamin Breuil [sup.1] [sup.2] , Justyna Siwy [sup.4] , Krzysztof Szaflik [sup.5] , Tomasz Talar [sup.6] [...]

Various uremic toxins accumulate in patients with chronic renal failure (CRF) and one of them is indoxyl sulfate, which accelerates the progression of CRF through unknown mechanisms. The present study investigates how indoxyl sulfate promotes CRF using the proximal tubular cell line HK-2 and CRF rats. Indoxyl sulfate inhibited serum-induced cell proliferation and promoted the activation of senescence-associated [beta]-galactosidase, a marker of cellular senescence, and the expression of [alpha]-smooth muscle actin ([alpha]-SMA), a marker of fibrosis, through inducing p53 expression and phosphorylation. Pifithrin-[alpha], p-nitro, a p53 inhibitor, blocked these effects. Indoxyl sulfate evoked reactive oxygen species (ROS), and the antioxidant N-acetylcysteine inhibited indoxyl sulfate-induced p53 expression and phosphorylation, as well as indoxyl sulfate-induced [alpha]-SMA expression. We previously demonstrated that although cellular senescence and fibrosis are detectable in the kidneys of CRF rats, the oral adsorbent AST-120 repressed these effects. Here, we found that [beta]-galactosidase, p53 and [alpha]-SMA were expressed and colocalized in the renal tubules of CRF rats, whereas AST-120 decreased the expression of these genes. Taken together, these findings indicate that indoxyl sulfate induces the expression and phosphorylation of p53 though ROS production, thus inhibiting cell proliferation and promoting cellular senescence and renal fibrosis. renal failure; uremic toxin; fibrosis; nephrotoxicity doi: 10.1152/ajpcell.00217.2010.

Hemoproteins, hemoglobin and myoglobin, once released from cells can cause severe oxidative damage as a consequence of heine redox cycling between ferric and ferryl states that generates radical species that induce lipid peroxidation. We demonstrate in vitro that acetaminophen inhibits hemoprotein-induced lipid peroxidation by reducing ferryl heme to its ferric state and quenching globin radicals. Severe muscle injury (rhabdomyolysis) is accompanied by the release of myoglobin that becomes deposited in the kidney, causing renal injury. We previously showed in a rat model of rhabdomyolysis that redox cycling between ferric and ferryl myoglobin yields radical species that cause severe oxidative damage to the kidney. In this model, acetaminophen at therapeutic plasma concentrations significantly decreased oxidant injury in the kidney, improved renal function, and reduced renal damage. These findings also provide a hypothesis for potential therapeutic applications for acetaminophen in diseases involving hemoprotein-mediated oxidative injury. isoprostanes | oxidative damage | hemoglobin | myoglobin www.pnas.org/cgi/doi/10.1073/pnas.0910174107

Oxalate-induced oxidative stress contributes to cell injury and promotes renal deposition of calcium oxalate crystals. However, we do not know how oxalate stimulates reactive oxygen species (ROS) in renal tubular epithelial cells. We investigated the signaling mechanism of oxalate-induced ROS formation in these cells and found that oxalate significantly increased membrane-associated protein kinase C (PKC) activity while at the same time lowering cytosolic PKC activity. Oxalate markedly trans-located PKC-[alpha] and -[delta] from the cytosol to the cell membrane. Pretreatment of LLC-[PK.sub.1] cells with specific inhibitors of PKC-[alpha] or -[delta] significantly blocked oxalate-induced generation of superoxide and hydrogen peroxide along with NADPH oxidase activity, LDH release, lipid hydroperoxide formation, and apoptosis. The PKC activator PMA mimicked oxalate's effect on oxidative stress in LLC-[PK.sub.1] cells as well as cytosol-to-membrane translocation of PKC-[alpha] and -[delta]. Silencing of PKC-[alpha] expression by PKC-[alpha]-specific small interfering RNA significantly attenuated oxalate-induced cell injury by decreasing hydrogen peroxide generation and LDH release. We believe this is the first demonstration that PKC-[alpha]- and -[delta]-dependent activation of NADPH oxidase is one of the mechanisms responsible for oxalate-induced oxidative injury in renal tubular epithelial cells. The study suggests that the therapeutic approach might be considered toward attenuating oxalate-induced PKC signaling-mediated oxidative injury in recurrent stone formers. protein kinase C; oxidative stress; calcium oxalate; kidney stone; urolithiasis doi: 10.1152/ajprenal.00051.2009.

Uromodulin-associated kidney disease is a heritable renal disease in humans caused by mutations in the uromodulin (UMOD) gene. The pathogenesis of the disease is mostly unknown. In this study, we describe a novel chemically induced mutant mouse line termed [Umod.sup.A227T] exhibiting impaired renal function. The A227T amino acid exchange may impair uromodulin trafficking, leading to dysfunction of thick ascending limb cells of Henle's loop of the kidney. As a consequence, homozygous mutant mice display azotemia, impaired urine concentration ability, reduced fractional excretion of uric acid, and a selective defect in concentrating urea. Osteopenia in mutant mice is presumably a result of chronic hypercalciuria. In addition, body composition, lipid, and energy metabolism are indirectly affected in heterozygous and homozygous mutant [Umod.sup.A227T] mice, manifesting in reduced body weight, fat mass, and metabolic rate as well as reduced blood cholesterol, triglycerides, and nonesterified fatty acids. In conclusion, [Umod.sup.A227T] might act as a gain-of-toxic-function mutation. Therefore, the [Umod.sup.A227T] mouse line provides novel insights into consequences of disturbed uromodulin excretion regarding renal dysfunction as well as bone, energy, and lipid metabolism. N-ethyl-N-nitrosourea; kidney; renal disease; Umod doi: 10.1152/ajprenal.00261.2009.

Disruption of cell contact sites in renal epithelial cells contributes to organ dysfunction after ischemia. We hypothesized that heat shock protein 27 (Hsp27), a known cytoprotectant protein, preserves cell architecture and cell contact site function during ischemic stress. To test this hypothesis, renal epithelial cells were subjected to transient ATP depletion, an in vitro model of ischemia-reperfusion injury. Compared with control, selective Hsp27 overexpression significantly preserved cell-cell junction function during metabolic stress as evidenced by reduced stress-mediated redistribution of the adherens junction protein E-cadherin, higher transepithelial electrical resistance, and lower unidirectional flux of lucifer yellow. Hsp27 overexpression also preserved paxillin staining within focal adhesion complexes and significantly decreased cell detachment during stress. Surprisingly, Hsp27, an F-actin-capping protein, only minimally reduced stress induced actin cytoskeleton collapse. In contrast to Hsp27 overexpression, siRNA-mediated knockdown had the opposite effect on these parameters. Since ischemia activates c-Src, a tyrosine kinase that disrupts both cell-cell and cell-substrate interactions, the relationship between Hsp27 and c-Src was examined. Although Hsp27 and c-Src did not coimmunoprecipitate and Hsp27 overexpression failed to inhibit whole cell c-Src activation during injury, manipulation of Hsp27 altered active c-Src accumulation at cell contact sites. Specifically, Hsp27 overexpression reduced, whereas Hsp27 knockdown increased active [p-.sup.416]Src detected at contact sites in intact cells as well as in a purified cell membrane fraction. Together, this evidence shows that Hsp27 overexpression prevents sublethal REC injury at cell contact sites possibly by a c-Src-dependent mechanism. Further exploration of the biochemical link between Hsp27 and c-Src could yield therapeutic interventions for ameliorating ischemic renal cell injury and organ dysfunction. ischemia; renal failure; acute kidney injury; ATP depletion; renal epithelial cells

The Br/+ mutant mouse displays decreased embryological expression of the homeobox transcription factor Six2, resulting in hertitable renal hypoplasia. The purpose of this study was to characterize the renal physiological consequences of embryonic haploinsuffiency of Six2 by analyzing renal morphology and function in the adult Br heterozygous mutant. Adult Br/+ kidneys weighed 50% less than those from wild-type mice and displayed glomerulopathy. Stereological analysis of renal glomeruli showed that Br/+ kidneys had an average of 88% fewer glomeruli than +/+ kidneys, whereas individual glomeruli in Br/+ mice maintained an average volume increase of 180% compared with normal nephrons. Immunostaining revealed increased levels of endothelin-1 (ET-1), endothelin receptors A ([ET.sub.A]) and B ([ET.sub.B]), and Na-K-ATPase were present in the dilated renal tubules of mutant mice. Physiological features of chronic renal failure (CRF) including elevated mean arterial pressure, increased plasma creatinine, and dilute urine excretion were measured in Br/+ mutant mice. Electron microscopy of the Br/+ glomeruli revealed pathological alterations such as hypercellularity, extracellular matrix accumulation, and a thick irregular glomerular basement membrane. These results indicate that adult Br/+ mice suffer from CRF associated with reduced nephron number and renal hypoplasia, as well as glomerulopathy. Defects are associated with embryological deficiencies of Six2, suggesting that proper levels of this protein during nephrogenesis are critical for normal glomerular development and adult renal function. Br mutant mouse; glomerulus

Rho kinase signaling regulates inflammatory cell migration and chemokine production. We therefore investigated the mechanisms of Rho-kinase-dependent inflammation in lipopolysaccharide (LPS)-induced renal failure. C57/ BL6 mice received intraperitoneal LPS with or without daily treatment with specific Rho kinase inhibitors (Y-27632 or HA-1077; 5 mg/kg). Rho kinase inhibitors were applied in a preventive (12 or 1 h before LPS) or a therapeutic (6 h after LPS) scheme. Both protected renal function and decreased tubular injury in LPS-treated mice. Enhanced Rho kinase activity was inhibited by HA-1077 in capillary endothelial cells, inflammatory cells, and tubuli by analysis of Rho kinase substrate phosphorylation. Early neutrophil influx was reduced by HA-1077 without reduction of the proinflammatory cytokine TN[F.sub.[alpha]]. In contrast, HA-1077 decreased the influx of monocytes/ macrophages coinciding with reduced expression of the NF-[kappa]B-regulated chemokines CCL5 and CCL2. We therefore examined NF-[kappa]B signal transduction and found that NF-[kappa]B p65 phosphorylation and nuclear translocation were reduced by Rho kinase inhibition. I[kappa]B[alpha] degradation was not altered during the first 6 h but was reduced by HA-1077 at later time points. NF-[kappa]B p50-deficient mice were similarly protected from renal injury by Rho kinase inhibition further supporting the prominent role for p65 in Rho kinase inhibition. Together, these data suggest that Rho kinase inhibition by preventive or therapeutic treatment effectively reduced endotoxic kidney injury in part by attenuation of NF-[kappa]B p65 activation. lipopolysaccharide; nephritis; nuclear factor-[kappa]B

Ischemic nephropathy describes progressive renal failure, defined by significantly reduced glomerular filtration rate, and may be due to renal artery stenosis (RAS), a narrowing of the renal artery. It is unclear whether ischemia is present during RAS since a decrease in renal blood flow (RBF), [O.sub.2] delivery, and [O.sub.2] consumption occurs. The present study tests the hypothesis that despite proportional changes in whole kidney [O.sub.2] delivery and consumption, acute progressive RAS leads to decreases in regional renal tissue [O.sub.2]. Unilateral acute RAS was induced in eight pigs with an extravascular cuff. RBF was measured with an ultrasound flow probe. Cortical and medullary tissue oxygen [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] of the stenotic kidney was measured continuously with sensors during baseline, three sequentially graded decreases in RBF, and recovery. [O.sub.2] consumption decreased proportionally to [O.sub.2] delivery during the graded stenosis (19 [+ or -] 10.8, 48.2 [+ or -] 9.1, 58.9 [+ or -] 4.7 vs. 15.1 [+ or -] 5, 35.4 [+ or -] 3.5, 57 [+ or -] 2.3%, respectively) while arterial venous [O.sub.2] differences were unchanged. Acute RAS produced a sharp reduction in [O.sub.2] efficiency for sodium reabsorption (P < 0.01). Cortical [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] decreases are exceeded by medullary decreases during stenosis (34.8 [+ or -] 1.3%). Decreases in tissue oxygenation, more pronounced in the medulla than the cortex, occur despite proportional reductions in [O.sub.2] delivery and consumption. This demonstrates for the first time that hypoxia is present in the early stages of RAS and suggests a role for hypoxia in the pathophysiology of this disease. Furthermore, the notion that arteriovenous shunting and increased stoichiometric energy requirements are potential contributors toward ensuing hypoxia with graded and progressive acute RAS cannot be excluded. ischemia; renal tissue oxygenation; renal blood flow; pig

Byline: Suzanne Heemskerk (1), Frank M. P. Haren (2), Norbert A. Foudraine (3), Wilbert H. M. Peters (4), Johannes G. Hoeven (5), Frans G. M. Russel (1), Rosalinde Masereeuw (1), Peter Pickkers (5) Keywords: Inducible nitric oxide synthase expression; Acute kidney injury; Glutathione S-Transferase; Nitric oxide metabolites Abstract: Objective We previously demonstrated that upregulation of renal inducible nitric oxide synthase (iNOS) is associated with proximal tubule injury during systemic inflammation in humans. In this study we investigated the short-term effect of methylene blue (MB), an inhibitor of the NO pathway, on kidney damage and function in septic shock patients. Design and setting A prospective clinical study conducted in an intensive care unit. Patients Nine patients (four men, five women, mean age 71a-+-a-3a-years) with confirmed or suspected bacterial infection and with refractory septic shock defined as a mean arterial pressure a$?a-70a-mmHg despite norepinephrine infusion aY=a-0.2a-ug/kg per minute. Interventions A 4a-h continuous intravenous infusion of 1a-mg/kg MB per hour. Measurements and results The urinary excretion of NO metabolites decreased with median 90% (range 75--95%) from baseline to 6a-h after MB administration. The first 24a-h creatinine clearance improved by 51% (18--173%) after MB treatment but was still strongly impaired. During the first 6a-h after the start of MB treatment both the urinary excretion of cytosolic glutathione S-transferase A1-1 and P1-1, markers for proximal and distal tubule damage, respectively, decreased by 45% (10--70%) and 70% (40--85) vs. baseline. After termination of the MB infusion the NO metabolites and markers of tubular injury returned to pretreatment levels. Conclusions In septic patients with refractory shock short-term infusion of MB is associated with a decrease in NO production and an attenuation of the urinary excretion of renal tubular injury markers. Author Affiliation: (1) Department of Pharmacology and Toxicology, Nijmegen Center for Molecular Life Sciences, Radboud University, Nijmegen Medical Centre, 6500 HB, Nijmegen, The Netherlands (2) Department of Intensive Care Medicine, Waikato Hospital, Hamilton, New Zealand (3) Department of Intensive Care Medicine, VieCuri Medical Centre, Venlo, The Netherlands (4) Department of Gastroenterology, Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands (5) Department of Intensive Care Medicine, Radboud University, Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands Article History: Registration Date: 06/09/2007 Received Date: 24/01/2007 Accepted Date: 31/08/2007 Online Date: 10/10/2007 Article note: S.a-H. was supported by a grant from The Netherlands Organization for Scientific Research F.a-v.a-H. was supported by a grant from the Waikato Medical Research Foundation P.a-P. is recipient of a Clinical Fellowship grant of The Netherlands Organization for Scientific Research. Electronic supplementary material The online version of this article (doi: 10.1007/s00134-007-0867-9) contains supplementary material, which is available to authorized users.

The present study evaluated the effects of heme oxygenase-1 (HO-1) induction on the changes in renal outer medullary nitric oxide (NO) and peroxynitrite levels during 45-min renal ischemia and 30-min reperfusion in anesthetized rats. Glomerular filtration rate (GFR), outer medullary blood flow (OMBF), HO and nitric oxide synthase (NOS) isoform expression, and renal low-molecular-weight thiols (--SH) were also determined. During ischemia significant increases in NO levels and peroxynitrite signal were observed (from 832.1 [+ or -] 129.3 to 2,928.6 [+ or -] 502.0 nM and from 3.8 [+ or -] 0.7 to 9.0 [+ or -] 1.6 nA before and during ischemia, respectively) that dropped to preischemic levels during reperfusion. OMBF and--SH significantly decreased after 30 min of reperfusion. Twenty-four hours later, an acute renal failure was observed (GFR 923.0 [+ or -] 66.0 and 253.6 [+ or -] 55.3 [micro]l x [min.sup.-1] x g kidney [wt.sup.-1] in sham-operated and ischemic kidneys, respectively; P < 0.05). The induction of HO-1 (Co[Cl.sub.2] 60 mg/kg sc, 24 h before ischemia) decreased basal NO concentration (99.7 [+ or -] 41.0 nM), although endothelial and neuronal NOS expression were slightly increased. CO[Cl.sub.2] administration also blunted the ischemic increase in NO and peroxynitrite (maximum values of 1,315.6 [+ or -] 445.6 nM and 6.3 [+ or -] 0.5 nA, respectively; P < 0.05), preserving postischemic OMBF and GFR (686.4 [+ or -] 45.2 [micro]l x [min.sup.-1] x g kidney [wt.sup.-1]). These beneficial effects of CO[Cl.sub.2] on ischemic acute renal failure seem to be due to HO-1 induction, because they were abolished by stannous mesoporphyrin, a HO inhibitor. In conclusion, HO-1 induction has a protective effect on ischemic renal failure that seems to be partially mediated by decreasing the excessive production of NO with the subsequent reduction in peroxynitrite formation observed during ischemia. cobalt chloride; nitric oxide stores; Western blot; nitric oxide synthase; peroxynitrite amperometry; nitric oxide voltammetry

Hemolytic uremic syndrome (HUS) is an important cause of acute renal failure in children. Mutations in one or more genes encoding complement-regulatory proteins have been reported in approximately one-third of nondiarrheal, atypical HUS (aHUS) patients, suggesting a defect in the protection of cell surfaces against complement activation in susceptible individuals. Here, we identified a subgroup of aHUS patients showing persistent activation of the complement alternative pathway and found within this subgroup two families with mutations in the gene encoding factor B (BF), a zymogen that carries the catalytic site of the complement alternative pathway convertase (C3bBb). Functional analyses demonstrated that F286L and K323E aHUS-associated BF mutations are gain-of-function mutations that result in enhanced formation of the C3bBb convertase or increased resistance to inactivation by complement regulators. These data expand our understanding of the genetic factors conferring predisposition to aHUS, demonstrate the critical role of the alternative complement pathway in the pathogenesis of aHUS, and provide support for the use of complement-inhibition therapies to prevent or reduce tissue damage caused by dysregulated complement activation. renal disease

Recovery from acute renal failure (ARF) requires the replacement of injured cells with new cells that restore tubule epithelial integrity. We described recently the expression of a wide range of nephrogenic proteins in tubular cells after ARF induced by ischemia-reperfusion (I/R) (Villanueva S, Cespedes C, and Vio CP. Am J Physiol Regul Integr Comp Physiol 290: R861-R870, 2006). These markers, namely, Vimentin, neural cell adhesion molecules (Ncam), basic fibroblast growth factor (bFGF), paired homeobox-2 (Pax-2), bone morphogene protein-7 (BMP-7), Noggin, Lira-1, Engrailed, Smad, phospho-Smad, hypoxia-induced factor-1[alpha] (HIF-1[alpha]), VEGF, and Tie-2, are expressed in a time frame similar to that observed in normal kidney development, bFGF participates in early kidney development as a morphogen involved in mesenchyme/epithelial transition, and it is reexpressed in the recovery phase of ARF. To test the hypothesis that bFGF can accelerate the regeneration after renal damage, we used recombinant bFGF and studied the expression pattern of the above described morphogens in ARF. Male Sprague-Dawley rats were subjected to 30 min of renal ischemic injury and were injected with bFGF 30 [micro]g/kg followed by reperfusion. Rats were killed and the expression of nephrogenic proteins were analyzed by immunohistochemistry and Western blot analysis. In the animals subjected to I/R treated with bFGF, we observed a 12- to 24-h earlier and more abundant reexpression of the proteins Ncam, bFGF, Pax-2, BMP-7, Noggin, Lim-1, Engrailed, VEGF, and Tie-2 than the I/R untreated rats. In addition, we observed a reduction in renal damage markers ED-1 and [alpha]-smooth muscle actin. These results indicate that bFGF can participate in the regeneration process and suggest that the treatment with bFGF can induce an earlier regeneration process after ischemic acute renal failure. kidney; morphogen; regeneration

Acute renal failure (ARF) in septic patients drastically increases the mortality to 50-80%. Sepsis induces several proinflammatory cytokines including tumor necrosis factor-[alpha] (TNF-[alpha]), a major pathogenetic factor in septic ARF. Pentoxifylline has several functions including downregulation of TNF-[alpha] and endothelia-dependent vascular relaxation. We hypothesized that pentoxifylline may afford renal protection during endotoxemia either by downregulating TNF-[alpha] and/or by improving endothelial function. In wild-type mice, pentoxifylline protected against the fall in glomerular filtration rate (GFR; 105.2 [+ or -] 6.6 vs. 50.2 [+ or -] 6.6 [micro]l/min, P < 0.01) at 16 h of LPS administration (2.5 mg/kg ip). This renal protective effect of pentoxifylline was associated with an inhibition of the rise in serum TNF-[alpha] (1.00 [+ or -] 0.55 vs. 7.02 [+ or -] 2.40 pg/ml, P < 0.05) and serum IL-l[beta] (31.3 [+ or -] 3.6 vs. 53.3 [+ or -] 5.9 pg/ml, P < 0.01) induced by LPS. Pentoxifylline also reversed the LPS-related increase in renal iNOS and ICAM-1 and rise in serum nitric oxide (NO). Enhanced red blood cell deformability by pentoxifylline may have increased shear rate and upregulated eNOS. Studies were therefore performed in eNOS knockout mice. The renal protection against endotoxemia with pentoxifylline was again observed as assessed by GFR (119.8 [+ or -] 18.0 vs. 44.5 [+ or -] 16.2 [micro]l/min, P < 0.05) and renal blood flow (0.86 [+ or -] 0.08 vs. 0.59 [+ or -] 0.05 ml/min, P < 0.05). Renal vascular resistance significantly decreased with the pentoxifylline (91.0 [+ or -] 5.8 vs. 178.0 [+ or -] 7.6 mmHg x [ml.sup.-1] x [min.sup.-1], P < 0.01). Thus pentoxifylline, an FDA-approved drug, protects against endotoxemia-related ARF and involves a decrease in serum TNF-[alpha], IL-1[beta], and NO as well as a decrease in renal iNOS and ICAM-1. sepsis; tumor necrosis factor

OBJECTIVES. The goals were to (1) compare the causes, clinical presentation, and prevalence of acute renal failure in pediatric rhabdomyolysis with the published data for adults; (2) determine predictors of acute renal failure in pediatric patients with rhabdomyolysis; and (3) explore the relationship of acute renal failure with treatment modalities such as fluid and bicarbonate administration. METHODS. We performed a retrospective chart review to identify patients with creatinine kinase levels of >1000 IU/L who were treated in the emergency department of a tertiary pediatric hospital between 1993 and 2003, and we constructed regression models. RESULTS. Two hundred ten patients were studied. One hundred ninety-one patients met study eligibility (128 male and 63 female), with a median age of 11 years. The most common documented symptoms were muscle pain (45%), fever (40%), and symptoms of viral infection (39%). The most common causes of pediatric rhabdomyolysis were viral myositis (38%), trauma (26%), and connective tissue disease (5%). Six of 37 patients with creatinine kinase levels of [greater than or equal to] 6000 IU/L had previously undiagnosed dermatomyositis or hereditary metabolic disease, compared with 10 of 154 patients with creatinine kinase levels of 1000 to 5999 IU/L. Nine of 191 patients developed acute renal failure. None of 99 patients with initial urinary heme dipstick results of CONCLUSIONS. The cause of acute pediatric rhabdomyolysis is different from that of adult rhabdomyolysis. The risk of acute renal failure in children is much less than the risk reported for adults. Key Words musculoskeletal complaints, renal failure, renal disease/dysfunction Abbreviations CI--confidence interval CK--creatinine kinase ARF--acute renal failure IQR--interquartile range ED--emergency department VIF--variance inflation factor, RHABDOMYOLYSIS WAS FIRST described in German medical literature by Fleischer in 1881. However, it was not until the work of Bywaters and colleagues, (1,2) who reported 4 cases of renal [...]

A study on use of aprotinin was associated with a dose-dependent doubling to tripling in the risk of renal failure requiring dialysis among patients undergoing primary and complex coronary-artery surgery. The findings indicate that reconsideration of the safety of aprotinin among patients undergoing cardiac surgery is warranted and indicate replacement of aprotinin with either aminocaproic acid or tranexamic acid.

During renal failure, abnormalities of BCAA and branched-chain keto acid (BCKA) metabolism are due to both the lack of renal contribution to amino acid metabolism and the impact of renal failure and acidosis on whole-body nitrogen metabolism. Abnormal BCAA and BCKA metabolism result in BCAA depletion as reflected by low plasma BCAAs and cellular valine. BCAA metabolic disturbances can alter tissue activities, particularly brain function, and nutritional status. In dialysis patients, BCAA oral supplementation can induce an improvement of appetite and nutritional status. During chronic renal failure, the aims of nutritional interventions are to minimize uremic toxicity, avoid malnutrition and delay progression of kidney disease. BCAA and BCKA supplements have been proposed to decrease further protein intake while maintaining satisfactory nutritional status. In this setting, BCAAs or BCKAs have not been administrated solely but in association with other essential AA or keto analogs. Therefore, the proper effects of BCAAs and/or BCKAs have not been studied separately. Protein restriction together with keto acids and/or essential AAs has been reported to improve insulin sensitivity and hyperparathyroidism and to be compatible with a preservation of nutritional status. Nonetheless, a careful monitoring of protein-calorie intake and nutritional status is needed. A recent meta-analysis concluded that reducing protein intake in patients with chronic renal failure reduces the occurrence of renal death by ~40% as compared with larger or unrestricted protein intake. The additional effect of essential amino acids and keto acids on retardation of progression of renal failure has not been demonstrated. KEY WORDS: * branched-chain amino acids * valine, leucine * renal failure * protein metabolism * low-protein diets * nutrition

Byline: Elizabeth Ferrara (1), Jacques Lemire (1,2), Vivian M. Reznik (1,2), Paul C. Grimm (1,2) Keywords: Sevelamer; RenaGel (Genzyme); Hyperphosphatemia; Renal failure; Infants; Toddlers; Pretreatment Abstract: Hyperphosphatemia leading to hyperparathyroidism and ultimately renal osteodystrophy is a well-known complication of chronic renal failure. A new hydrogel binder, sevelamer, has recently become available for use in hyperphosphatemic patients with renal failure. We had previously mixed the capsule with pumped breast milk and formula, but discovered that the hydrogel formed a viscous solution that infants were unable or unwilling to swallow. We therefore evaluated the phosphorus content of fresh and frozen breast milk before and after treating with different doses of sevelamer at different temperatures and for varying lengths of time. The hydrogel bound promptly to phosphorus, reducing the phosphorus content 78% within 5 min. The viscous hydrogel settled to the bottom of the container within 10 min allowing the supernatant to be easily decanted. We also evaluated the breast milk for changes in other electrolytes, osmolality, pH, and macronutrient content. These results show that fresh or frozen breast milk can be safely pretreated with sevelamer without significantly changing its macronutrient or ionic content, with the exception of calcium and protein. The supernatant can be fed to infants or instilled through a gastrostomy tube without difficulty since the viscous hydrogel settles rapidly to the bottom of the container. Author Affiliation: (1) Division of Pediatric Nephrology, Department of Pediatrics, Naval Medical Center San Diego, 34800 Bob Wilson Drive, San Diego, CA 92134--5000, USA (2) Division of Pediatric Nephrology, Department of Pediatrics, University of California San Diego, 200 W. Arbor Drive MC 0831, San Diego, CA 92103, USA Article History: Registration Date: 06/02/2004 Received Date: 26/06/2003 Accepted Date: 28/01/2004 Online Date: 22/04/2004 Article note: The Chief, Bureau of Medicine and Surgery, Navy Department, Washington, D.C., Clinical Investigation Program, sponsored this report S03--014 as required by NSHSBETHINST 6000.41A. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2003.12.010 Byline: Frederick A Masoudi (a)(b), Mary E Plomondon (c), David J Magid (d), Anne Sales (e), John S Rumsfeld (b)(c) Abstract: Although there is accumulating evidence that renal insufficiency is an independent risk factor for mortality after acute myocardial infarction (AMI), it is not known whether renal dysfunction is associated with an increased mortality rate after a broad range of acute coronary syndromes, including unstable angina. Author Affiliation: (a) Department of Medicine, Denver Health Medical Center, Denver, Colo, USA (b) Department of Medicine, University of Colorado Health Sciences Center, Denver, Colo, USA (c) Department of Medicine, Denver VA Medical Center, Denver, Colo, USA (d) Clinical Research Unit, Colorado Permanente Medical Group, Denver, Colo, USA (e) Health Services Research, VA Puget Sound Health Care System, Seattle, Wash, USA Article History: Received 22 January 2003; Accepted 2 December 2003 Article Note: (footnote) [star] Supported by the Veterans Health Administration Health Services Research and Development Service (ACC 97-079). Dr Masoudi is supported by the National Institute on Aging NIH Research Career Award (K08-AG01011). Dr Rumsfeld is supported by VA Health Services Advanced Research Career Development Award (RCD-98-341-2). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.

Byline: Kai Singbartl (1), Klaus Ley (2) Keywords: Kidney failure, acute; Leukocytes; Neutrophils Abstract: Despite advances in medical technology, acute renal failure (ARF) still represents a major challenge in clinical medicine, as morbidity and mortality have remained unchanged over the past two decades. The pathophysiology of ARF is highly complex and only poorly understood new insights into the pathophysiology of ARF are therefore of utmost importance to develop better understanding and therapies. Acute tubular necrosis (ATN) is the predominant cause of ARF and often arises as a consequence of septic, toxic, or ischemic insults. The recruitment of leukocytes into the kidney has recently emerged as a key event in the development of experimental ischemic and septic ARF. A few descriptive clinical studies support this idea. However, the clinical relevance of various animal models remains unclear, as does the importance of different leukocyte subsets, and even methodological aspects as how to quantify renal leukocyte recruitment. This review summarizes and critically evaluates experimental findings that provide insight into the role of leukocytes and their recruitment during ARF. We aim to provide a valid description of ARF, illustrate animal models of ARF, review qualitative and quantitative methods to assess renal leukocyte recruitment, and discuss the components of the leukocyte recruitment cascade and their role in ARF. Author Affiliation: (1) Klinik und Poliklinik fur Anasthesiologie und operative Intensivmedizin, Universitatsklinikum Munster, Albert-Schweitzer-Strasse 33, 48129, Munster, Germany (2) Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA Article History: Received Date: 01/08/2003 Accepted Date: 22/09/2003 Online Date: 10/12/2003

Byline: M.M.J. van der Vorst (1), I. Ruys-Dudok van Heel (3), J.E. Kist-van Holthe (1), J. den Hartigh (2), R.C. Schoemaker (3), A.F. Cohen (3), J. Burggraaf (3) Keywords: Furosemide Child Cardiac surgery Renal insufficiency Abstract: Objective: The commonly used continuous intravenous (IV) furosemide dosing schedule after cardiac surgery in children is largely empirical and may not be optimal. This may even be more marked in children after cardiac surgery who are haemodynamically unstable, and in whom transient renal insufficiency may occur. A study was performed to obtain an impression regarding which clinically applicable measures may be used to design a rational scheme for continuous IV furosemide therapy in children after cardiac surgery. Subjects and methods: Twelve paediatric patients (5F/7 M, age 0--33 weeks) post-cardiac surgery, who were to receive 3 days of continuous IV furosemide treatment, were included in an open study. Blood and urine samples were taken for furosemide, creatinine, and electrolyte levels, and fractionated urinary output was measured. Furosemide in blood and urine was measured using high performance liquid chromatography (HPLC). Results: The mean starting dose of continuous IV furosemide was 0.093 (+-0.016) mg/kg per hour. The mean dose was increased to 0.175 (+-0.045) mg/kg per hour per hour on day 2, and changed to 0.150 (+-0.052) mg/kg per hour on day 3. Infusion rates were increased from day 1 to day 2 in ten cases, and decreased from day 2 to day 3 in three cases. Serum furosemide levels never exceeded ototoxic levels. The urinary furosemide excretion rate was inversely related to serum creatinine levels. Conclusions: This study extends the observation of the beneficial effects of continuous IV furosemide also to those children who are haemodynamically unstable after cardiac surgery. However, as the effects of furosemide are dependent on renal function, it can be hypothesised that the dosing schedule may be optimised. Contrary to the currently used dosage schedule in which the dose of furosemide is gradually increased over time, it may be more rational to start with a higher dose and adapt this dose (downward) guided by the observed effect (urine output). Because the infusion rate was increased to 0.2 mg/kg per hour in nine out of 12 patients on day 2 and was never increased further, this suggests that a starting rate of 0.2 mg/kg per hour may be optimal. Author Affiliation: (1) Department of Paediatrics, Leiden University Medical Centre, PO Box 9600, 2300 Leiden, The Netherlands (2) Department of Clinical Pharmacy and Toxicology of Leiden University Medical Centre, Leiden, The Netherlands (3) Centre for Human Drug Research, Zernikedreef 10, 2333 Leiden, The Netherlands Article History: Received Date: 08/05/2000 Accepted Date: 16/11/2000 Article note: Final revision received: 8 November 2000 Electronic Publication

Byline: M. Bajpai (1), S. Dave (1), D. K. Gupta (1) Keywords: KeywordsaUrethral obstruction; Kidney failure; Urinary diversion; Infant; Newborn Abstract: aChildren with posterior urethral valves (PUV) are at high risk for renal failure (RF). The outcome of renal function is significantly influenced by early diagnosis and the choice of primary therapy. We reviewed the outcome of renal function in 58 children with PUV. The choice of therapy in each case -- primary valve fulguration, vesicostomy, or high ureterostomy -- was individually decided on the basis of the response to initial catheter drainage of the bladder. Patient age at diagnosis varied from newborn to 5.5 years, and follow-up ranged from 1.6 to 6 years (mean 3.9 years). The most common procedure was primary endoscopic valve ablation, which was carried out in 56.8% of cases. The other procedures were vesicostomy in 32.75% and high ureterostomy in 10.45%. Most neonates (66.6%) had RF at presentation, but one-half of them had achieved normal serum creatinine values at last follow-up. The recovery of renal function was lowest (33%) in older children where the diagnosis was delayed. A comparison between two groups of neonates and infants who differed on the basis of creatinine concentrations at 1 year of age suggested a statistically significant trend: children with normal or near-normal serum creatinine (0.8mg/dl or less) by 12 months of age maintained good renal function at the time of final evaluation (1.0mg/dl or less). Children with higher creatinine values at 1 year of age continued to have progressive RF. Seventy-five percent of the patients who had undergone early high ureterostomy after failure to respond to initial catheter drainage had regained normal renal function. We conclude that: serum creatinine at presentation is not predictive of subsequent renal function, but the values after a period of urinary-tract decompression are prognostically more useful delay in diagnosis results in a poor outcome of renal function and for optimal recovery of renal function, the choice of the primary procedure varies from case to case and can be determined by a systematic, stepwise approach (stepladder protocol). Author Affiliation: (1) Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi -- 110029, India, IN Article note: Accepted: 8 May 2000

Byline: T. S. Van der Werf (1), J. W. Fijen (1), N. C. Van de Merbel (2), R. Spanjersberg (1), A. V. M. Moller (3), J. J. M. Ligtenberg (1), J. E. Tulleken (1), J. G. Zijlstra (1), C. A. Stegeman (4) Keywords: Key words Cefpirome; Pharmacokinetics; Renal failure; Multiple organ failure; Continuous veno-venous hemofiltration Abstract: Objective: To study the cefpirome pharmacokinetics of patients with sepsis and multiple organ failure treated with CVVH. Design: Measurements of serum and ultrafiltrate (UF) concentrations and in vitro sensitivity testing of isolated micro-organisms. Setting: University hospital-based, single ICU. Patients: Six critically ill CVVH- dependent patients with sepsis and multiple organ dysfunction syndrome in need of antimicrobial therapy. Age range: 60--75 years APACHE II score for severity of illness on admission: 19--30. One patient survived. Interventions: Cefpirome i. v. was started at 2 g in 30 min, then continued 1 g i. v. b. i. d. Measurements: The UF rate was 27 +- 7 ml/min on day 1 and 34 +- 2 ml/min on day 2. Serum and ultrafiltrate samples were measured by a validated high performance liquid chromatography assay. Volume of distribution: 23 * 5(SD +- 4 * 6) l. Total cefpirome clearance was 32 +- 6 * 3 ml/min cefpirome CVVH clearance (Cl.sub.CVVH): 17 +- 4.2 ml/min mean serum half-life (t.sup.1/2): 8.8 +- 2.3 h mass transfer on day 1: 660 +- 123 mg/12 h (33 +- 6 % of administered dose)and day 2: 642 +- 66 mg/12 h (64 +- 7 %). Estimated sieving coefficient (Cl.sub.CVVH/UF rate): 64 +- 11 %. In vitro sensitivity of isolated microbes was excellent except for two non-sensitive enterococci and Candida spp. Conclusions: The sieving coefficient (64 %) indicates that a substantial fraction of the drug is not filtered clearance by pathways other than CVVH mounted to 50 % of the total clearance and increased on day 2, indicating that the dosing schedule used is appropriate for this setting. Cefpirome appeared to be safe in these patients and effective for most of the nosocomial microbial isolates. During more than 90 % of the time, serum levels were maintained above killing concentrations for susceptible micro-organisms. Author Affiliation: (1) Intensive and Respiratory Care Unit (ICB), Department of Internal Medicine, Groningen University Hospital, PO Box 30.001, 9700 RB Groningen, The Netherlands e-mail: t. s.van.der.werf@int.azg.nl Tel.: + 31-50-3 61 15 01 Fax: + 31-50-3 61 32 16, NL (2) Pharma Bio-Research Group, PO Box 200, 9470 AE Zuidlaren, The Netherlands, NL (3) Department of Medical Microbiology, Groningen University Hospital, PO Box 30.001, 9700 RB Groningen, The Netherlands, NL (4) Division of Nephrology, Department of Internal Medicine, Groningen University Hospital, PO Box 30.001, 9700 RB Groningen, The Netherlands, NL Article note: Received: 23 July 1999 Accepted: 19 October 1999

Byline: A. M. Christensen (1), G. H. Daouk (1), L. L. Norling (1), E. A. Catlin (2), J. R. Ingelfinger (1) Keywords: Key wordsaFeto-fetal transfusion syndrome; Acute renal failure; Twinning; Multiple gestation Abstract: aTwinning and higher-order multiple-gestation pregnancies have become relatively frequent in the current era of assisted reproductive techniques. Vascular interconnections are present in nearly all monochorionic twin placentae, yet hemodynamically significant arteriovenous anastomoses resulting in the feto-fetal transfusion syndrome occur in only 5%--18% of these. When arteriovenous connections through a shared placental cotyledon are present, variable amounts of blood may be transfused from one fetus to the other, and feto-fetal transfusion syndrome may result. While reports of renal failure due to a small non-functioning kidney in the donor infant pre- or postnatally have been published, recoverable renal insufficiency has not been previously delineated in feto-fetal transfusion syndrome. This article describes a case of postnatal transient renal insufficiency in a donor infant from a pair of monozygotic twins. Author Affiliation: (1) Division of Pediatric Nephrology, Pediatric Service, Massachusetts General Hospital, Fruit Street, Boston, MA 02114, USA e-mail: Ingelfinger@helix.mgh.harvard.edu, Tel.: +1-617-726-2908, Fax: +1-617-724-3044, US (2) Division of Neonatology, Pediatric Service, Massachusetts General Hospital, Boston, USA, US Article note: Received: 14 August 1997 / Revised: 25 June 1998 / Accepted: 1 July 1998

Byline: A. M. Simckes (1), Selina S. Chen (2), Alexies V. Osorio (1), Robert E. Garola (3), Gerald M. Woods (4) Keywords: Key wordsaNonsteroidal anti-inflammatory drug; Ketorolac; Sickle cell disease; Perirenal hematoma; Renal failure Abstract: aNonsteroidal anti-inflammatory drugs are often used in the management of those with acute pain secondary to sickle cell disease due to potent analgesic effects along with a lack of addictive potential, respiratory depression, and central nervous system effects, as may occur with narcotics. Caution should be observed in the use of nonsteroidal anti-inflammatory drugs in patients with compromised renal function. We present a case of a 17-year-old sickle cell disease patient with an acute painful episode and normal renal function indices who subsequently developed irreversible renal failure and a perirenal hematoma following the administration of ketorolac, despite adequate hydration. Due to its inhibitory effect on prostaglandin-mediated vasodilation, we advise caution in the use of ketorolac for the pain management of sickle cell painful episodes. We recommend following the administration guidelines for ketorolac for renal-compromised patients in those with painful episodes of sickle cell disease, and if used in this patient population, renal function must be very closely monitored. Author Affiliation: (1) Section of Pediatric Nephrology, The Children&apos;s Mercy Hospital, 2401 Gillham Road, Kansas City, MO 64108, USA Tel.: +1-816-234-3010, Fax: +1-816-234-3494, US (2) School of Medicine, University of Missouri at Kansas City, Kansas City, Missouri, USA, US (3) Department of Pathology, The Children&apos;s Mercy Hospital, Kansas City, Missouri, USA, US (4) Section of Pediatric Hematology-Oncology, The Children&apos;s Mercy Hospital, Kansas City, Missouri, USA, US Article note: Received: 24 March 1998 / Revised: 5 June 1998 / Accepted: 10 June 1998

Introduction: Tenofovir disoproxil fumarate (TDF)–associated renal dysfunction may abate when TDF is replaced with abacavir (ABC). The extent to which the third drug atazanavir contributes to renal dysfunction is unclear. Methods: A retrospective analysis was conducted on adults who had plasma viral load (pVL) Results: A total of 286 patients switched from TDF to ABC between 2004 and 2014: 232 (81%) male, median age 48 years (interquartile range (IQR) 42, 56). The third drug was atazanavir (± ritonavir) in 141 (49%) cases. The pVL was Conclusions: Viral suppression was maintained among patients who switched from TDF/3TC or TDF/FTC to ABC/3TC. Serum creatinine and eGFR improved up to 12 months after switching to ABC/3TC, irrespective of whether or not patients were also receiving atazanavir±ritonavir., Introduction The appropriate use of active antiretroviral therapy (ART) among HIV‐1‐infected individuals leads to the suppression of viral replication, sustained undetectable plasma viral load (pVL) and CD4 recovery. ART thus [...]