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BACKGROUND: Knowledge of the long-term prognosis of patients with diarrhea-associated hemolytic uremic syndrome (HUS) is important for patient counseling and follow-up. Estimates in the literature are highly variable, and previous studies did not use a healthy control group to establish outcomes attributable to HUS. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 19 children who recovered from HUS after contamination of their municipal water supply by Escherichia coli O157:H7. PREDICTOR: Outcomes of children who recovered from HUS were compared with a control group of 64 children who were healthy at the time of the outbreak. Both groups were similar in their demographics and follow-up testing. OUTCOMES & MEASUREMENTS: Proteinuria, blood pressure, glomerular filtration rate (GFR) estimated by using serum creatinine or cystatin C level, and biochemical measures 5 years after the outbreak. RESULTS: More children who recovered from HUS showed microalbuminuria than controls (20% versus 3%; relative risk, 6.0; 95% confidence interval, 1.1 to 32.8). There were no differences between groups in blood pressure or GFR when estimated by using serum creatinine level. GFR estimated by using cystatin C level was lower after HUS compared with controls (100 versus 110 mL/min/1.73 m(2); P = 0.02), but no child had a GFR less than 80 mL/min/1.73 m(2). Other results, including fasting glucose, albumin, and C-reactive protein levels, did not differ between groups. LIMITATIONS: Although the homogenous nature of this outbreak is a strength, long-term results may generalize less well to patients with other strains of toxigenic E coli or in other settings. CONCLUSIONS: The prognosis of patients with HUS in this cohort was better than in other studies. Ongoing follow-up will clarify the clinical relevance of microalbuminuria and mild decreases in GFR 5 years after HUS recovery. Copyright © 2008 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Renal interstitial fibrosis contributes to the progression of most chronic kidney diseases and is an important pathologic feature of urinary tract obstruction. To study the origin of this fibrosis, we used a fetal non-human primate model of unilateral ureteric obstruction focusing on the role of medullary collecting duct (CD) changes. Obstruction at 70 days gestation (full term approximately 165 days) results in cystic dysplasia with significant medullary changes including loss of the epithelial phenotype and gain of a mesenchymal phenotype. These changes were associated with disruption of the epithelial basement membrane and concomitant migration of transitioning cells presumed responsible for the observed peritubular collars of fibrous tissue. There was an abundance of cells that co-expressed the intercalated cell marker carbonic anhydrase II and smooth muscle actin. These cells migrated through the basement membrane and were significantly reduced in obstructed ducts with peritubular collars. Our studies suggest that fetal urinary tract obstruction results in a CD epithelial–mesenchymal transition contributing to the interstitial changes associated with poor prognosis. This seems restricted to the intercalated cells, which contribute to the expansion of the principal cell population and the formation of peritubular collars, but are depleted in progressive injury.Kidney International (2007) 72, 936–944; doi:10.1038/sj.ki.5002457; published online 1 August 2007 [ABSTRACT FROM AUTHOR]

Background: Disorders of kidney development represent a major cause of renal failure and end-stage renal disease in the pediatric population. To understand further the prenatal pathogenesis of obstructive renal dysplasia, a fetal monkey model was developed using ultrasound-guided techniques. Methods: Ureteropelvic obstruction (N = 13) was induced during the early or late second trimester by the injection of purified guluronic alginate spheres. All fetuses were monitored sonographically, and then fetal tissues were removed at varying time points during the second and third trimesters. Results: There was no evidence of oligohydramnios during the course of gestation, and the obstructed kidneys were typically progressively smaller than the contralateral (nonobstructed) kidneys when monitored sonographically over time. Obstructed kidneys displayed most features of renal dysplasia, including numerous cortical cysts of various sizes derived predominantly from collecting ducts and glomeruli. Mesenchymal changes included expansion of both the cortical and medullary interstitium, as well as mesenchymal-myocyte transformation, expressed as pericystic and peritubular fibromuscular collar formation. An important feature of this model was the disruption of normal glomerular development and architecture, associated with significant podocyte apoptosis, evident as early as the prevascularized S-shaped nephron. As in other models, collecting duct cell apoptosis was apparent, particularly in areas of cyst formation and cellular atrophy. Conclusions: These results demonstrate the importance of this nonhuman primate model for exploring the pathophysiology of congenital obstructive uropathy and highlight the potential role of podocyte injury in determining long-term renal function associated with this condition. [ABSTRACT FROM AUTHOR]

Background: Enteric infections and their chronic sequelae are a major cause of disability and death. Despite the increasing use of administrative health data in measuring the burden of chronic diseases in the population, there is a lack of validated International Classification of Disease (ICD) code-based case definitions, particularly in the Canadian context. Our objective was to validate ICD code definitions for sequelae of enteric infections in Canada: acute kidney injury (AKI); hemolytic uremic syndrome (HUS); thrombotic thrombocytopenic purpura (TTP); Guillain-Barré syndrome/Miller-Fisher syndrome (GBS/MFS); chronic inflammatory demyelinating polyneuropathy (CIDP); ankylosing spondylitis (AS); reactive arthritis; anterior uveitis; Crohn's disease, ulcerative colitis, celiac disease, erythema nodosum (EN); neonatal listeriosis (NL); and Graves' disease (GD)., Methods: We used a multi-step approach by conducting a literature review to identify existing validated definitions, a clinician assessment of the validated definitions, a chart review to verify proposed definitions and a final clinician review. We measured the sensitivity and positive predictive value (PPV) of proposed definitions., Results: Forty studies met inclusion criteria. We identified validated definitions for 12 sequelae; clinicians developed three (EN, NL, GD). We reviewed 181 charts for 6 sequelae (AKI, HUS, TTP, GBS/MFS, CIDP, AS). Sensitivity (42.8%-100%) and PPV (63.6%-100%) of ICD code definitions varied. Six definitions were modified by clinicians following the chart review (AKI, TTP, GBS/MFS, CIDP, AS, reactive arthritis) to reflect coding practices, increase specificity or sensitivity, and address logistical constraints., Conclusion: The multi-step design to derive ICD code definitions provided flexibility to identify existing definitions, to improve their sensitivity and PPV and adapt them to the Canadian context., Competing Interests: Competing interests Ethics approval was received from the University of British Columbia Clinical Review Ethics Board (H18-01664). EG and SEM report funding for this study as per the funding statement. At the time of the study, EG’s spouse worked for an electronic medical records’ company; this interest was not related to, or used in, this study. SEM reports other relationships though these interests were not used in this study: she has served as a paid expert on behalf of the Attorney General of Canada in legal proceedings, providing evidence on the public health risks and benefits of unpasteurised milk; she is an expert on the Joint FAO/WHO Expert Meetings on Microbiological Risk Assessment (JEMRA) Roster of Experts; she is a Member of the WHO Foodborne Disease Burden Epidemiology Reference Group. GK reports honoraria for speaking from AbbVie, Janssen, Pfizer, Amgen, Sandoz, and Pendophram; research support from Ferring; shared ownership of a patent: treatment of inflammatory disorders, autoimmune disease, and PBC. UTI Limited Partnership, assignee. Patent WO2019046959A1. PCT/CA2018/051098. 7 Sept. 2018; these interests were not related to, or used in, this study. JC reports research support from Pfizer and UCB for unrelated research; advisory board consulting fees from Abbvie, Organon, UCB, Novartis, Eli Lilly, Sandoz, Jansen, Pfizer, Roche, Merck, Viatris, and Fresenius Kabi; paid lectures from Eli Lilly, Viatris, Abbvie, Pfizer, Novartis, Fresenius Kabi, and UCB; support for attending ACR 2021 meeting from Jansen; unpaid leadership roles at Spondyloarthritis Research Consortium of Canada, Spondyloarthritis Research and Treatment Network, Group for Research and Assessment of Psoriasis and Psoriatic arthritis, and Assessment of Spondyloarthritis International Society; these interests were not related to, or used in, this study. KC reports board membership at CIDP Foundation of Canada, though this interest was not related to this study. All other authors declare no competing interests.

Background: Poor adherence to immunosuppressive medications is a major cause of premature graft loss among children and young adults. Multicomponent interventions have shown promise but have not been fully evaluated., Study Design: Unblinded parallel-arm randomized trial to assess the efficacy of a clinic-based adherence-promoting intervention., Setting & Participants: Prevalent kidney transplant recipients 11 to 24 years of age and 3 or more months posttransplantation at 8 kidney transplantation centers in Canada and the United States (February 2012 to May 2016) were included., Intervention: Adherence was electronically monitored in all participants during a 3-month run-in, followed by a 12-month intervention. Participants assigned to the TAKE-IT intervention could choose to receive text message, e-mail, and/or visual cue dose reminders and met with a coach at 3-month intervals when adherence data from the prior 3 months were reviewed with the participant. "Action-Focused Problem Solving" was used to address adherence barriers selected as important by the participant. Participants assigned to the control group met with coaches at 3-month intervals but received no feedback about adherence data., Outcomes: The primary outcomes were electronically measured "taking" adherence (the proportion of prescribed doses of immunosuppressive medications taken) and "timing" adherence (the proportion of doses of immunosuppressive medications taken between 1 hour before and 2 hours after the prescribed time of administration) on each day of observation. Secondary outcomes included the standard deviation of tacrolimus trough concentrations, self-reported adherence, acute rejection, and graft failure., Results: 81 patients were assigned to intervention (median age, 15.5 years; 57% male) and 88 to the control group (median age, 15.8 years; 61% male). Electronic adherence data were available for 64 intervention and 74 control participants. Participants in the intervention group had significantly greater odds of taking prescribed medications (OR, 1.66; 95% CI, 1.15-2.39) and taking medications at or near the prescribed time (OR, 1.74; 95% CI, 1.21-2.50) than controls., Limitations: Lack of electronic adherence data for some participants may have introduced bias. There was low statistical power for clinical outcomes., Conclusions: The multicomponent TAKE-IT intervention resulted in significantly better medication adherence than the control condition. Better medication adherence may result in improved graft outcomes, but this will need to be demonstrated in larger studies., Trial Registration: Registered at ClinicalTrials.gov with study number NCT01356277., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac surgery is a known risk factor for acute kidney injury (AKI) in children. However, cardiac surgery-associated AKI (CS-AKI) in neonates has not been well studied. The objectives of this study were: (1) to describe the epidemiology of CS-AKI in neonates utilizing the Acute Kidney Injury Network (AKIN) definition, (2) to identify risk factors for neonatal CS-AKI, and (3) to determine if neonatal CS-AKI is associated with increased morbidity and mortality., Methods: This was a retrospective study involving 122 neonates (≤28 days) undergoing cardiac surgery from 2006 to 2009. Neonates with and without AKI were identified using serum creatinine (SCr) and urine output (UO) data., Results: Cardiac surgery-AKI occurred in 76 (62 %) neonates, of whom 22 (29 %) were AKIN stage 1, 19 (25 %) were stage 2, and 35 (46 %) were stage 3. AKI mostly occurred early as 75 % of patients achieved their maximal AKIN stage within the first 48 h post-operatively. In the multivariate analysis, cardiopulmonary bypass duration of ≥120 min was independently associated with AKI [odds ratio (OR) 2.53, 95 % confidence interval (CI) 1.03-6.30]. Severe AKI (AKIN stage 3) was independently associated with mortality (OR 6.70, 95 % CI 1.08-41.50) and a longer stay in the pediatric intensive care unit (hazard ratio 9.09, 95 % CI 1.35-60.95). The majority of severe AKI cases (65 %) were identified with AKIN UO criteria alone without significant rises in SCr., Conclusions: Cardiac surgery-AKI is common in neonates when the AKIN definition is utilized and is associated with higher morbidity and mortality, especially in those with more severe AKI.

Background: The long-term health consequences of acute bacterial gastroenteritis remain uncertain. We studied the risk of hypertension and reduced kidney function after an outbreak of acute gastroenteritis due to contamination of a regional drinking water supply with Escherichia coli O157:H7 and Campylobacter species., Methods: A total of 1958 adults with no known history of hypertension or kidney disease before the outbreak participated in a long-term follow-up study. Of the participants, 675 had been asymptomatic during the outbreak, 909 had had moderate symptoms of acute self-limited gastroenteritis, and 374 had had severe symptoms that necessitated medical attention. The outcomes of interest were a diagnosis of hypertension or the presence of reduced kidney function and albuminuria during the follow-up period., Results: After a mean follow-up of 3.7 years after the outbreak, hypertension was diagnosed in 27.0% of participants who had been asymptomatic during the outbreak and in 32.3% and 35.9% of those who had had moderate and severe symptoms of acute gastroenteritis respectively (trend p = 0.009). Compared with the asymptomatic participants, those with moderate and severe symptoms of gastroenteritis had an adjusted relative risk of hypertension of 1.15 (95% confidence interval [CI] 0.97-1.35) and 1.28 (95% CI 1.04-1.56) respectively. A similar graded association was seen for reduced kidney function, defined as the presence of an estimated glomerular filtration rate below 60 mL/min per 1.73 m2 (trend p = 0.03). No association was observed between gastroenteritis and the subsequent risk of albuminuria., Interpretation: Acute bacterial gastroenteritis necessitating medical attention was associated with an increased risk of hypertension and reduced kidney function 4 years after infection. Maintaining safe drinking water remains essential to human health, as transient bacterial contaminations may have implications well beyond a period of acute self-limited illness.

Renal leiomyoma is a rare smooth muscle tumor of the kidney. An association between Epstein-Barr virus and smooth muscle tumors in immunocompromised patients recently has been recognized. We describe a pediatric renal transplant patient who developed an Epstein-Barr virus-associated renal leiomyoma in his transplant kidney 5 years posttransplantation. Possible factors involved in the tumor pathogenesis in our patient are discussed, including immunosuppression, growth hormone therapy, and Epstein-Barr virus induction.

Repeated administration of agents (e.g., cancer chemotherapy) that can cause drug-induced nephrotoxicity may lead to acute or chronic renal damage. This will adversely affect the health and well-being of children, especially when the developing kidney is exposed to toxic agents that may lead to acute glomerular, tubular or combined toxicity. We have previously shown that the cancer chemotherapeutic ifosfamide (IF) causes serious renal damage substantially more in younger children (less than 3 years of age) than among older children. The mechanism of the age-related IF-induced renal damage is not known. Our major hypothesis is that renal CYP P450 expression and activity are responsible for IF metabolism to the nephrotoxic chloroacetaldehyde. Presently, the ontogeny of these catalytic enzymes in the kidney is sparsely known. The presence of CYP3A4, 3A5 and 2B6 was investigated in human fetal, pediatric and adult kidney as was the metabolism of IF (both R-IF and S-IF enantiomers) by renal microsomes to 2-dechloroethylifosfamide (2-DCEIF) and 3-dechloroethylifosfamide (3-DCEIF). Our analysis shows that CYP 3A4 and 3A5 are present as early as 8 weeks of gestation. IF is metabolized in the kidney to its two enantiomers. This metabolism can be inhibited with CYP 3A4/5 and 2B6 specific monoclonal inhibitory antibodies, whereby the CYP3A4/5 inhibitory antibody decreased the production of R-3-DCEIF by 51%, while the inhibitory CYP2B6 antibody decreased the production of S-2-DCEIF and S-3-DCEIF by 44 and 43%, respectively, in patient samples. Total renal CYP content is approximately six-fold lower than in the liver.

Background: Knowledge of the long-term renal prognosis of diarrhea associated hemolytic uremic syndrome (HUS) is important for patient counseling and follow-up. However, estimates of long-term risk are highly variable, with previous studies not using a healthy control group., Methods: A municipal water system in the small rural town of Walkerton, Ontario, became contaminated with Escherichia coli O157:H7 in 2000. A cohort of 19 children who recovered from HUS was randomly age- and sex-matched to 38 children with no symptoms at the time of the outbreak. Both groups had detailed renal function testing 3 years after the outbreak, including a random urine albumin to creatinine, glomerular filtration rate estimated by Schwartz formula, and automated and manual blood pressure measurements., Results: There were no baseline differences between the groups with respect to age (mean 4.8 years, range 1 to 15), sex, or birth weight (mean 3.4 kg). In follow-up there were no differences between the groups in body surface area (mean 1.0 m(2)), or in the methods by which renal function was assessed. Compared to the group with no symptoms, patients with HUS demonstrated more microalbuminuria [32% vs. 5%, relative risk 4.8 (95% CI 1.1 to 22.0)], a nonsignificant trend toward lower GFR (124 vs. 134 mL/min per 1.73 m(2)), and no difference in blood pressure., Conclusion: Children may demonstrate microalbuminuria 3 years after recovering from HUS. Longer follow-up is needed to determine if this finding has clinical relevance and utility.

Context: The long-term renal prognosis of patients with diarrhea-associated hemolytic uremic syndrome (HUS) remains controversial., Objectives: To quantify the long-term renal prognosis of patients with diarrhea-associated HUS and to identify reasons for different estimates provided in the literature., Data Sources: We searched MEDLINE and Experta Medica (EMBASE) bibliographic databases and conference proceedings, and we contacted experts until February 2003. We also searched the Institute for Scientific Information index and reference lists of all studies that fulfilled our eligibility criteria. The search strategy included the terms hemolytic-uremic syndrome, purpura, thrombotic thrombocytopenic, Escherichia coli O157, longitudinal studies, kidney diseases, hypertension, and proteinuria, Study Selection: Any study that followed up 10 or more patients with primary diarrhea-associated HUS for at least 1 year for renal sequelae., Data Extraction: Two authors independently abstracted data on study and patient characteristics, renal measures, outcomes, and prognostic features. Disagreements were resolved by a third author or by consensus., Data Synthesis: Forty-nine studies of 3476 patients with a mean follow-up of 4.4 years (range, 1-22 years at last follow-up) from 18 countries, 1950 to 2001, were summarized. At the time of recruitment, patients were aged 1 month to 18 years. In the different studies, death or permanent end-stage renal disease (ESRD) ranged from 0% to 30%, with a pooled incidence of 12% (95% confidence interval [CI], 10%-15%). A glomerular filtration rate lower than 80 mL/min per 1.73 m2, hypertension, or proteinuria was extremely variable and ranged from 0% to 64%, with a pooled incidence of 25% (95% CI, 20%-30%). A higher severity of acute illness was strongly associated with worse long-term prognosis. Studies with a higher proportion of patients with central nervous system symptoms (coma, seizures, or stroke) had a higher proportion of patients who died or developed permanent ESRD at follow-up (explaining 44% of the between-study variability, P =.01). Studies with a greater proportion of patients lost to follow-up also described a worse prognosis (P =.001) because these patients were typically healthier than those followed up. One or more years after diarrhea-associated HUS, patients with a predicted creatinine clearance higher than 80 mL/min per 1.73 m2, no overt proteinuria, and no hypertension appeared to have an excellent prognosis., Conclusions: Death or ESRD occurs in about 12% of patients with diarrhea-associated HUS, and 25% of survivors demonstrate long-term renal sequelae. Patients lost to follow-up contribute to worse estimates in some studies. The severity of acute illness, particularly central nervous system symptoms and the need for initial dialysis, is strongly associated with a worse long-term prognosis.

Glomerulonephritis is an important complication of systemic lupus erythematosus (SLE). The tissue distribution and exact role of the insulin-like growth factors (IGFs) in the development of lupus nephritis in the MRL/lpr mouse model have not been established. The present study was undertaken to evaluate the changes over time in mRNA and peptide expression of IGF-I and IGFBP-2 in the MRL/lpr mouse. Using in situ hybridization and immunocytochemistry techniques, the expression of IGF-I and IGFBP-2 in MRL/lpr mouse was examined and compared to their congenic normal MRL-++ mouse counterparts from nine to 24 weeks of age. In the MRL-++ and MRL/lpr mouse kidneys, IGF-I and IGFBP-2 mRNA expression was limited to the cortical and medullary collecting ducts, while their immunoreactivity (IR) was localized to the cortical and medullary collecting ducts, loop of Henle, glomeruli and proximal tubules. Over time, and with progression of disease, the MRL/lpr mice displayed a significant increase in IGF-I IR and a modest increase in IGFBP-2 IR within the outer cortical glomeruli, which was associated with a significant increase in glomerulosclerosis and glomerular cell proliferation and with a significant decrease in renal function. In conclusion, this overexpression of IGF-I and IGFBP-2 within the glomeruli of the MRL/lpr mouse kidney supports their potential role in the alterations in renal function and morphology that accompany lupus nephritis.

Objective: To provide an effective approach for family physicians treating children presenting with urinary tract infections (UTIs)., Quality of Evidence: The information presented, and articles quoted, are drawn from both review of the literature and recent consensus guidelines. Data and recommendations come from prospective multicentre trials; retrospective reviews; expert consensus statements; and some smaller trials, commentaries, and editorials., Main Message: Urinary tract infections are often seen in family practice. Diagnosis requires suspicion and a realization that children, especially those younger than 2 years, often have very few, nonspecific signs of infection. Obtaining a proper urine sample is vital, because true infections require radiographic studies. Antibiotic prophylaxis is promoted because of the link between vesicoureteral reflux, recurrent UTIs, and renal scarring and hypertension. We generally provide prophylaxis until children are 3 or 4 years, when risk of damage from reflux is lessened and timely urine samples are easier to obtain for prompt therapy. Surgical opinion is sought only when medical management has failed. Failure is defined as either recurrent infections and pyelonephritis or poor renal growth., Conclusion: To diagnose UTIs in children, physicians must suspect them, obtain proper urine samples, order appropriate investigations to rule out underlying anatomic abnormalities, and treat with appropriate antibiotics considering both organism sensitivities and length of therapy.

Renal dysplasia is a clinically important consequence of abnormal nephrogenesis. Various forms are encountered in clinical practice; however, renal dysplasia may represent the final common end point of defects in the normal cascade of fetal kidney development. Typical histopathologic changes characterize renal dysplasia, including architectural distortion, metaplasia, and primitive glomeruli and tubules. Cystic changes are not universal but can be found in most situations. The advent of recent molecular techniques, including gene targeting and positional cloning, has expanded our knowledge of the molecular control of normal mammalian nephrogenesis and with it our understanding of the pathogenesis of renal dysplasia. A defect in the ability of the branching ureteric duct and the undifferentiated metanephric blastema to communicate appears to be the basic underlying principle for the formation of dysplasia. Mutation, defective regulation of transcription, and alteration in spatial or temporal expression of a number of classes of genes, including growth factors, have been implicated in the development of renal dysplasia. Numerous examples, both experimental and in nature, highlight this point.

We have developed a unique human fetal kidney explant model to study the role of the insulin-like growth factor (IGF) system in metanephric development. Kidneys from 10-18 wk gestation human abortuses were maintained in serum-free conditions and defined medium, which was shown to support the induction and differentiation of the viable metanephric blastema. Histologically the tissue remained viable to 192 h of serum-free culture, while metanephric differentiation, reflected by a shrinking nephrogenic zone and the formation of maturing S-shape and glomerular forms, was accelerated and occurred between 48 and 96 h. In the nephrogenic zone, a significant decrease in IGF-II gene expression occurred, which reflected the differentiation of the metanephric blastema cell mass, IGF-II expression persisted, however, in the expanded interstitial mesenchyme. With differentiation over 48 h an increase in IGFBP-2 and WT1 gene expression by Northern blot analysis occurred, and was localized by in situ hybridization to the differentiating glomerular epithelial cell mass. Analysis of the explant-conditioned media by Western ligand blot demonstrated an increase in the rate of IGF binding protein (IGFBP)-2 peptide production by the differentiating explant, consistent with an increase in IGFBP-2 gene expression and with metanephric differentiation. This pattern of temporal and spatial gene expression closely approximates that of normal in vivo fetal renal development and of glomerular epithelial cell differentiation.

Traditionally, bulk amino acid reabsorption in the kidney has been thought to be localized to the early portions of the proximal nephron. Adult Sprague-Dawley rats were fed diets with low, normal, and high taurine content for two weeks. Kidneys were hybridized with an 35S-radiolabeled complementary RNA probe to the rB16a subclone encoding the extracellular and transmembrane domains of the rat brain taurine transporter. Identical fragments were generated by RT-PCR from rat brain and kidneys as confirmed by DNA sequencing. Hybridization was localized to the outer zone of the medulla of all the kidneys. In the normal diet animals, taurine transporter mRNA was localized to the S3 segment of the proximal tubule, to the loop of Henle in the medulla, and to the glomerular epithelial cell layer. With taurine restriction, taurine transporter mRNA expression was up-regulated predominantly in the S3 segment and was virtually absent in this segment in animals supplemented with taurine. These experiments have precisely localized the rat kidney taurine transporter gene, demonstrating regulation that is limited to the S3 segment of the proximal tubule.

Objective: The etiology and pathogenesis of renal dysplasia are poorly understood. To characterize the histologic changes in fetal renal dysplasia, we studied a fetal ovine model of urinary obstruction., Design: Animal study., Animals: Seven fetal lambs, and other lambs of the same gestational age as controls., Interventions: Unilateral ureteral ligation on fetal lambs at approximately 70 days' gestation (term for sheep is 145 days), during nephrogenesis. Kidneys were subsequently collected, examined histologically and characterized by immunohistochemical tests involving cytokeratin antiserum and a monoclonal antibody to alpha-actin., Outcome Measures: Histologic changes in ligated fetal lamb kidneys, based on comparison with normal fetal lamb kidneys., Results: At near term (140 days' gestation), the ligated kidney showed distorted and less abundant renal parenchyma than a normal control kidney. Upon microscopic examination, the ligated kidney displayed marked architectural distortion of the outer cortex, with abundant interstitial fibrosis, primitive ductules and glomeruli, and cysts of varying sizes lined by squamous and cuboidal epithelia and surrounded by a loose mesenchyme. The renal medulla contained differentiated collecting ducts, which were structurally distorted and less abundant than in normal control kidneys. The proximal and distal tubule elements were primitive and markedly underdeveloped. Cytokeratin immunoreactivity was present in the collecting duct epithelium and in the cuboidal epithelium lining many of the cortical cysts. Smooth muscle alpha-actin immunoreactivity was localized in the cortical region of the kidney, which highlighted the abundance and disorganization of the undifferentiated mesenchyme and identified the fibromuscular collars of the primitive ductules of the cortex and the distorted collecting ducts of the medulla., Conclusions: These results highlight the histologic changes resulting from unilateral ureteral ligation in fetal lambs. This model is useful in the study of the pathogenesis of fetal obstructive renal dysplasia.

The pathogenesis of multicystic dysplastic kidney disease (MCDKD) is unknown. Most morphologic studies of MCDKD kidneys have been performed when the kidneys are resected postnatally, when their architecture has been distorted by massive cyst enlargement. We obtained two MCDKD kidneys at an early stage of development (14 and 19 weeks' gestation) and examined the pattern of nephrogenesis in detail. In both affected kidneys, we identified islands of spatially dislocated metanephric blastema adjacent to zones containing all the normal structural elements of nephrogenesis, including aggregates of induced mesenchyme, S-shaped bodies and maturing glomerull, and proximal and distal tubules. Metanephric blastemal cells displayed characteristic vimentin and smooth muscle actin immunoreactivity and insulin-like growth factor II gene expression, whereas induced elements exhibited appropriate cytokeratin immunoreactivity and Wilms' tumor gene expression. In most other zones, renal cysts were lined with epithelia varying from a flattened squamous to a cuboidal morphology and expression of markers suggested their origin to be from all portions of the nephron including Bowman's space, proximal tubule, and collecting duct. In some cysts, small clusters of epithelial cells were identified within the cyst lumen. These studies suggest that in the early stages of MCDKD, normal nephrogenesis occurs in what seems to be a normal metanephric blastema; however, an intrinsic abnormality in the branching morphogenesis of the ureteric duct might be responsible for the development of the histopathologic changes described.

Insulin-like growth factors (IGF-I and IGF-II) are synthesized by most embryonic and fetal tissues, and regulate cellular growth and differentiation as autocrine/paracrine factors. A family of six IGF-binding proteins (IGFBPs) modulate IGF biological actions as both negative (inhibitory) and positive (potentiating) modulators. To determine the tissue distribution of IGFBP mRNA expression, we performed Northern blot analysis and in situ hybridization of human fetal tissues during gestational ages 10-16 weeks (n = 8). IGFBP-1 mRNA was expressed only in the liver, whereas other IGFBP mRNAs were expressed in variable abundance in every tissue examined. IGFBP-2 mRNA was expressed in moderate abundance in every tissue with the highest level observed in the liver; IGFBP-3 mRNA was expressed most abundantly in the skin, muscle and heart; IGFBP-4 mRNA was expressed in moderate abundance equally in all tissues; IGFBP-5 mRNA was expressed most abundantly in the skin, muscle and stomach, and IGFBP-6 mRNA was expressed in low abundance in all tissues. Notable exceptions were that liver expressed little or no IGFBP-4, -5 and -6 mRNAs, spleen and thymus expressed low levels of IGFBP-5 mRNA, and brain expressed little or no IGFBP-5 and IGFBP-6 mRNA. In situ hybridization of human fetal tissues showed IGFBP mRNAs were expressed in both epithelial and mesenchymal cells depending on the specific IGFBP and the stage of development. IGFBP-3, -4, and -5 mRNAs were localized mainly in the mesenchymal cells, and IGFBP-2 mRNA was localized predominantly in the epithelial cells. IGFBP-6 mRNA was localized in low abundance in both epithelial and mesenchymal cells. These studies indicate that IGFBPs are important paracrine modulators of IGF action on cellular growth and differentiation, by modulating IGF-dependent or IGF-independent actions.

Activation of the complement cascade occurs in most cases of acute poststreptococcal glomerulonephritis (APSGN) and results in the formation of the terminal complement complexes (TCC). To examine the possible role of TCC in the pathogenesis of glomerular injury in APSGN, we studied 30 patients with the clinical diagnosis of APSGN. All patients had an elevated plasma SC5b-9 concentration at the onset of clinical nephritis. Serial plasma concentrations showed an inverse linear relationship with time after onset of clinical disease (r = -0.59, P = 0.0008), while plasma C3 concentrations showed a positive linear relationship (r = 0.78, P = 0.0001). Renal biopsies of 5 patients demonstrated co-localization of C5b-9, S-protein, and C3 deposition in a glomerular capillary loop and mesangial distribution. Urinary excretion of TCC in the acute phase of APSGN was not elevated and was not a useful marker of disease activity. These data suggest that in APSGN with terminal complement pathway activation the local generation of TCC may contribute to the pathogenesis of the disease.

To study the role of insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) in human nephrogenesis, we examined the temporal and spatial pattern of expression of these genes using in situ hybridization. The uninduced metanephric blastema (MB) expressed abundant IGF-II mRNA. With induction by the ureteric duct (UD), the aggregated MB additionally expressed IGFBP-2 and IGFBP-4 mRNAs. The mature UD expressed IGFBP-3 mRNA while the ampulla in contact with the MB lacked IGFBP-3 mRNA and expressed IGFBP-2 exclusively. Upon formation of the S-shape nephron, IGFBP-2 mRNA was expressed in the committed glomerular and epithelial cells which also expressed IGF-II and IGFBP-4, and the mesenchyme of the vascular cleft expressed IGFBP-5 mRNA. In the maturing glomerulus, the glomerular epithelial cells expressed IGF-II mRNA together with IGFBP-2 and IGFBP-4 mRNAs, while IGFBP-5 mRNA was localized to the mesangium and supporting mesenchyme. As the proximal tubule was formed the epithelium expressed less of IGFBP-2 mRNA and more of IGFBP-4 mRNA. The renal mesenchyme in the cortex and medulla expressed abundant IGF-II mRNA, and lower levels of IGFBP-4 and -5 mRNAs. The epithelium of the collecting ducts and pelvicalyceal system expressed abundant IGFBP-3. In contrast, IGF-I, IGFBP-1, and IGFBP-6 mRNAs were expressed at low levels. The specific temporal and spatial pattern of expression of IGFBP genes on the background of abundant IGF-II gene expression suggests that the IGFBP peptides, as modulators of IGF action, are expressed locally at specific points of nephrogenesis to interact with IGF-II to regulate mesenchymal induction, renal epithelial cell commitment, differentiation and growth.

Mesangial cell proliferation contributes to glomerulosclerosis and is associated with the development of end-stage renal disease. We examined the effects of the cytokines interleukin 1 (IL-1 beta) and interleukin 6 (IL-6) on the mitogenesis and proliferation of rat glomerular mesangial cells. Exposure of serum-stimulated cells to IL-1 beta and IL-6 for 48 hours resulted in a dose-dependent inhibition of both mitogenesis, determined by 3H-thymidine incorporation, and proliferation, determined by absolute cell counts. Both IL-1 beta and IL-6 stimulated endogenous PGE2 production in this cell system. Cyclooxygenase inhibition by indomethacin and meclofenamate abrogated the inhibitory effects of both IL-1 beta and IL-6. Furthermore, addition of exogenous PGE2 to cytokine-stimulated cells in which cyclooxygenase activity was blocked resulted in inhibition of mitogenesis, while addition of exogenous aracidonic acid to the cytokine-stimulated cells enhanced the induced inhibition of mitogenesis. These results demonstrate that in serum-stimulated mesangial cells, both IL-1 beta and IL-6 inhibit mitogenesis and proliferation, and that these effects are mediated, in part, by stimulated endogenous prostaglandin production.

Children with nephrotic syndrome (NS) are susceptible to bacterial infections, including primary bacterial peritonitis. Immunologic abnormalities associated with NS include low serum levels of the complement proteins I and B of the alternative complement pathway. We developed a novel and highly sensitive enzyme immunoassay using murine MAb to I and B to quantitate urinary concentrations of these proteins. We studied 22 patients with minimal change NS, including seven with a history of peritonitis (1.6 +/- 0.3 episodes, mean +/- SEM) and 15 without such a history. The two groups did not differ significantly in age, sex, race, age at onset of disease, or duration of disease. Children with minimal change NS complicated by peritonitis had 1) increased urinary excretion of both I (p < 0.05) and B (p < 0.05) in relapse versus remission, 2) greater excretion of I in both relapse (p < 0.01) and remission (p < 0.05) compared with patients without peritonitis, 3) greater excretion of B in relapse compared with patients without peritonitis (p < 0.05), and 4) decreased plasma levels of I compared with patients without peritonitis and controls (p < 0.01) and decreased plasma levels of B compared with controls. Increased urinary excretion of I correlated with decreased plasma levels of I (r = 0.88, p < 0.001). These data support our initial hypothesis that depressed plasma concentrations of these proteins of the alternative complement pathway may predispose patients with minimal change NS to peritonitis and that urinary loss of these proteins is a tenable mechanism.

An 11-year-old renal transplant recipient was noted to have a bruit over her transplant graft 26 months post transplant and 17 months following percutaneous renal biopsy during an episode of rejection. Diagnosis of an arteriovenous (AV) fistula was made by ultrasound examination with Doppler flow and was confirmed with arteriography. The AV fistula was occluded by transcatheter embolotherapy with placement of a steel coil into the fistula from the renal vein approach. This procedure allowed nonsurgical closure of the AV shunt without significant change in renal function.

In most instances of acute poststreptococcal glomerulonephritis (APSGN), activation of the complement system occurs, as reflected by decreased levels of the complement proteins C3, C5, and properdin (P). Recent studies implicate terminal complement complexes (TCC) in the pathogenesis of glomerular injury. The fluid phase TCC, SC5b-9, reflects the formation of membrane-bound C5b-9 and has been used as a clinical marker in various diseases. Plasma concentrations of SC5b-9 were measured with an enzyme immunoassay using a monoclonal antibody to a neoantigen expressed on the SC5b-9 complex in 13 children who presented with clinical and pathologic features of APSGN. SC5b-9 was significantly elevated in all plasmas obtained within 30 days after onset of clinical glomerulonephritis. Concentrations of SC5b-9 in acute plasmas were significantly higher than those of paired convalescent samples. For individual patients, as SC5b-9 concentration returned to normal there was a coincident decrease in serum creatinine concentration and urinary protein excretion, signifying clinical improvement in glomerulonephritis. Thus, TCC generation commonly occurs in the early stages of APSGN and may be of importance in the pathogenesis of the condition.

Isolated angiitis of the central nervous system, a rare inflammatory condition of the nervous system, characterized by vasculitis of the small vessels, has not, to the best of our knowledge, been described in childhood. It usually presents with a diversity of neurological symptoms in the fifth to eighth decades of life. We reviewed the case of an 8 year old male with autopsy proven isolated cerebral angiitis, to encourage the consideration of this disorder in children; and to emphasize the lack of sensitivity of present modalities of neurological investigation in the diagnosis.

Group A streptococcus can cause both acute glomerulonephritis and acute rheumatic fever. The occurrence of characteristic acute poststreptococcal glomerulonephritis and acute rheumatic fever in the same patient is rare. We describe a 10-year-old girl with acute rheumatic fever who presented with the typical clinical and biopsy findings of acute poststreptococcal glomerulonephritis.