Renal Insufficiency In Children Research Articles

Hemolytic uremic syndrome in a Pediatric Intensive Care Unit- Rapid review with case series

Hemolytic uremic syndrome (HUS) is a multiorgan clinical syndrome characterized by the simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. This is the most important form of thrombotic microangiopathies in children and is considered the main cause of acute renal insufficiency in children, especially under the age of five. Over 90% of HUS in children is associated with infection, and the prodromal manifestation most often includes bloody diarrhea. Atypical hemolytic uremic syndrome (aHUS) is a rare but progressive, life-threatening condition that affects about 10% of HUS cases in children. It is predominantly caused by dysregulation of the alternative complement pathway and genetic predisposition. Conditions that enhance complement, such as some viral infections, malignancies, autoimmune diseases and transplantation may be comorbid in up to 70% of aHUS cases. The 2016 International Hemolytic Uremic Syndrome Group classification, based on the etiology, separates 4 groups: caused by infection, with coexisting conditions, due to cobalamin C disorders and due to complement dysregulation. Monoclonal antibody that effectively blocks complement activation, has significantly changed aHUS treatment and outcome. Early etiological recognition in order to start specific treatment as soon as possible is crucial for the outcome. This paper, through a rapid review and series of three children treated for HUS in our pediatric intensive care unit over a two-year period, aims to emphasize the complexity of the diagnosis and treatment of HUS, and the importance of a multidisciplinary team in order to to avoid complications, and achieve the best short- and long-term outcome

Evaluation of Kidney Functioning in Children with Renal Complications During COVID-19 Pandemic: A Retrospective Observational Cohort Clinical Study

Background. An increase in a quantity of children with acute renal insufficiency associated with infectious diseases, including COVID-19 is a growing problem in nephrology. Such insufficiency is often expressed in pyelonephritis. Due to a lack of specific signs or obvious clinical symptoms and their correct interpretation, acute renal insufficiency against the background of COVID-19 is first identified in the period of steady worsening of the kidney functioning. An accurate non-invasive diagnostic test is yet to be fully developed, therefore, determination of the mechanisms of complications is considered to be challenging and can contribute to the formation of irreversible renal injury.Objective — to determine and evaluate characteristics of the renal status in children with acute pyelonephritis against the background of COVID-19.Methods. A retrospective observational cohort clinical study of 65 children with acute pyelonephritis was carried out. The study also included a control group of 20 healthy children, who were observed during routine health checkup. The patients were observed at the Nephrology Unit, Samarkand Regional Pediatric Multidisciplinary Medical Center, Uzbekistan. Laboratory examination was carried out on the basis of Clinical Diagnostic Laboratory, Samarkand Regional Pediatric Multidisciplinary Medical Center, Uzbekistan, and Laboratory of Innova Clinic, Uzbekistan. The study was conducted from January 2021 to December 2022 and involved participants with the history of COVID-19 before treatment. Thus, two cohorts were formed: group 1 comprised 30 children with acute pyelonephritis and without a history of COVID-19; group 2 consisted of 35 patients with acute pyelonephritis against the background of COVID-19. In order to evaluate the renal status, examination of the glomeruli, proximal and distal tubules was carried out. The study included investigation of “urinary syndrome” indicators — leukocyturia of neutrophil origin, microhematuria, proteinuria, and bacteriuria. The obtained laboratory data were analyzed using variance and given in SI System — the International System of Units. The calculations were carried out using StatPlus 7 (AnalystSoft Inc., USA).Results. Renal function is decreased in an acute period due to reduced functionality of concentration and distal tubule, which were more significantly affected in group 2. Inflammatory changes in the renal tissue due to the toxic effects of coronavirus infection underlie the abnormalities detected. The history of COVID-19 is reckoned from the date of admission and ranges from 3 weeks to 2 months. Renal insufficiency in children with COVID-19 history is manifested irrespective of their clinical polymorphism, due to impairment of its tubular structures (reabsorption, acidogenesis and ammoniogenesis, osmotic concentration) and glomerular filtration. A statistically significant reduction in acidogenesis (p = 0.001) was recorded in patients with acute COVID-associated pyelonephritis.Conclusion. Children with COVID-19 respiratory symptoms require monitoring their renal functions for early diagnosis and treatment. Long-term monitoring of patients with isolated urinary syndrome in the acute period is needed to detect the underlying renal disease.

Renal insufficiency in children born preterm: examining the role of neonatal acute kidney injury.

To identify the prevalence of renal insufficiency (RI) in children with a history of prematurity and acute kidney injury (AKI). This prospective cohort study evaluated renal function in children born preterm at 5-9 years of age. Univariable analyses compared perinatal and follow-up data from subjects with and without AKI history, and with and without current RI. Regression analyses were attempted to model RI as a function of AKI and other clinical risk factors. Fifteen of 43 (35%) participants had previously undiagnosed RI. Only children with no AKI history or neonatal stage 1 AKI presented for follow-up. Children born preterm with a history of stage 1 AKI had higher serum creatinine (sCr) at follow-up, but were not more likely to have RI compared to children without stage 1 AKI history (RI prevalence 30% and 36% in AKI and non-AKI group, respectively). The high prevalence of RI in this preterm cohort at middle childhood follow-up highlights the need for routine kidney health assessments in this population. Large multicenter studies are needed to further characterize the impact of premature birth and mild AKI on renal function throughout childhood.

A study proposal on short term outcome and prognosis of primary and delayed fulguration in posterior urethral valve

Background: Posterior urethral valve (PUV) is the most common cause of lower urinary tract obstruction in male neonates. The incidence is 1 in 4000, 1 in 7500 births PUV occur exclusively in males. This disease has a broad spectrum of presentations. They may present at any age during childhood and may vary from ascites in the neonate to renal failure in infants and only minor voiding dysfunction in an older child. Urinary tract infection is common at all ages. The objectives of the study were to assess the impact of primary impaction on short term outcomes and to assess the outcome of diversion and delayed fulguration.Methods: This retrospective study was conducted at the Pediatric Urology outpatient department (OPD) at the Institute of Child Health and Hospital for Children, Madras Medical College, Chennai including the patients who attended the pediatric surgery from August 2008 to December 2011.Results: In the current series, the incidence of renal insufficiency in patients with urosepsis was 45%. Recurrent urosepsis >3 episodes in a year (fever with urine culture showing infection) primarily due to poor patient compliance lead to progressing pyelonephritis and nephron damage and plays an important role in the outcome of these children.Conclusions: The incidence of renal insufficiency in children with posterior urethral valves in this series was 38% (30-45%) with an average follow up 3 years. Several factors were important in prognosticating the progression towards renal insufficiency and bladder dysfunction. Urodynamics is of immense help in cases having symptoms despite good stream. The use of anticholinergic for abnormal urodynamics gives encouraging results.

Renal scarring on DMSA scan is associated with hypertension and decreased estimated glomerular filtration rate in spina bifida patients in the age of transition to adulthood

Improved management for spina bifida (SB) has increased the number of patients transitioning to adult care. This trend increases the importance of maintaining renal function concurrently with bladder function in patients with SB. Dimercaptosuccinic acid (DMSA) renal scanning is an optimal tool for investigating renal insufficiency in children with SB; however, the benefits of DMSA scans in adulthood are unclear. The role of DMSA renal scans for patients with SB during the transition to adulthood (15-25 years of age) to reveal their association with current renal function was investigated. DMSA renal scanning was routinely performed patients with SB aged 15-25 years concurrently with examination of serum creatinine, serum cystatin C, urinalysis, and blood pressure between January 2006 and August 2016. Hypertension was defined as systolic or diastolic pressure above the age-specific normal range. The estimated glomerular filtration rate (eGFR) using serum creatinine or cystatin C was calculated; decreased eGFR was defined as eGFR below 90mL/min/1.73m2. Patients were divided into two groups according to the absence or presence of renal scarring on DMSA scan. Factors associated with renal function, including hypertension, decreased eGFR, and proteinuria, were compared between groups. Eighty-seven patients (36 males and 51 females) were analyzed. Median age was 19 years (range 15-24 years); 28 patients (32%) had renal scarring. Patients with renal scarring had significantly higher rates of hypertension (n=13, 46%) and decreased eGFR (n=5, 18%). However, there was no difference in proteinuria between the groups (Table). The group with renal scarring had significantly lower eGFR. This study showed that DMSA scans in patients with SB aged between 15 and 25 years were useful for assessing renal scarring despite a history of febrile urinary tract infection. DMSA scans could be performed in all patients with SB in the transition to adulthood to detect renal scarring. This study also showed that renal scarring was associated with hypertension and decreased eGFR in this age group. Treatment with antihypertensive drugs should be considered for patients with SB with renal scarring in this age range to protect renal function. Spina bifida patients in the age of transition to adulthood with renal scarring already showed signs of chronic kidney disease, suggesting that DMSA renal scans could be useful to identify patients who require close monitoring of renal function.

Long-term consequences of renal insufficiency in children: lessons learned from the Dutch LERIC study.

Few data exist on the prospects in adulthood for children on chronic renal replacement therapy (RRT). This article summarizes the results of a comprehensive Dutch long-term follow-up study performed in 2000 and 2010 of patients with RRT onset at age <15 years between 1972 and 1992. After a median of 25.5 RRT years, patients had stayed 23% of RRT time on dialysis. We observed a 30 times greater mortality risk compared with age-matched peers with cardiovascular disease (CVD) as the main cause of death during 1972-2000 and infections during 2000-10. The observed shift towards infections was associated with more RRT time with a graft and receiving a stricter CVD protective treatment. For patients >40 years of age, motor disabilities affecting routine activities, skin cancer and severe fatigue were the most disabling sequelae. After 30 years of transplantation, 41% of the survivors had developed cancer, a life-threatening form of squamous cell skin carcinoma being most prevalent. Important delays in autonomy development and educational attainment and a relatively high level of unemployment were observed. Transplanted patients reported a good mental and physical quality of life, but the latter tended to decrease over time. A long period of dialysis was associated with all adverse somatic and psychosocial outcomes. Paediatric nephrologists should aim for transplantation at the earliest possible time and focus on autonomy and educational attainment. Nephrologists should focus on strict CVD prevention, adjustment of immunosuppression to the lowest possible dose and surveillance of malignancy-associated viral infections in patients with childhood end-stage renal disease.

Cystatin C as a Marker of Early Renal Insufficiency in Children with Congenital Neuropathic Bladder

Due to decreased muscle mass in children with congenital neuropathic bladder there may be significant inaccuracy when using the creatinine based estimated glomerular filtration rate. Cystatin C is highly sensitive and specific for measuring changes in the glomerular filtration rate in children and in patients with muscle wasting conditions. We hypothesized that a cystatin C calculated glomerular filtration rate would be more sensitive than the standard creatinine based modified Schwartz equation to detect renal insufficiency in children with congenital neuropathic bladder. We prospectively identified children with congenital neuropathic bladder at a multidisciplinary spina bifida clinic who underwent serum creatinine and serum cystatin C testing. Clinical history and anthropomorphic variables at the time of laboratory testing were catalogued. The creatinine based glomerular filtration rate was estimated using the modified (bedside) Schwartz formula and the cystatin C based rate was calculated using the Zappitelli cystatin C formula. Dual estimated glomerular filtration rate calculation was done in 69 children at a total of 74 patient encounters. Absolute creatinine was within age range normal limits in each patient, including 1 with chronic kidney disease stage 3A. The median creatinine based estimated glomerular filtration rate was 123 ml per minute/1.73 m(2) (range 58 to 229). The median cystatin C based estimated rate was 103 ml per minute/1.73 m(2) (range 47 to 144) for an absolute median rate reduction of 15.4%. Using cystatin C estimates chronic kidney disease stage was upgraded from stage 1 to 2 in 13 patients (18.8%). In children with neuropathic bladder the cystatin C estimated glomerular filtration rate is a better screening test for early renal insufficiency that is not detected by creatinine based rate calculations. To our knowledge it remains to be determined whether the cystatin C estimated glomerular filtration rate can ultimately improve the clinical outcome in this population.

Loss of a kidney during fetal life: long-term consequences and lessons learned

Epidemiological studies reveal that children born with a solitary functioning kidney (SFK) have a greater predisposition to develop renal insufficiency and hypertension in early adulthood. A congenital SFK is present in patients with unilateral renal agenesis or unilateral multicystic kidney dysplasia, leading to both structural and functional adaptations in the remaining kidney, which act to mitigate the reductions in glomerular filtration rate and sodium excretion that would otherwise ensue. To understand the mechanisms underlying the early development of renal insufficiency in children born with a SFK, we established a model of fetal uninephrectomy (uni-x) in sheep, a species that similar to humans complete nephrogenesis before birth. This model results in a 30% reduction in nephron number rather than 50%, due to compensatory nephrogenesis in the remaining kidney. Similar to children with a congenital SFK, uni-x sheep demonstrate a progressive increase in arterial pressure and a loss of renal function with aging. This review summarizes the compensatory changes in renal hemodynamics and tubular sodium handling that drive impairments in renal function and highlights the existence of sex differences in the functional adaptations following the loss of a kidney during fetal life.

Trend from cardiovascular to non-cardiovascular late mortality in patients with renal replacement therapy since childhood

To evaluate transitions in causes of death in patients with renal replacement therapy (RRT) since childhood over time, we performed a 10-year extension of the Late Effects of Renal Insufficiency in Children (LERIC) study. The LERIC cohort consisted of all 249 Dutch patients, who were born before 1979 and started RRT <15 years of age between 1972 and 1992. We collected data on mortality and causes of death over the period 2000-10 and compared them with the previously gathered data over the period 1972-99. The median duration of follow-up from the start of RRT was 25.5 (range 0.3-39.0 years). Overall, 97 patients died of whom 34 in 2000-10. The overall mortality rate and mortality rate ratios (MRRs) stabilized over time. The MRR for cardiovascular death decreased from 660 in 1972-89 to 70 in 1990-99 and to 20 in 2000-10. Conversely, the MRR for infectious death showed a U-shape; it decreased from 503 in 1972-89 to 102 in 1990-99 and increased again to 350 in 2000-10. In 2000-10, infections became the most prevalent cause of death (44%). In 2000-10, the cardiovascular mortality had decreased with 91% since 1972-89 [adjusted hazard ratio (HR): 0.09, 95% confidence interval (95% CI): 0.02-0.45, P = 0.003], while infectious mortality had doubled over time, although not significantly (adjusted HR: 2.12, 95% CI: 0.88-5.11, P = 0.09). Over the last decade, we found a substantial shift from cardiovascular disease to infections as the main cause of death at long-term follow-up in patients with chronic kidney disease since childhood and who were born before 1979.

Risk factors for renal insufficiency in children with urethral valves

Posterior urethral valves (PUV) associated with renal dysplasia are one of the most common causes of end stage kidney disease (ESKD) in childhood. In order to identify risk factors for the progression of this condition to early renal failure, we have retrospectively analyzed the clinical course, renal function, and first postnatal renal ultrasound in a sample of 42 young male patients with PUV, who were followed at a single center. Twelve (28.6%) were diagnosed with ESKD at a median age of 11.3 years. Our comparison of PUV patients without decreased estimated glomerular filtration rate (eGFR) (group A; K/DOQI CKD stage 0-1) with PUV patients showing a decreased eGFR (group B; K/DOQI CKD stage 2-5) revealed the following significant risk factors for loss of eGFR: renal volume <3rd percentile (P < 0.001), elevated echogenicity (P = 0.001), pathologic corticomedullary differentiation (P < 0.001), >3 febrile urinary tract infections (P = 0.012), and decreased eGFR at 1 year of age (P < 0.001). Receiver operating characteristic curve analysis in the cohort confirms that patients showing a renal volume >88.2 ml/m(2) body surface area (BSA) are not at risk to develop K/DOQI CKD stage 5 (sensitivity 75%, specificity 77.3%, positive/negative predictive value 37.5/94.4%). Ultrasound promises to be a valuable tool for identifying endangered patients.

Pediatric febrile urinary tract infections: the current state of play

Studies undertaken in recent years have improved our understanding regarding the consequences and management of febrile urinary tract infections (UTIs), which are amongst the most common serious bacterial infections in childhood, with renal scarring a frequent outcome.In the past pyelonephritic scarring of the kidney, often associated with vesico-ureteral reflux (reflux nephropathy) was considered a frequent cause of chronic renal insufficiency in children. Increasing recognition as a consequence of improved antenatal ultrasound, that the majority of these children had congenital renal hypo-dysplasia, has resulted in a number of studies examining treatment strategies and outcomes following UTI.In recent years there is a developing consensus regarding the need for a less aggressive therapeutic approach with oral as opposed to intravenous antibiotics, and less invasive investigations, cystourethrography in particular, following an uncomplicated first febrile UTI. There does remain a concern that with this newer approach we may be missing a small subgroup of children more prone to develop severe kidney damage as a consequence of pyelonephritis, and in whom some form of intervention may prove beneficial. These concerns have meant that development of a universally accepted diagnostic protocol remains elusive.

Progression of Renal Insufficiency in Children and Adolescents With Neuropathic Bladder is Not Accelerated by Lower Urinary Tract Reconstruction

Children with chronic renal insufficiency and neuropathic bladder resistant to medical management may require lower urinary tract reconstruction before renal transplantation. A low pressure urinary reservoir optimizes the chance of graft survival and may slow native kidney death. We evaluated whether the renal deterioration rate is affected by augmentation cystoplasty. We performed a retrospective cohort study in children who presented to our institution with chronic renal insufficiency and neuropathic bladders from 2005 to 2009. Chronic renal insufficiency was defined as a glomerular filtration rate of less than 60 ml per minute. As a surrogate for renal function change, we used the inverse creatinine trend with respect to time to determine the progression rate of renal insufficiency before and after augmentation. A total of 11 patients with a mean glomerular filtration rate of 34 ml per minute per 1.73 m(2), mean bladder capacity 168 ml and mean compliance 3.5 ml/cm H(2)O met study inclusion criteria. Bladder augmentation or replacement was done at a mean age of 9.7 years with a resultant mean capacity of 486 ml and compliance of 14.7 ml/cm H(2)O. Mean followup was 4 years before and 1.9 years after augmentation. There was no statistically significant difference between the preoperative and postoperative slopes of inverse creatinine in 8 of 11 patients (73%). Two of the 3 patients (18%) with different preoperative and postoperative slopes had improving renal function after surgery. There was no statistically significant difference in slopes across all patients. In our series bladder augmentation did not appear to hasten progression to end stage renal disease in patients with severe chronic renal insufficiency and neuropathic bladder.

IL-18 neutralization ameliorates obstruction-induced epithelial–mesenchymal transition and renal fibrosis

Ureteral obstruction results in renal fibrosis in part due to inflammatory injury. The role of interleukin-18 (IL-18), an important mediator of inflammation, in the genesis of renal fibrosis was studied using transgenic mice overexpressing human IL-18-binding protein. In addition, HK-2 cells were analyzed following direct exposure to IL-18 compared to control media. Two weeks after ureteral obstruction, the kidneys of wild-type mice had a significant increase in IL-18 production, collagen deposition, alpha-smooth muscle actin and RhoA expression, fibroblast and macrophage accumulation, chemokine expression, and transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor-alpha (TNF-alpha) production, whereas E-cadherin expression was simultaneously decreased. The transgenic mice with neutralized IL-18 activity exhibited significant reductions in these indicators of obstruction-induced renal fibrosis and epithelial- mesenchymal transition, without demonstrating alterations in TGF-beta1 or TNF-alpha activity. Similarly, the HK-2 cells exhibited increased alpha-smooth muscle actin expression and collagen production, and decreased E-cadherin expression in response to IL-18 stimulation without alterations in TNF-alpha or TGF-beta1 activity. Our study demonstrates that IL-18 is a significant mediator of obstruction-induced renal fibrosis and epithelial- mesenchymal transition independent of downstream TGF-beta1 or TNF-alpha production.

Progression From Acute Kidney Injury to Chronic Kidney Disease: A Pediatric Perspective

Although emerging evidence indicates that the incidence of both acute kidney injury (AKI) and chronic kidney disease (CKD) in children is rising and the etiologies are dramatically changing, relatively little is currently known regarding the potential for transition from AKI to CKD. In both situations, early intervention can significantly improve the dismal prognosis. However, the lack of a uniform AKI definition and the paucity of early, predictive biomarkers have impaired our ability diagnose AKI early to institute potentially effective therapies in a timely manner. Fortunately, recent data has validated a multidimensional AKI classification system for children. In addition, the application of innovative technologies has identified candidates that are emerging as early biomarkers of both AKI and CKD. These include neutrophil gelatinase-associated lipocalin, liver-type fatty acid-binding protein, and kidney injury molecule-1. Studies to validate the sensitivity and specificity of these biomarkers in clinical samples from large cohorts and from multiple clinical situations are currently in progress, facilitated by the development of commercial tools for the reproducible measurement of these biomarkers across different laboratories.

Worsening renal function in children hospitalized with decompensated heart failure: Evidence for a pediatric cardiorenal syndrome?*

The purpose of this study was to determine the incidence of renal insufficiency in children hospitalized with acute decompensated heart failure and whether worsening renal function is associated with adverse cardiovascular outcome. Prospective observational cohort study. Single-center children's hospital. All pediatric patients from birth to age 21 yrs admitted to our institution with acute decompensated heart failure from October 2003 to October 2005. None. Acute decompensated heart failure was defined as new-onset or acute exacerbation of heart failure signs or symptoms requiring hospitalization and inpatient treatment. We required that heart failure be attributable to ventricular dysfunction only. Worsening renal function was defined as an increase in serum creatinine by > or = 0.3 mg/dL during hospitalization. Sixty-three patients (35 male, 28 female) comprised 73 patient hospitalizations. Median age at admission was 10 yrs (range 0.1-20.3 yrs). Median serum creatinine at admission was 0.6 mg/dL (range 0.2-3.5 mg/dL), and median creatinine clearance was 103 mL/min/1.73 m2 (range 22-431 mL/min/1.73 m2). Serum creatinine increased during 60 of 73 (82%) patient hospitalizations (median increase 0.2 mg/dL, range 0.1-2.7 mg/dL), and worsening renal function occurred in 35 of 73 (48%) patient hospitalizations. Clinical variables associated with worsening renal function included admission serum creatinine (p = .009) and blood urea nitrogen (p = .04) and, during hospitalization, continuous infusions of dopamine (p = .028) or nesiritide (p = .007). Worsening renal function was independently associated with the combined end point of in-hospital death or need for mechanical circulatory support (adjusted odds ratio 10.2; 95% confidence interval 1.7-61.2, p = .011). Worsening renal function was also associated with longer observed length of stay (33 +/- 30 days vs. 18 +/- 25 days, p < .03). These data suggest that an important cardiorenal interaction occurs in children hospitalized for acute decompensated heart failure. Renal function commonly worsens in such patients and is associated with prolonged hospitalization and in-hospital death or the need for mechanical circulatory assistance.

Leukocytes Induce Epithelial to Mesenchymal Transition after Unilateral Ureteral Obstruction in Neonatal Mice

Urinary tract obstruction during renal development leads to tubular apoptosis, tubular atrophy, and interstitial fibrosis. Epithelial to mesenchymal transition (EMT) has been proposed as a key mechanism of myofibroblast accumulation in renal fibrosis. We studied the interplay of leukocyte infiltration, tubular apoptosis, and EMT in renal fibrosis induced by unilateral ureteral obstruction (UUO) in neonatal mice. We show that leukocytes mediate tubular apoptosis and EMT in the developing kidney with obstructive nephropathy. Blocking leukocyte recruitment by using the chemokine receptor-1 antagonist BX471 protected against tubular apoptosis and interstitial fibrosis, as evidenced by reduced monocyte influx, a decrease in EMT, and attenuated collagen deposition. EMT was rapidly induced within 24 hours after UUO along with up-regulation of the transcription factors Snail1 and Snail2/Slug, preceding the induction of alpha-smooth muscle actin and vimentin. In the presence of BX471, the expression of chemokines, as well as of Snail1 and Snail2/Slug, in the obstructed kidney was completely attenuated. This was associated with reduced macrophage and T-cell infiltration, tubular apoptosis, and interstitial fibrosis in the developing kidney. Our findings provide evidence that leukocytes induce EMT and renal fibrosis after UUO and suggest that chemokine receptor-1 antagonism may prove beneficial in obstructive nephropathy.

Reactive oxygen species and nuclear factor-kappa B pathway mediate high glucose-induced Pax-2 gene expression in mouse embryonic mesenchymal epithelial cells and kidney explants

Diabetic mellitus confers a major risk of congenital malformations, and is associated with diabetic embryopathy, affecting multiple organs including the kidney. The DNA paired box-2 (Pax-2) gene is essential in nephrogenesis. We investigated whether high glucose alters Pax-2 gene expression and aimed to delineate its underlying mechanism(s) of action using both in vitro (mouse embryonic mesenchymal epithelial cells (MK4) and ex vivo (kidney explant from Hoxb7-green florescent protein (GFP) mice) approaches. Pax-2 gene expression was determined by reverse transcriptase-polymerase chain reaction, Western blotting, and immunofluorescent staining. A fusion gene containing the full-length 5'-flanking region of the human Pax-2 promoter linked to a luciferase reporter gene, pGL-2/hPax-2, was transfected into MK4 cells with or without dominant negative IkappaBalpha (DN IkappaBalpha) cotransfection. Fusion gene expression level was quantified by cellular luciferase activity. Reactive oxygen species (ROS) generation was measured by lucigenin assay. Embryonic kidneys from Hoxb7-GFP mice were cultured ex vivo. High D(+) glucose (25 mM), compared to normal glucose (5 mM), specifically induced Pax-2 gene expression in MK4 cells and kidney explants. High glucose-induced Pax-2 gene expression is mediated, at least in part, via ROS generation and activation of the nuclear factor kappa B signaling pathway, but not via protein kinase C, p38 mitogen-activated protein kinase (MAPK), and p44/42 MAPK signaling.

Osteopontin regulates renal apoptosis and interstitial fibrosis in neonatal chronic unilateral ureteral obstruction

Congenital obstructive nephropathy is a major cause of renal insufficiency in children. Osteopontin (OPN) is a phosphoprotein produced by the kidney that mediates cell adhesion and migration. We investigated the role of OPN in the renal response to unilateral ureteral obstruction (UUO) in neonatal mice. OPN null mutant (-/-) and wild-type (+/+) mice were subjected to sham operation or UUO within the first 2 days of life. At 7 and 21 days of age, fibroblasts (fibroblast-specific protein (FSP)-1), myofibroblasts (alpha-smooth muscle actin (SMA)), and macrophages (F4/80) were identified by immunohistochemical staining. Apoptotic cells were detected by terminal deoxy transferase uridine triphosphate nick end-labeling technique and interstitial collagen by Masson trichrome or picrosirius red stain. Compared to sham-operated or contralateral kidneys, obstructed kidneys showed increases in all parameters by 7 days, with further increases by 21 days. After 21 days UUO, there was an increase in tubular and interstitial apoptosis in OPN -/- mice as compared to +/+ animals (P<0.05). However, FSP-1- and alpha-SMA-positive cells and collagen in the obstructed kidney were decreased in OPN -/- compared to +/+ mice (P<0.05), whereas the interstitial macrophage population did not differ between groups. We conclude that OPN plays a significant role in the recruitment and activation of interstitial fibroblasts to myofibroblasts in the progression of interstitial fibrosis in the developing hydronephrotic kidney. However, OPN also suppresses apoptosis. Future approaches to limit the progression of obstructive nephropathy in the developing kidney will require targeting of specific renal compartments.

Tu-P9:342 Endothelial dysfunction precedes arterial wall stiffening in chronic renal insufficiency in children

Tu-P9:342 Endothelial dysfunction precedes arterial wall stiffening in chronic renal insufficiency in children

Cardiovascular Disease in Children with Chronic Kidney Disease

In children with end-stage renal disease (ESRD), cardiovascular disease (CVD) mortality has not changed for the past 3 decades. Cardiac disease remains the second most common cause of death. Recent data demonstrate a high incidence and prevalence of traditional and chronic kidney disease (CKD)-related CVD risk factors in children. Early markers of cardiomyopathy, such as left ventricular hypertrophy (LVH) and left ventricular dysfunction (LV dysfunction), and early markers of atherosclerosis, such as increased carotid artery intima-media thickness (IMT) and carotid arterial wall stiffness, are frequently found in this patient population. Early identification of modifiable risk factors and treatment of asymptomatic CVD might lead to decrease of cardiovascular morbidity and mortality in young adults who developed CKD during childhood.