Acute Renal Failure In Children Research Articles

Microalbuminuria and early renal response to lethal dose Shiga toxin type 2 in rats

In Argentina, hemolytic uremic syndrome (HUS) constitutes the most frequent cause of acute renal failure in children. Approximately 2%–4% of patients die during the acute phase, and one-third of the 96% who survive are at risk of chronic renal sequelae. Little information is available about the direct effect of Shiga toxin type 2 (Stx2) on the onset of proteinuria and the evolution of toxin-mediated glomerular or tubular injury. In this work, rats were injected intraperitoneally with recombinant Escherichia coli culture supernatant containing Stx2 (sStx2; 20 μg/kg body weight) to induce HUS. Functional, immunoblotting, and immunohistochemistry studies were carried out to determine alterations in slit diaphragm proteins and the proximal tubule endocytic system at 48 hours post-inoculation. We detected a significant increase in microalbuminuria, without changes in the proteinuria values compared to the control rats. In immunoperoxidase studies, the renal tubules and glomerular mesangium showed an increased expression of transforming growth factor β1(TGF-β1). The expression of megalin was decreased by immunoperoxidase and the cytoplasm showed a granular pattern of megalin expression by immunofluorescence techniques. Western blot analysis performed in the renal cortex from sStx2-treated and control rats using anti-nephrin and anti-podocalyxin antibodies showed a decreased expression of these proteins. We suggest that the alterations in slit diaphragm proteins and megalin expression could be related to the development of microalbuminuria in response to lethal doses of Stx2.

Mouse model for hemolytic uremic syndrome induced by outer membrane vesicles ofEscherichia coliO157:H7

Hemolytic uremic syndrome (HUS) is characterized by acute renal failure in children and is typically complicated with thrombocytopenia and hemolytic anemia. Although mouse models of HUS have been evaluated using Shiga toxin (STx) combined with or without lipopolysaccharide (LPS), no HUS model has been tested using purified outer membrane vesicles (OMVs) from STx-producing Escherichia coli (STEC) O157:H7. Accordingly, we investigated whether OMVs of STEC O157:H7 conveying STx2 and LPS can cause HUS-like symptoms in mice inoculated intraperitoneally. Three types of OMVs differing in LPS acylation status and STx2 amount were used to compare their ability to induce HUS-like symptoms. Native OMVs (nOMV) with fully hexa-acylated LPS caused HUS-like symptoms at 72-96h after dually divided injections of 1μg nOMV per animal. However, elevated doses of modified OMVs (mOMV) carrying mainly penta-acylated LPS were required to induce similar HUS signs. Moreover, mitomycin-C-induced OMVs (mcOMV) that were enriched with STx2 induced HUS-like symptoms similar to those of nOMV at the same dose. These results suggest that the OMVs of STEC O157:H7 potentiated with STx2 and fully hexa-acylated LPS can be utilized for inducing HUS-like symptoms in mice and could be the causative material involved in the development of HUS.

Melamine toxicity: one more culprit in calcium kidney lithiasis

An outbreak of uric acid and melamine kidney stones and obstructive acute renal failure in children appeared recently in China due to the ingestion of melamine-tainted formula. Liu and colleagues show that calcium urolithiasis is also strongly associated with urine melamine in adults in Taiwan. Although its effect measure is still uncertain, such an association is likely to be causal. These findings prompt further research into the source of exposure, impact in other settings, and changes over time.

Is complement a culprit in infection-induced forms of haemolytic uraemic syndrome?

Haemolytic uraemic syndrome (HUS) accounts for the most common cause of childhood acute renal failure. Characterized by the classical triad of a microangiopathic haemolytic anaemia, thrombocytopaenia and acute renal failure, HUS occurs as a result of Shiga-toxin producing microbes in 90% of cases. The remaining 10% of cases represent a heterogeneous subgroup in which inherited and acquired forms of complement dysregulation have been described in up to 60%. Emerging evidence suggests that microbes associated with HUS exhibit interaction with the complement system. With the advent of improved genetic diagnosis, it is likely that certain cases of infection-induced HUS may be attributed to underlying defects in complement components. This review summarises the interplay between complement and infection in the pathogenesis of HUS.

A Glucosylceramide Synthase Inhibitor Protects Rats Against the Cytotoxic Effects of Shiga Toxin 2

Postdiarrhea hemolytic uremic syndrome is the most common cause of acute renal failure in children in Argentina. Renal damage has been strongly associated with Shiga toxin (Stx), which binds to the globotriaosylceramide (Gb3) receptor on the plasma membrane of target cells. The purpose of the study was to evaluate the in vivo effects of C-9, a potent inhibitor of glucosylceramide synthase and Gb3 synthesis, on kidney and colon in an experimental model of hemolytic uremic syndrome in rats. Rats were i.p. injected with supernatant from recombinant Escherichia coli expressing Stx2 (sStx2). A group of these rats were orally treated with C-9 during 6 d, from 2 d prior until 4 d after sStx2 injection. The injection of sStx2 caused renal damage as well as a loss of goblet cells in colonic mucosa. Oral treatment with C-9 significantly decreased rat mortality to 50% and reduced the extension of renal and intestinal injuries in the surviving rats. The C-9 also decreased Gb3 and glucosylceramide expression levels in rat kidneys. It is particularly interesting that an improvement was seen when C-9 was administered 2 d before challenge, which makes it potentially useful for prophylaxis.

Nonenteropathic Hemolytic Uremic Syndrome: The Experience of a Medical Center

Hemolytic uremic syndrome (HUS) is an uncommon cause of acute renal failure in children. In contrast to Western countries, most HUSs in Taiwan are caused by Streptococcus pneumoniae. In this article, we demonstrate the clinical courses of children with HUS in Taiwan and try to explain the pathophysiology of complications. We retrospectively reviewed the medical records of children with HUS who were admitted to the Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan, between January 1997 and February 2008. The clinical courses, laboratory data, complications, and prognosis were recorded. We divided the patients into dialysis group and non-dialysis group. The laboratory data for the two groups were expressed as mean, standard deviation, and range. Nine patients were enrolled in the study, and all were diagnosed with S pneumoniae-associated HUS. One patient had meningitis, and the others had pneumonia. The mean durations of anemia and thrombocytopenia were 19.2 days and 10.2 days, respectively. Five patients received renal replacement therapy because of oligouria. The average of the peak total bilirubin levels of patients in the dialysis and non-dialysis groups were 24.6 ± 20.7mg/dL and 3.8 ± 1.9mg/dL, respectively. In addition to one patient who had meningitis, four other patients experienced central nervous system (CNS) complications. The mean durations of hypertension in five patients with CNS manifestations and four patients without CNS manifestations were 16.8 ± 7.8 days and 4.8 ± 6.6 days, respectively. Two patients died in acute stage, and most of the others had regained normal renal function at discharge or during follow-up. (1) Streptococcus pneumoniae is the most common causative pathogen of HUS in Taiwan; (2) the mean duration of hypertension in patients with CNS manifestations was much longer than that in patients without CNS manifestations; and (3) the average of the peak total bilirubin levels of patients in the dialysis group was much higher than that in the patients of the non-dialysis group.

Management of Acute Renal Failure in the Pediatric Intensive Care Unit

Pediatric acute renal failure (ARF) is a dynamic entity that has many causes. ARF is frequently seen in the pediatric population and is associated with increased mortality and long-term morbidity rates. Of importance is its early detection so as to allow interventions to either prevent or treat the disease timely during its course. Recent developments in the definitions and classification schemes and the identification of new biomarkers shall allow better predictive interventions for childhood ARF. ARF management in children requires special considerations. Optimal care for the pediatric patient requiring renal replacement therapy requires an understanding of the causes and patterns of pediatric ARF and recognition of the local expertise with respect to the personnel and equipment resources. The aim of this article is to review pediatric ARF management with an emphasis on emerging practice patterns and the modalities for renal replacement therapy.

354 Ouabain Protects Against Shiga Toxin Induced Renal Tubular Cell Apoptosis

Context: Though typical Hemolytic Uremic Syndrome - mainly caused by Shiga toxin (Stx) produced by Escherichia coli - is a major cause of acute renal failure in children, the available treatments remain symptomatic. The aim of our experimental study was to determine whether ouabain (OB) at non-inhibitive concentrations could decrease the shigatoxin-induced apoptotic level. Methods: Experiments were performed in rat proximal tubule cells (RPTC) cultured with Stx 2-4ng/mL, and treated with OB 5-10 nM. Group comparison was measured with the Apoptotic index, DNA fragmentation, and Fluorescence activated cell sorter (FACS). Immunoprecipitation and immunostaining techniques were used to determine the pathway of the antiapototic effect of OB. Results: Stx 3-4 ng/mL significantly increased the apoptotic index in comparison to the control group. OB 5 nM significantly decreased the apoptotic index in RPTC exposed to Stx 3- 4 ng/mL (Apotptotic index %: Stx3 6.4±3.2 versus Stx3+OB 1.5±2.4, p=0.003; Stx4 8.6±8.9 vs. 2.1±1.3, p< 10-4). It also decreased the level of DNA. FACS analyses demonstrated that OB drastically protected RPTC from Stx cytotoxins. Furthermore, immunoprecipitation as well as specific immunostaining showed that OB's protective effect was mediated through the Na, K-ATPase /IP3R interaction and triggering NFkB activity. Conclusion: Our results state that ouabain may be an interesting therapeutic agent to reduce kidney damage in children with HUS.

Shiga toxin 1 and ricin A chain bind to human polymorphonuclear leucocytes through a common receptor

The main cause of acute renal failure in children is HUS (haemolytic uraemic syndrome), a consequence of intestinal infections with Escherichia coli strains producing Stx (Shiga toxins). Stx released in the gut by the non-invasive bacteria reach the bloodstream and are targeted to cerebral and renal endothelium triggering HUS. PMN (polymorphonuclear leucocytes) seem to be involved in Stx delivery through an unidentified membrane receptor (Kd=10⁻⁸ M; 2×10⁵ binding sites) which does not allow internalization. Some experts in the field have defined the Stx-PMN interaction as non-specific and of little biological significance. In the present study, we show that the A chain of ricin, the well-known plant RIP (ribosome-inactivating protein), interacts with PMN (Kd=10⁻⁹ M; 2×10⁵ binding sites) competing for the same receptor that recognizes Stx, whereas diphtheria toxin and several agonists of TLRs (Toll-like receptors) or the mannose receptor were ineffective. No toxic effects of ricin A chain on PMN were observed, as assessed by measuring protein synthesis and the rate of spontaneous apoptosis of leucocytes. Moreover, two single-chain RIPs (gelonin and saporin S6) had the same competing effect. Thus RIPs and Stx1 share structural similarities, the same enzymatic activity and a common receptor on PMN. These observations reveal that the Stx-PMN interaction is specific, confirming that PMN recognize molecular patterns common to different foreign molecules.

Advances in our understanding of the pathogenesis of glomerular thrombotic microangiopathy

Glomerular thrombotic microangiopathy is a hallmark feature of haemolytic uraemic syndrome, the leading cause of acute renal failure in childhood. This paper is a review of the different mechanistic pathways that lead to this histological picture in the kidney. It will focus on atypical HUS and complement dysregulation, but will also highlight some other recent advances in our understanding of this condition, including the potential role of the molecule vascular endothelial growth factor- A (VEGF-A).

Characterization of Stx2 Tubular Response in a Rat Experimental Model of Hemolytic Uremic Syndrome

Background/Aims: In Argentina, hemolytic uremic syndrome (HUS) constitutes the most frequent cause of acute renal failure in children. The aim of our study was to analyze the early tubular response under the effect of Shiga toxin type 2 (Stx2) in a rat experimental model of HUS. Methods: Adult male Sprague-Dawley rats were injected intraperitoneally with culture supernatant from recombinant Escherichia coli expressing Stx2. Functional, histological, immunohistochemical and Western blot studies were performed at 48 h postinoculation. Results: Renal tubules showed the loss of the epithelial markers E-cadherin and β-catenin, and an increase in transforming growth factor-β1 expression. We detected the expression of α-smooth muscle actin in the interstitium and fibrosis in the periglomerular areas. Conclusion: Our results indicate that the early tubular response to the effects of Stx2 is related to an immunophenotype change of tubular cells and the presence of mild fibrosis in the interstitium.

Postinfectious glomerulonephritis: a case summary

Summary Postinfectious glomerulonephritis is the most common cause of nephritic syndrome and acute renal failure in children. This condition usually results from a recent group A streptococcal infection and the diagnosis is based on clinical suspicion and laboratory data. This case describes a child with new onset hypertension and a past history of untreated streptococcal pharyngitis. Treatment is supportive and recent reviews demonstrate that antibiotic therapy directed at the infection does not modify the course of glomerulonephritis.

Pneumococcal Induced T-activation with Resultant Thrombotic Microangiopathy

Thrombotic microangiopathies are disorders resulting from platelet thromboses forming in the microvasculature with resultant schistocyte forms. Hemolytic uremic syndrome (HUS) is a microangiopathic hemolytic anemia often complicated by acute renal failure in children. HUS is typically caused by bacterial infection, most commonly enterohemorrhagic Escherichia coli. Neuraminidase-producing organisms, such as Streptococcus pneumoniae have also been reported as potential etiologies. The pathogenesis in these cases involves cleavage of sialic acid residues from the surfaces of erythrocytes, platelets, and glomerular capillary endothelial cells, exposing the Thomsen-Friedenreich antigen, a process known as T-activation. We describe a 2-year-old girl who presented with pneumococcal pneumonia and sepsis ultimately resulting in a thrombotic microangiopathy with acute renal failure, most consistent with HUS. The patient's direct antiglobulin test was positive. Polyagglutination was observed with human adult serum, but not with umbilical cord serum. Her red blood cells (RBCs) were reactive against peanut and soybean lectins, but not Salvia sclarea or Salvia horminum lectins. These findings are consistent with T-activation. Clinicians should be cognizant of the possibility of T-activation with resultant HUS in patients infected with neuraminidase-producing bacteria. Such patients may be difficult to identify using monoclonal typing antisera, as these typically do not have anti-T antibodies. Whether such patients are at risk for transfusion-associated hemolysis is debatable.

The MAP kinase-activated protein kinase 2 (MK2) contributes to the Shiga toxin-induced inflammatory response

Infection with Shiga toxin (STx)-producing bacteria can progress to a toxemic, extraintestinal injury cascade known as haemolytic uremic syndrome (HUS), the leading cause of acute renal failure in children. Mounting evidence suggests that STx activates stress response pathways in susceptible cells and has implicated the p38 mitogen-activated protein kinase (MAPK) pathway. More importantly, some of the pathology associated with HUS is believed to be a result of a STx-induced inflammatory response. From a siRNA screen of the human kinome adapted to a high-throughput format, we found that knock-down of the MAPK-activated protein kinase 2 (MK2), a downstream target of the p38 MAPK, protected against Shiga toxicity. Further characterization of the in vitro role of MK2 revealed that STx activates the p38-MK2 stress response pathway in both p38- and MK2-dependent manners in two distinct cell lines. MK2 activation was specific to damage to the ribosome by an enzymatically active toxin and did not result from translational inhibition per se. Genetic and chemical inhibition of MK2 significantly decreased the inflammatory response to STx. These findings suggest that MK2 inhibition might play a valuable role in decreasing the immuopathological component of STx-mediated disease.

Hemolytic-uremic syndrome in Switzerland: a nationwide surveillance 1997–2003

Hemolytic-uremic syndrome (HUS) is a leading cause of acute renal failure in childhood. In its typical presentation, it is preceded by an episode of diarrhea mostly due to Shiga-toxin-producing Escherichia coli. There is important geographical variation of many aspects of this syndrome. Nationwide data on childhood HUS in Switzerland have not been available so far. In a prospective national study through the Swiss Pediatric Surveillance Unit 114 cases (median age 21 months, 50% boys) were reported between April 1997 and March 2003 by 38 pediatric units (annual incidence 1.42 per 10(5) children < or =16 years). Shiga-toxin-producing E. coli were isolated in 32 (60%) of tested stool samples, serotype O157:H7 in eight. Sixteen children presented with only minimal renal involvement, including three with underlying urinary tract infection. Six patients presented with atypical hemolytic-uremic syndrome, and six with HUS due to invasive Streptococcus pneumoniae infection. Mortality was 5.3%, including two out of six children with S. pneumoniae infection. The severity of thrombocytopenia and the presence of central nervous system involvement significantly correlated with mortality. In conclusion, childhood HUS is not rare in Switzerland. Contrasting other countries, E. coli O157:H7 play only a minor role in the etiology. Incomplete manifestation is not uncommon.

Clinical practice

The haemolytic uraemic syndrome (HUS) includes the triad of haemolytic anaemia, thrombocytopenia, and acute renal failure. The classical form [D(+) HUS] is caused by infectious agents, and it is a common cause of acute renal failure in children. The enterohaemorrhagic Escherichia coli-producing Shiga toxin (Stx) is the most common infectious agent causing HUS. Other infectious agents are Shigella and Streptococcus pneumoniae. Infections by S. pneumoniae can be particularly severe and has a higher acute mortality and a higher long-term morbidity compared to HUS by Stx. Atypical HUS [D(-)Stx(-)HUS] are often used by paediatricians to indicate a presentation of HUS without preceding diarrhoea. Almost all patients with D(-)Stx(-)HUS have a defect in the alternative pathway, for example, mutations in the genes for complement factor H, factor I, and membrane co-factor protein. Mutations in the factor H gene are described more often. The majority of children with D(+) HUS develop some degree of renal insufficiency, and approximately two thirds of children with HUS will require dialysis therapy, while about one third will have milder renal involvement without the need for dialysis therapy. General management of acute renal failure includes appropriate fluid and electrolyte management, antihypertensive therapy, and the initiation of renal replacement therapy when appropriate. Specific management issues in HUS include management of the haematological complications of HUS, monitoring for extra-renal involvement, avoiding antidiarrhoeal drugs, and possibly avoiding of antibiotic therapy. In addition to the obligatory supportive treatment and tight control of hypertension, there is anecdotal evidence that plasma therapy may induce remission and, in some cases, maintain it. Fresh frozen plasma contains factor H at physiological concentrations. A new therapy for D(-)Stx(-)HUS is a humanised monoclonal antibody (Eculizumab) that blocks complement activity by cleavage of the complement protein C5. It prevents the generation of the inflammatory peptide C5a and the cytotoxic membrane-attack complex C5b-9. We have first positive results, but it is still not approved for HUS.

Hemolytic uremic syndrome: pathogenesis and update of interventions

The typical form of hemolytic uremic syndrome (HUS) is the major complication of Shiga toxin-producing Escherichia coli infections. HUS is a critical health problem in Argentina since it is the main cause of acute renal failure in children and the second cause of chronic renal failure, accounting for 20% of renal transplants in children and adolescents in Argentina. Despite extensive research in the field, the mainstay of treatment for patients with HUS is supportive therapy, and there are no specific therapies preventing or ameliorating the disease course. In this review, we present the current knowledge about pathogenic mechanisms and discuss traditional and innovative therapeutic approaches, with special focus in Argentinean contribution. The hope that a better understanding of transmission dynamics and pathogenesis of this disease will produce better therapies to prevent the acute mortality and the long-term morbidity of HUS is the driving force for intensified research.

Clinical Analysis of modified Peritoneal Dialysis for Acute Renal Failure in Children

Objective To explore the effect of dialysis therapy for children with acute renal failure (ARF)and compare the effects between the modified peritoneal dialysis (MPD) and peritoneal dialysis (PD). Methods The clinical data of MPD and PD for ARF from January 2007 to December 2008 were collcted and analyzed retrospectively.We used small numerus silicone tubes instead of peritoneal dialysis catheter by making a gill-side hole and disinfection by venae profundae catheter device. PD fluid flowed in and out the abdominal cavity through two different pathways, Results Comparing RPD (treatment group) to peritoneal dialysis (control group), the dialyzed effects markedly improved, and there was a statistically significance difference between the MPD group and PD group(P<0.05). Conclusion MPD is a new economical and simple treatment to cure child with ARF. it is worth to developing in grass-roots hospital. Key words: Children; Acute renal failure; Modified peritoneal dialysis; Peritoneal dialysis

Sorbitol-fermenting Shiga toxin-producing Escherichia coli O157 in Austria

Infections with enterohemorrhagic Escherichia coli (EHEC) are the major cause of hemolytic uremic syndrome (HUS), the most common cause of acute renal failure in childhood. Shiga toxins are considered to be the most important virulence factor of EHEC strains. Non-sorbitol-fermenting EHEC O157:H7 is still the most prevalent serotype isolated worldwide; however, sorbitol-fermenting (SF) EHEC O157:H- (H- indicates nonmotility) strains are increasingly reported. Thirteen SF EHEC O157:H- strains (11 of human origin, two from animals) were detected in Austria between 2002 and 2008. Among the 11 human cases, seven suffered from HUS, two from diarrhea and the remaining two were asymptomatic. Seven of the cases were identified in patients living in or visiting (in one case) the province Salzburg, four were in patients from the province Vorarlberg. Three outbreaks with no more than three persons involved were detected, the other four cases occurred sporadically. The pulsed-field gel-electrophoresis banding patterns of the 13 SF EHEC O157:H- isolates were grouped into three distinct clusters (groups 1, 2 and 3). Strains of the three outbreaks were identical (except for one outbreak strain with one band difference) within each outbreak. In comparison, the Bavarian epidemic strain showed a pattern different from all SF O157:H- strains isolated in Austria. For effective detection of SF EHEC O157:H-, screening for Shiga toxins by ELISA and/or Shiga toxin genes by PCR is absolutely necessary; screening on the basis of phenotypic characteristics such as sorbitol-non-fermentation is not sufficient. Typing methods relying solely on investigation of O157 will detect these strains but should nevertheless also be avoided, so that the prevalent non-O157 strains causing HUS are not missed.

Acute renal failure following wasp sting in children

The medical records of patients admitted between 1985 and 2007 with wasp stings were retrospectively analyzed. Among the 45 children, seven developed acute renal failure. Classical clinical and laboratory data pointed to hemolysis and rhabdomyolysis as the underlying pathophysiology. All patients had hyponatremia and hyperkalemia as well as metabolic acidosis. Six patients had anemia. Five patients were oliguric for 9 to 15 days. Maximum serum creatinine was 4.0 to 11.9 mg/dl. Peritoneal dialysis was performed for 3 to 15 days. One patient died due to hyperkalemia, the remaining ones recovered completely. This paper wants to remind pediatricians to watch for acute renal failure in children with wasp stings.