The role of chronic colitis in the pathogenesis of Hirschsprung 's disease in children]

The role of chronic colitis in pathogenesis of Hirschsprung's disease was studied ultrastructurally and morphometrically. Morphological features of chronic colitis were revealed by examination of full-layers biopsies and excised fragments of the colon in 26 children aged from 2 to 14 years with Hirschsprung's disease. Atrophic-sclerotic form of colitis develops in various disturbances of colo-rectal innervation. In this condition diffuse sclerosis of bowel wall could be considered as pathognomonic symptom of Hirschsprung's disease. As a result of development of sclerosis insufficiency of the bowel motor function increases.     

The role of reactive oxygen species in animal models of glomerular disease.

Reactive oxygen metabolites have been demonstrated to play a pathobiologic role in a number of experimental models of both immune and nonimmune glomerular injury. Using scavenging substances, enzyme inhibitors, and transition metal chelators, all of the major reactive oxygen metabolites have been implicated in glomerular injury. In addition, in neutrophil-dependent models, interaction between neutrophil-derived myeloperoxidase and halide anions has been shown to be involved in glomerular damage, as well as halogenation of the glomerular basement membrane (GBM). Finally, recent attention has focused on the role of cytokines (perhaps elaborated by infiltrating monocytes/macrophages) in stimulating mesangial cells (MC) to produce reactive oxygen species. Theoretically, this pathobiologic sequence could further enhance an inflammatory state within the glomerular tuft and enable the propagation of initial glomerular injury, which may be associated with an increase in monocyte infiltration into the mesangium, to glomerulosclerosis in experimental models that manifest this transition.     

Islet autoimmunity in children with Down's syndrome

There is an unexplained excess of type 1 diabetes and other organ-specific autoimmune diseases in children with Down's syndrome, but the immunogenetic characteristics of diabetes in Down's syndrome have not been investigated. We studied the frequency of islet autoantibodies in 106 children with Down's syndrome and no history of autoimmunity and analyzed HLA class II genotypes in 222 children with Down's syndrome, 40 children with Down's syndrome and type 1 diabetes, 120 age- and sex-matched children with type 1 diabetes, and 621 healthy control subjects. Co-occurrence of at least two islet autoantibody markers was observed in 6 of 106 nondiabetic children with Down's syndrome compared with 13 of 2,860 healthy age-matched children (P < 0.001). There was an excess of diabetes-associated HLA class II genotypes in children with Down's syndrome and type 1 diabetes compared with age- and sex-matched healthy control subjects (P < 0.001). Down's syndrome children with type 1 diabetes were, however, less likely to carry the highest risk genotype DR4-DQ8/DR3-DQ2 than children with type 1 diabetes from the general population (P = 0.01) but more likely to carry low-risk genotypes (P < 0.0001). The frequency of subclinical islet autoimmunity is increased in Down's syndrome, and susceptibility to type 1 diabetes in Down's syndrome is partially HLA mediated. Other factors, possibly including genes on chromosome 21, may increase the penetrance of type 1 diabetes in Down's syndrome.     

The role of podocytes in glomerular pathobiology

Podocytes are unique cells with a complex cellular organization. With respect to their cytoarchitecture, podocytes may be divided into three structurally and functionally different segments: cell body, major processes, and foot processes (FPs). The FPs of neighboring podocytes regularly interdigitate, leaving between them the filtration slits that are bridged by an extracellular structure, known as the slit diaphragm (SD). Podocytes cover the outer aspect of the glomerular basement membrane (GBM). They therefore form the final barrier to protein loss, which explains why podocyte injury is typically associated with marked proteinuria. Chronic podocyte injury may lead to podocyte detachment from the GBM. Our knowledge of the molecular structure of the SD has been remarkably improved in the past few years. Several molecules, including nephrin, CD2AP, FAT, ZO-1, P-cadherin, Podocin, and Neph 1-3 have all been shown to be associated with the SD complex, and some of these molecules are critical for its integrity. Podocytes are injured in many forms of human and experimental glomerular disease. The early events are characterized either by alterations in the molecular composition of the SD without visible changes in morphology or, more obviously, by a reorganization of FP structure with the fusion of filtration slits and the apical displacement of the SD. Based on recent insights into the molecular pathology of podocyte injury, at least four major causes have been identified that lead to the uniform reaction of FP effacement and proteinuria: (1) interference with the SD complex and its lipid rafts; (2) direct interference with the actin cytoskeleton; (3) interference with the GBM or with podocyte-GBM interaction; and (4) interference with the negative surface charge of podocytes. There is also evidence, in focal segmental glomerular sclerosis (FSGS) and in idiopathic nephrotic syndrome in humans and rats, that podocyte damage may be caused by circulating albuminuric factors. Ongoing studies in many laboratories are aiming at an understanding of the dynamic relationship between SD proteins, the actin cytoskeleton, and the dynamics of FP structure in nephrotic syndrome and FSGS. These studies should provide us with a better understanding of the biological mechanism underlying the podocyte response to injury. Such studies will potentially translate into more refined treatment and the prevention of proteinuria and progressive glomerular disease.     

Circadian rhythms of diuresis,proteinuria and natriuresis in children with chronic glomerular disease

The aim of our study was to examine diurnal variation in urine volume (UV) output, proteinuria (UPRT), urine creatinine (UCr) and urine sodium ion excretion (UNa) in children with chronic glomerulopathy. In 56 patients (20 boys/36 girls, aged 11.7 ± 0.6 years) samples for UPRT, UCr and UNa were collected during the day and night, with continuous ambulatory blood pressure (BP) monitoring. On the basis of creatinine clearance (CrCl) the patients were divided into group I (n = 44, with CrCl 131 ± 3.6 ml/min per 1.73 m² body surface area), or group II (n = 12, with CrCl 44.6 ± 7.7 ml/min per 1.73 m² body surface area). Nocturnal polyuria was defined as night time UV ≥ 35% of the 24 h UV. Age, gender, body mass index of the patients, 24 h UV, UCr and UNa were similar in both groups. However, arterial hypertension and nocturnal polyuria were widespread (P < 0.01) in group II. In addition, proteinuria was higher (P < 0. 05) in group II. The nocturnal decline in CrCl, UV, UPRT and UNa was significantly attenuated (P < 0.005) in patients in group II compared with those in group I. The night time mean arterial pressure (MAP), as well as the night/day ratios of MAP, UV, UPRT and UNa, showed negative associations with CrCl. Our findings strongly suggest that renal function diurnal variation and nocturnal MAP are related to decreased glomerular filtration rate at the time of examination.     

Congenital disorders of hemostasis in children with Perthes disease]

The level of selected parameters of the coagulation system and fibrynolysis (prothrombin time, partial thromboplastin time, fibrinogen level, albumin C system, V Leiden factor and III antithrombin level) in 25 children who had been treated with Perthes disease was evaluated. In three children prolonged prothrombin time occurred; in one child anomalous protein C system was noted. The remaining parameters were normal in all children. The investigation results reveal that congenital disturbances of the haemostasis system were not the cause of Perthes disease in 24 children.     

Comparison of glomerular function tests in children with cancer

Evaluation of renal function should be performed as part of the follow-up during and after chemotherapy in pediatric cancer patients. The aim of this study was to compare an isotope clearance method [isotope glomerular filtration rate (iGFR)] with alternative methods to determine GFR in such patients. Isotope GFR [^99mTc-labeled diethylene triaminopentoacetic acid (DTPA) or ⁵¹Cr-labeled ethylenediaminetetra-acetate (EDTA)] was measured in 36 children (112 studies) and compared with simultaneously measured creatinine clearance (CrCl), serum creatinine (SCr), and cystatin C (CysC) concentrations, as well as the results of Schwartz, Counahan–Barratt, and Cockroft–Gault formulae, using general linear mixed models. Our results showed a significant association between iGFR and CysC concentrations (p < 0.001). No linear relationship was observed between CrCl and iGFR (p = 0.7). As expected, the results of height-based formulae (Counahan–Barratt and Schwartz) had significantly (p = 0.004) better correlation to iGFR than the results of a formula based on weight (Cockroft–Gault) (p = 0.19). Despite significant linear correlation, intraclass correlation coefficients showed poor agreement. Tests of similarity between iGFR estimates showed differences between average values of GFR. Therefore, determination of iGFR remains the method of choice in estimation of GFR in cancer patients. In our study population, assay of serum CysC was the most reliable alternative method to measure glomerular function.     

Complement in glomerular disease

The role of the complement system in renal disease has long been recognized, but there have been major advances in our understanding of its role over the past decade. Complement plays a critical role not only in host's defense against infection and preventing damage to "self" tissues but also mediates tissue injury, both in the glomerulus and tubulointerstitium. Although injury may originate in the glomerulus, resulting proteinuria and complement activation within the tubular lumen may lead to tubulointerstitial damage and progressive renal disease. Recent advances in our understanding of the mechanisms by which complement mediates renal injury have led to the development of promising strategies with which complement may be targeted to prevent renal injury and its associated complications.     

The genetic basis of human glomerular disease

Clinical and molecular research aimed to understand glomerular disease has emerged to one of the most active areas in renal research at large. The unraveling of genetic causes resulting in proteinuria has helped to define roles for each component of the glomerular filtration barrier in the development of urinary protein loss. Although most of the inherited glomerular diseases have in common defects in the podocyte, the glomerular basement membrane is also of critical importance for normal kidney permselectivity. This review summarizes recent progress in the eludication of genetic causes of glomerular disease and discusses their implications for the understanding of the pathogenic mechanisms, which can lead to disruption of the glomerular filtration barrier.     

The NLRP3 inflammasome in kidney disease and autoimmunity

The NLRP3 inflammasome is an intracellular platform that converts the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18 to their active forms in response to ‘danger’ signals, which can be either host or pathogen derived, and mediates a form of inflammatory cell death called pyroptosis. This component of the innate immune system was initially discovered because of its role in rare autoinflammatory syndromes called cryopyrinopathies, but it has since been shown to mediate injurious inflammation in a broad range of diseases. Inflammasome activation occurs in both immune cells, primarily macrophages and dendritic cells, and in some intrinsic kidney cells such as the renal tubular epithelium. The NLRP3 inflammasome has been implicated in the pathogenesis of a number of renal conditions, including acute kidney injury, chronic kidney disease, diabetic nephropathy and crystal‐related nephropathy. The inflammasome also plays a role in autoimmune kidney disease, as IL‐1β and IL‐18 influence adaptive immunity through modulation of T helper cell subsets, skewing development in favour of Th17 and Th1 cells that are important in the development of autoimmunity. Both IL‐1 blockade and two recently identified specific NLRP3 inflammasome blockers, MCC950 and β‐hydroxybutyrate, have shown promise in the treatment of inflammasome‐mediated conditions. These targeted therapies have the potential to be of benefit in the growing number of kidney diseases in which the NLRP3 inflammasome has been implicated.     

The role of surgery in children with neurofibromatosis

BACKGROUND/PURPOSE: Neurofibromatosis frequently is complicated by the development of symptomatic lesions such as optic gliomas and plexiform neurofibromas that require operative resection. Although characteristically benign, these neoplasms have often devastating functional and cosmetic effects and must be monitored for malignant transformation. The purpose of this study is to identify and describe the surgical considerations in the care of children with neurofibromatosis. METHODS: The authors reviewed the charts of all children (<21) at our institution with neurofibromatosis who underwent an operative procedure from 1979 to 1999. Patient demographics, symptomatic lesions, malignant transformation, form of surgical intervention, type of anesthesia, and outcome were collected. RESULTS: A total of 249 patients with either neurofibromatosis 1 or 2 were identified. Of these, 50 (20%) underwent a total of 93 operations. The average age at operation was 9.4 years (1.2 to 21 years). There were 40 soft tissue procedures, 21 intracranial, and 32 miscellaneous. The soft tissue masses typically were treated with wide local excision, and in 8 of these procedures multiple resections were performed. Fourteen of the 50 patients had malignancies. Five of the tumors were soft tissue sarcomas, and 9 were intracranial malignancies. Three patients died, 2 from malignancy and 1 from acute, obstructive hydrocephalus after operation. There were 3 patients alive with malignancy and 8 others living with varying levels of disability. CONCLUSIONS: Neurofibromatosis in the pediatric patient frequently requires surgical intervention, often because of symptoms such as pain or cosmetic deformity, or for malignancy. Children should be watched carefully for signs of malignant transformation and undergo biopsy for neurofibromas that exhibit rapid growth. Management of sarcomas should be aggressive with consideration given to re-excision, placement of brachytherapy catheters, metastectomy, and limb salvage with adjuvant therapy when possible. Preoperatively, children should receive clinical and radiographic (computed tomography or magnetic resonance imaging) evaluation for hydrocephalus.     

The role of gender in estimating glomerular filtration rate.

Sir, In a recent article, Chung and colleagues [1] report that alcoholconsumption is associated     

The role of heparan sulfate in the glomerular basement membrane

Recent studies, including those by van den Hoven and colleagues, have challenged the classic negative-charge theory of glomerular filtration. However, the possibility remains that heparan sulfate in the glomerular basement membrane plays a role in maintaining the glomerular filtration barrier.