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1.
Pediatr Nephrol ; 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33629141

RESUMO

BACKGROUND: Hypertension is prevalent in children on dialysis and associated with cardiovascular disease. We studied the blood pressure (BP) trends and the evolution of BP over 1 year in children on conventional hemodialysis (HD) vs. hemodiafiltration (HDF). METHODS: This is a post hoc analysis of the "3H - HDF-Hearts-Height" dataset, a multicenter, parallel-arm observational study. Seventy-eight children on HD and 55 on HDF who had three 24-h ambulatory BP monitoring (ABPM) measures over 1 year were included. Mean arterial pressure (MAP) was calculated and hypertension defined as 24-h MAP standard deviation score (SDS) ≥95th percentile. RESULTS: Poor agreement between pre-dialysis systolic BP-SDS and 24-h MAP was found (mean difference - 0.6; 95% limits of agreement -4.9-3.8). At baseline, 82% on HD and 44% on HDF were hypertensive, with uncontrolled hypertension in 88% vs. 25% respectively; p < 0.001. At 12 months, children on HDF had consistently lower MAP-SDS compared to those on HD (p < 0.001). Over 1-year follow-up, the HD group had mean MAP-SDS increase of +0.98 (95%CI 0.77-1.20; p < 0.0001), whereas the HDF group had a non-significant increase of +0.15 (95%CI -0.10-0.40; p = 0.23). Significant predictors of MAP-SDS were dialysis modality (ß = +0.83 [95%CI +0.51 - +1.15] HD vs. HDF, p < 0.0001) and higher inter-dialytic-weight-gain (IDWG)% (ß = 0.13 [95%CI 0.06-0.19]; p = 0.0003). CONCLUSIONS: Children on HD had a significant and sustained increase in BP over 1 year compared to a stable BP in those on HDF, despite an equivalent dialysis dose. Higher IDWG% was associated with higher 24-h MAP-SDS in both groups.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33536243

RESUMO

In the past 20 years, we have witnessed tremendous advances in our ability to diagnose and treat genetic diseases of the kidney caused by complement dysregulation. Staggering progress was realized toward a better understanding of the genetic underpinnings and pathophysiology of many forms of atypical hemolytic uremic syndrome (aHUS) and C3-dominant glomerulopathies that are driven by complement system abnormalities. Many of these seminal discoveries paved the way for the design and characterization of several innovative therapies, some of which have already radically improved patients' outcomes. This review offers a broad overview of the exciting developments that have occurred in the recent past, with a particular focus on single-gene (or Mendelian), complement-driven aHUS and C3-dominant glomerulopathies that should be of interest to both nephrologists and kidney researchers. The discussion is restricted to genes with robust associations with both aHUS and C3-dominant glomerulopathies (complement factor H, complement component 3, complement factor H-related proteins) or only aHUS (complement factor B, complement factor I, and membrane cofactor protein). Key questions and challenges are highlighted, along with potential avenues for future directions.

3.
Pediatr Nephrol ; 36(1): 93-102, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32671615

RESUMO

BACKGROUND: Steroids and/or steroid-sparing medications are commonly used for nephrotic syndrome treatment; however, the impact of these medications on health-related quality of life over time is not well described. METHODS: Longitudinal cohort is up to 5 years where children were assessed with baseline and annual Pediatric Quality of Life Inventory questionnaire. A mixed-effects linear regression determined differences in scores among children receiving steroids and/or steroid-sparing agents for at least 30 days compared with those not on medication at 1, 3, 6, and 12 months prior to assessment. RESULTS: Among 295 children, 64% were male, with a median age of 3.7 (interquartile range [IQR], 2.7, 5.9) years at diagnosis, and comprised 25% Europeans, 40% South Asians, and 8% East/Southeast Asians. Adjusted HRQOL scores were reduced among children taking steroids and steroid-sparing agents among 705 HRQOL measures (median 2 [IQR, 1, 3] per child). Compared to children without medication, steroid and steroid-sparing agent use up to 12 months prior to assessment were associated with an overall HRQOL drop of 3.17 (95% confidence interval [CI], - 5.25, - 1.08) and 3.18 (95% CI, - 5.24, - 1.12), respectively, after adjustment. Functioning domain scores were reduced by 4.41 points (95% CI, - 6.57, - 2.25) in children on steroids, whereas fatigue domain scores were reduced by 5.47 points (95% CI, - 9.28, - 1.67) in children on steroid-sparing agents after adjustment. CONCLUSIONS: HRQOL is consistently decreased in children receiving steroids and steroid-sparing agents, with differential effects on functioning and fatigue. Counseling families on possible effects of prolonged treatment periods is important in the management of childhood nephrotic syndrome.

4.
Kidney Int Rep ; 5(12): 2313-2324, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33305125

RESUMO

Introduction: The reclassification of membranoproliferative glomerulonephritis (MPGN) into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G) has provided insights into 2 distinct diseases. Although outcomes in adults are poor in both diseases, the pediatric literature is scarce and limited to small, single-center cohorts. Methods: We conducted a retrospective analysis of 165 pediatric patients across 17 hospitals to compare outcomes between children with IC-MPGN and C3G. Results: Forty-two percent of patients initially diagnosed with MPGN were reclassified as C3G after a review of renal biopsy reports. There was a trend toward higher serum creatinine levels in patients with C3G compared with IC-MPGN both at diagnosis (mean 168.9 [range 45.4-292.4] vs. 93.7 [range 70.7-116.6] µmol/l, P = 0.25) and after a mean follow-up time of 4 years (mean 145.0 (range -8.1 to 298.1) vs 99.1 (range 46.3-151.9) µmol/l, P = 0.47), although the estimated glomerular filtration rate (eGFR) was not significantly different. Steroid treatment was associated with a significant improvement in eGFR versus no steroids in C3G (mean +43.0 (range 12.9-73.0) vs. -3.0 (range -23.1 to 17.2) ml/min per 1.73 m2, P = 0.02) but not in IC-MPGN. Overall kidney function was preserved in both groups although hypertension remained prevalent in 42.5% of the cohort at the last follow-up, and the urine protein/creatinine ratio remained elevated (mean 253.8 [range 91.9-415.7] mg/mmol). Conclusion: This large pediatric IC-MPGN/C3G cohort revealed nearly half of the patients were misclassified, and there may be a trend toward worse renal prognosis in C3G although they may have greater steroid responsiveness. The overall prognosis appears to be more favorable than in adults; however, persistent hypertension and proteinuria suggest suboptimal disease control.

5.
Lancet Child Adolesc Health ; 4(11): 828-836, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33068549

RESUMO

BACKGROUND: Acute flaccid myelitis (AFM) is characterised by rapid onset of limb weakness with spinal cord grey-matter abnormalities on MRI scan. We aimed to assess whether detection of enterovirus in respiratory or other specimens can help predict prognosis in children with AFM. METHODS: In this nationwide, longitudinal study, we evaluated the significance of detection of enterovirus in any sample in predicting outcomes in a cohort of Canadian children younger than 18 years presenting with AFM to tertiary paediatric hospitals in Canada in 2014 and 2018. All patients fulfilled the 2015 US Centers for Disease Control and Prevention case definition for definite AFM or probable AFM. Clinical data, laboratory findings, treatment, and neuroimaging results were collected (follow up period up to 5 years). We assessed neurological function and motor outcomes using Kurtzke's Expanded Disability Status Scale (EDSS) and a Weakest Limb Score. FINDINGS: 58 children with AFM (median age 5·1 years, IQR 3·8-8·3) were identified across five of Canada's ten provinces and three territories. 25 (43%) children had enterovirus detected in at least one specimen: 16 (64%) with EV-D68, two (8%) with EV-A71, two (8%) with coxsackievirus, 10 (40%) with untyped enterovirus. Children who were enterovirus positive were more likely than those that were negative to have had quadriparesis (12 [48%] of 25 vs four [13%] of 30; p=0·028), bulbar weakness (11 [44%] of 25 vs two [7%] of 30; p=0·028), bowel or bladder dysfunction (14 [56%] of 25 vs seven [23%] of 30; p=0·040), cardiovascular instability (nine [36%] of 25 vs one [3%] of 30; p=0·028), and were more likely to require intensive care unit admission (13 [52%] of 25 vs 5 [17%] of 30; p=0·028). On MRI, most children who were enterovirus positive showed brainstem pontine lesions (14 [61%] of 23), while other MRI parameters did not correlate with enterovirus status. Median EDSS of enterovirus positive (EV+) and enterovirus negative (EV-) groups was significantly different at all timepoints: baseline (EDSS 8·5, IQR 4·1-9·5 vs EDSS 4·0, IQR 3·0-6·0; p=0·0067), 3 months (EDSS 4·0, IQR 3·0-7·4 vs EDSS 3·0, IQR 1·5-4·3; p=0·0067), 6 months (EDSS 3·5, IQR 3·0-7·0 vs EDSS 3·0, IQR 1·0-4·0; p=0·029), and 12 months (EDSS 3·0, IQR 3·0-6·9 vs EDSS 2·5 IQR 0·3-3·0; p=0·0067). Kaplan-Meier survival analysis of a subgroup of patients showed significantly poorer motor recovery among children who tested positive for enterovirus than for those who tested negative (p=0·037). INTERPRETATION: Detection of enterovirus in specimens from non-sterile sites at presentation correlated with more severe acute motor weakness, worse overall outcomes and poorer trajectory for motor recovery. These results have implications for rehabilitation planning as well as counselling of families of children with these disorders. The findings of this study support the need for early testing for enterovirus in non-CNS sites in all cases of AFM. FUNDING: None.


Assuntos
Viroses do Sistema Nervoso Central , Enterovirus/isolamento & purificação , Debilidade Muscular , Mielite , Doenças Neuromusculares , Medula Espinal/diagnóstico por imagem , Canadá/epidemiologia , Viroses do Sistema Nervoso Central/diagnóstico , Viroses do Sistema Nervoso Central/epidemiologia , Viroses do Sistema Nervoso Central/microbiologia , Viroses do Sistema Nervoso Central/terapia , Pré-Escolar , Enterovirus/classificação , Feminino , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética/métodos , Imagem por Ressonância Magnética/estatística & dados numéricos , Masculino , Destreza Motora , Debilidade Muscular/diagnóstico , Debilidade Muscular/etiologia , Debilidade Muscular/reabilitação , Mielite/diagnóstico , Mielite/epidemiologia , Mielite/microbiologia , Mielite/terapia , Doenças Neuromusculares/diagnóstico , Doenças Neuromusculares/epidemiologia , Doenças Neuromusculares/microbiologia , Doenças Neuromusculares/terapia , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Recuperação de Função Fisiológica
6.
Clin Nephrol ; 94(4): 197-206, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32870147

RESUMO

C3 glomerulonephritis (C3GN) is a rare but severe form of kidney disease caused by fluid-phase dysregulation of the alternative complement pathway. Causative mutations in complement regulating genes as well as auto-immune forms of C3GN have been described. However, therapy and prognosis in individual patients remain a matter of debate and long-term data are scarce. This also applies for the management of transplant patients as disease recurrence post-transplant is frequent. Here, we depict the clinical courses of two sisters with the unique combination of an identical, homozygous mutation in the complement factor H (CFH) gene as well as autoantibodies with a clinical follow-up of more than 20 years. Interestingly, the sisters presented with discordant clinical courses of C3GN with normal kidney function in one (patient A) and end-stage kidney disease in the other sister (patient B). In patient B, eculizumab was administered immediately prior to and in the course after kidney transplantation, with the result of a stable graft function without any signs of disease recurrence. Comprehensive genetic work-up revealed no further disease-causing mutation in both sisters. Intriguingly, the auto-antibody profile substantially differed in both sisters: autoantibodies in patient A reduced the C3b deposition, while the antibodies identified in patient B increased complement activation and deposition of split products. This study underlines the concept of a personalized-medicine approach in complement-associated diseases after thorough evaluation of the individual risk profile in each patient.

7.
Front Immunol ; 11: 1833, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922395

RESUMO

Podocytes are an important part of the glomerular filtration barrier and the key player in the development of proteinuria, which is an early feature of complement mediated renal diseases. Complement factors are mainly liver-born and present in circulation. Nevertheless, there is a growing body of evidence for additional sites of complement protein synthesis, including various cell types in the kidney. We hypothesized that podocytes are able to produce complement components and contribute to the local balance of complement activation and regulation. To investigate the relevant balance between inhibiting and activating sides, our studies focused on complement factor H (CFH), an important complement regulator, and on C3, the early key component for complement activation. We characterized human cultured podocytes for the expression and secretion of activating and regulating complement factors, and analyzed the secretion pathway and functional activity. We studied glomerular CFH and C3 expression in puromycin aminonucleoside (PAN) -treated rats, a model for proteinuria, and the physiological mRNA-expression of both factors in murine kidneys. We found, that C3 and CFH were expressed in cultured podocytes and expression levels differed from those in cultivated glomerular endothelial cells. The process of secretion in podocytes was stimulated with interferon gamma and located in the Golgi apparatus. Cultured podocytes could initiate the complement cascade by the splitting of C3, which can be shown by the generation of C3a, a functional C3 split product. C3 contributed to external complement activation. Podocyte-secreted CFH, in conjunction with factor I, was able to split C3b. Podocytes derived from a patient with a CFH mutation displayed impaired cell surface complement regulation. CFH and C3 were synthesized in podocytes of healthy C57Bl/6-mice and were upregulated in podocytes of PAN treated rats. These data show that podocytes produce functionally active complement components, and could therefore influence the local glomerular complement activation and regulation. This modulating effect should therefore be considered in all diseases where glomerular complement activation occurs. Furthermore, our data indicate a potential novel role of podocytes in the innate immune system.

8.
Toxins (Basel) ; 12(8)2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32751286

RESUMO

Hemolytic uremic syndrome (HUS) is a rare disease primarily characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. Endothelial damage is the hallmark of the pathogenesis of HUS with an infection with the Shiga toxin (Stx) producing Escherichia coli (STEC-HUS) as the main underlying cause in childhood. In this study, blood outgrowth endothelial cells (BOECs) were isolated from healthy donors serving as controls and patients recovered from STEC-HUS. We hypothesized that Stx is more cytotoxic for STEC-HUS BOECs compared to healthy donor control BOECs explained via a higher amount of Stx bound to the cell surface. Binding of Shiga toxin-2a (Stx2a) was investigated and the effect on cytotoxicity, protein synthesis, wound healing, and cell proliferation was studied in static conditions. Results show that BOECs are highly susceptible for Stx2a. Stx2a is able to bind to the cell surface of BOECs with cytotoxicity in a dose-dependent manner as a result. Pre-treatment with tumor necrosis factor alpha (TNF-α) results in enhanced Stx binding with 20-30% increased lactate dehydrogenase (LDH) release. Endothelial wound healing is delayed in a Stx2a-rich environment; however, this is not caused by an effect on the proliferation rate of BOECs. No significant differences were found between control BOECs and BOECs from recovered STEC-HUS patients in terms of Stx2a binding and inhibition of protein synthesis.

10.
Kidney Int Rep ; 5(8): 1161-1171, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32775815

RESUMO

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a progressive and potentially life-threatening disease characterized by complement-mediated thrombotic microangiopathy. Patients with aHUS may experience fatigue, which can negatively impact their lives, but there is a knowledge gap regarding disease burden in these patients. Methods: In this longitudinal study, patients with aHUS from the Global aHUS Registry who completed patient-reported outcome assessments (Functional Assessment of Chronic Illness Therapy-Fatigue scale [FACIT-Fatigue], general health status, and work status) at ≥2 time points were assessed relative to treatment status: (i) never treated with eculizumab; (ii) on eculizumab at registry enrollment and continued therapy; and (iii) started eculizumab after registry enrollment. Results: Patients who started eculizumab after the baseline visit (n = 23) exhibited improvements in fatigue (nearly 75% achieved clinically meaningful improvement), improved general health status (55%), and 25% to 30% rate reduction in symptoms of fatigue, weakness, irritability, nausea/vomiting, and swelling at last follow-up. Among patients already on eculizumab at registry enrollment (n = 295) and those never treated (n = 233), these parameters changed minimally relative to the baseline. Emergency room visits and hospital admissions were similar between groups. The number of health care provider visits and work days missed were higher in patients who started eculizumab after registry enrollment. Conclusion: These real-world findings confirm the detrimental effects of aHUS on patients' daily lives, including high levels of fatigue and impairments in general health status. The results suggest clinically meaningful improvement in fatigue, other patient-reported outcomes, and symptoms with eculizumab initiation after enrollment into the aHUS registry.

11.
Kidney Int Rep ; 5(4): 426-434, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32280840

RESUMO

Introduction: It is unknown whether steroid sensitivity and other putative risk factors collected at baseline can predict the disease course of idiopathic nephrotic syndrome in childhood. We determined whether demographic, clinical, and family reported factors at presentation can predict outcomes in idiopathic nephrotic syndrome. Methods: An observational cohort of 631 children aged 1 to 18 years diagnosed with idiopathic nephrotic syndrome between 1993 and 2016 were followed up until clinic discharge, 18 years of age, end-stage kidney disease (ESKD), or the last clinic visit. Baseline characteristics were age, sex, ethnicity, and initial steroid sensitivity. Of these, 287 (38%) children also reported any family history of kidney disease, preceding infection, microscopic hematuria, and history of asthma/allergies. The outcomes were complete remission after initial steroid course, need for a second-line agent, frequently relapsing disease, and long-term remission. The discriminatory power of the models was described using the c-statistic. Results: Overall, 25.7% of children had no further disease after their initial steroid course. In addition, 31.2% developed frequently relapsing disease; however, 77.7% were disease-free at 18 years of age. Furthermore, 1% of children progressed to ESKD. Logistic regression modeling using the different baseline exposures did not significantly improve the prediction of outcomes relative to the observed frequencies (maximum c-statistic, 0.63; 95% confidence interval [CI], 0.59-0.67). The addition of steroid sensitivity did not improve outcome prediction of long-term outcomes (c-statistic, 0.63; 95% CI, 0.54-0.70). Conclusions: Demographic, clinical, and family reported characteristics, specifically steroid sensitivity, are not useful in predicting relapse rates or long-term remission in idiopathic nephrotic syndrome. Further studies are needed to address factors that contribute to long-term health.

12.
J Vasc Interv Radiol ; 31(5): 778-786, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32305244

RESUMO

PURPOSE: Evaluate technical aspects and outcomes of insertion/maintenance of hemodialysis (HD) central venous catheter (CVC) during infancy. MATERIALS AND METHODS: Single-center retrospective study of 29 infants who underwent 49 HD-CVC insertions between 2002 and 2016. Demographics, procedural, and post-procedural details, interventional radiology (IR) maintenance procedures, technical modifications, complications, and outcomes were evaluated. Technical adjustments during HD-CVC placement to adapt catheter length to patient size were labeled "modifications." CVCs requiring return visit to IR were called IR-maintenance procedures. Mean age and weight at HD-CVC insertion were 117 days and 4.9 kg. RESULTS: Of the 29 patients, 13 (45%) required renal-replacement-therapy (RRT) as neonates, 10 (34%) commenced RRT with peritoneal dialysis (PD), and 19 (66%) with HD. Fifteen nontunneled and 34 tunneled HD-CVCs were inserted while patients were ≤1 year. Technical modifications were required placing 25/49 (51%) HD-CVCs: 5/15 (33%) nontunneled and 20/34 (59%) tunneled catheters (P = .08). Patients underwent ≤6 dialysis-cycles/patient during infancy (mean 2.3), and a mean of 4.1 and 49 HD-sessions/catheter for nontunneled and tunneled HD-CVCs, respectively. Mean primary and secondary device service, and total access site intervals for tunneled HD-CVCs were 75, 115, and 201 days, respectively. A total of 26 of 49 (53%) patients required IR-maintenance procedures. Nontunneled lines had greater catheter-related bloodstream infections per 1,000 catheter-days than tunneled HD-CVCs (9.25 vs. 0.85/1,000 catheter days; P = .02). Nineteen patients (65%) survived over 1 year. At final evaluation (December 2017): 8/19 survived transplantation, 5/19 remained on RRT, 2/19 completely recovered, 1/19 lost to follow-up, and 3 died at 1.3, 2, and 10 years. CONCLUSIONS: Placement/maintenance of HD-CVCs in infants pose specific challenges, requiring insertion modifications, and IR-maintenance procedures to maintain function.


Assuntos
Cateterismo Venoso Central/instrumentação , Cateteres de Demora , Cateteres Venosos Centrais , Falência Renal Crônica/terapia , Diálise Renal/instrumentação , Fatores Etários , Peso Corporal , Obstrução do Cateter/etiologia , Infecções Relacionadas a Cateter/etiologia , Cateterismo Venoso Central/efeitos adversos , Cateterismo Venoso Central/mortalidade , Desenho de Equipamento , Humanos , Lactente , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/mortalidade , Transplante de Rim , Recuperação de Função Fisiológica , Diálise Renal/efeitos adversos , Diálise Renal/mortalidade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
13.
Can J Kidney Health Dis ; 7: 2054358119897229, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32047641

RESUMO

Background: Atypical hemolytic uremic syndrome (aHUS) is an extremely rare, heterogeneous disease of uncontrolled activation of the alternative complement pathway that is difficult to diagnose. We have evaluated the Canadian patients enrolled in the Global aHUS Registry to provide a Canadian perspective regarding the diagnosis and management of aHUS and the specific challenges faced. Objective: To evaluate Canadian patients enrolled in the Global aHUS Registry to provide a Canadian perspective regarding the diagnosis and management of aHUS and the specific challenges faced. Methods: The Global aHUS Registry is an observational, noninterventional, multicenter study that has prospectively and retrospectively collected data from patients of all ages with an investigator-made clinical diagnosis of aHUS, irrespective of treatment. Patients of all ages with a clinical diagnosis of aHUS were eligible and invited for enrollment, and those with evidence of Shiga toxin-producing Escherichia coli infection, or with ADAMTS13 activity ≤10%, or a subsequent diagnosis of thrombotic thrombocytopenic purpura were excluded. Data were collected at enrollment and every 6 months thereafter and were analyzed descriptively for categorical and continuous variables. End-stage renal disease (ESRD)-free survival was evaluated using Kaplan-Meier estimates, and ESRD-associated risk factors of interest were assessed using Cox proportional hazards regression models. Patients were censored at start of eculizumab for any outcome measures. Results: A total of 37 Canadian patients were enrolled (15 pediatric and 22 adult patients) between February 2014 and May 2017; the median age at initial aHUS presentation was 25.9 (interquartile range = 6.7-51.7) years; 62.2% were female and 94.6% had no family history of aHUS. Over three-quarters of patients (78.4%) had no conclusive genetic or anti-complement factor H (CFH) antibody information available, and most patients (94%) had no reported precipitating factors prior to aHUS diagnosis. Nine patients (8 adults and 1 child) experienced ESRD prior to the study. After initial presentation, there appears to be a trend that children are less likely to experience ESRD than adults, with 5-year ESRD-free survival of 93 and 56% (P = .05) in children and adults, respectively. Enrolling physicians reported renal manifestations in all patients at initial presentation, and 68.4% of patients during the chronic phase (study entry ≥6 months after initial presentation). Likewise, extrarenal manifestations also occurred in more patients during the initial presenting phase than the chronic phase, particularly for gastrointestinal (61.1% vs 15.8%) and central nervous system sites (38.9% vs 5.3%). Fewer children than adults experienced gastrointestinal manifestations (50.0% vs 70.0%), but more children than adults experienced pulmonary manifestations (37.5% vs 10.0%). Conclusions: This evaluation provides insight into the diagnosis and management of aHUS in Canadian patients and the challenges faced. More genetic or anti-CFH antibody testing is needed to improve the diagnosis of aHUS, and the management of children and adults needs to consider several factors such as the risk of progression to ESRD is based on age (more likely in adults), and that the location of extrarenal manifestations differs in children and adults.

14.
J Thromb Haemost ; 18(6): 1484-1494, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32073731

RESUMO

BACKGROUND: Defective complement inhibition can lead to the formation of membrane attack complexes (MAC; C5b-9) on the plasma membranes of vascular endothelial cells, resulting in injury that drives the progression of thrombotic microangiopathy (TMA), a key pathology in kidney disease. OBJECTIVE/METHODS: We examined the response of human endothelial cells to complement-mediated damage using blood outgrowth endothelial cells (BOECs) derived from healthy donors. BOECs were sensitized to complement factors present in normal human serum to induce the formation of C5b-9 on their plasma membranes. RESULTS: This triggered an expected abrupt rise in intracellular Ca2+ reflecting membrane leakage. Remarkably, while intracellular Ca2+ remained elevated, membrane leakage ceased within 30 minutes, and cells did not show significant death. Extensive mobilization of Weibel-Palade bodies (WPBs) was observed along with secretion of von Willebrand factor (VWF). The potential role of WPBs and VWF in mitigating complement-mediated damage was examined by comparing the effects of C5b-9 on BOECs derived from von Willebrand disease (VWD) patients expressing reduced amounts of VWF, lacking expression of functional VWF, or lacking both VWF and WPBs. BOECs lacking WPBs were not resistant to complement-mediated damage, but became resistant when transfected to express VWF (and thus WPBs). CONCLUSION: We conclude that BOECs exposed to C5b-9 attack respond by mobilizing WPBs, which mitigate and repair damage by fusing with the plasma membrane. We propose that a similar cell-specific response may protect the vascular endothelium from complement-mediated damage in vivo.

17.
Pediatr Nephrol ; 34(11): 2427-2448, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31446483

RESUMO

BACKGROUND: Intentional or unintentional ingestions among children and adolescents are common. There are a number of ingestions amenable to renal replacement therapy (RRT). METHODS: We systematically searched PubMed/Medline, Embase, and Cochrane databases for literature regarding drugs/intoxicants and treatment with RRT in pediatric populations. Two experts from the PCRRT (Pediatric Continuous Renal Replacement Therapy) workgroup assessed titles, abstracts, and full-text articles for extraction of data. The data from the literature search was shared with the PCRRT workgroup and two expert toxicologists, and expert panel recommendations were developed. RESULTS AND CONCLUSIONS: We have presented the recommendations concerning the use of RRTs for treatment of intoxications with toxic alcohols, lithium, vancomycin, theophylline, barbiturates, metformin, carbamazepine, methotrexate, phenytoin, acetaminophen, salicylates, valproic acid, and aminoglycosides.


Assuntos
Lesão Renal Aguda/terapia , Consenso , Envenenamento/terapia , Guias de Prática Clínica como Assunto , Terapia de Substituição Renal/normas , Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/etiologia , Adolescente , Criança , Pré-Escolar , Conferências de Consenso como Assunto , Feminino , Humanos , Lactente , Masculino , Nefrologia/normas , Envenenamento/diagnóstico , Envenenamento/etiologia , Adulto Jovem
18.
J Clin Apher ; 34(6): 646-655, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31424127

RESUMO

BACKGROUND: Peripheral hematopoietic stem cell (HSC) collections are needed for autologous hematopoietic stem cell transplantation (HSCT). Since 2015, our institution has utilized a secondary chamber mononuclear cell (MNC) protocol on the Spectra Optia apheresis system. Recently, a new continuous mononuclear collection protocol (CMNC) was developed for the same device. As there is limited data available regarding the use of the CMNC protocol in children, we compared collection efficiency (CE2), side effects, and clinical feasibility between the two protocols in patients <18 years old. STUDY DESIGN AND METHODS: We prospectively collected clinical, laboratory, and technical collection data from HSC collection procedures performed with the Spectra Optia apheresis system utilizing the CMNC protocol. Data were compared to retrospectively collected data utilizing the MNC protocol. Data collection included donor demographics, precollection peripheral CD34+ cell counts, total CD34+ cells collected, collection efficiency, side effects, and collection product characteristics. RESULTS: A total of 96 HSC collection procedures were performed on 79 pediatric patients utilizing either the MNC (61 patients) or CMNC (18 patients) protocol. The collection efficiencies were comparable between MNC and CMNC cohorts (52.9% vs 54.9%, P = 0.711). Platelet loss was significantly lower in the CMNC cohort (P = 0.002), especially in children weighing <15 kg. Product volumes were higher with CMNC. No significant collection-related side effects were noted with either protocol. CONCLUSIONS: MNC and CMNC protocols have comparable collection efficiencies and are both feasible and safe for the use in children. Centers may choose between the methods depending on clinical needs.


Assuntos
Leucaférese/métodos , Adolescente , Antígenos CD34/sangue , Criança , Coleta de Dados/métodos , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucaférese/instrumentação , Leucócitos Mononucleares , Pediatria , Transplante Autólogo
19.
BMC Nephrol ; 20(1): 125, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971227

RESUMO

BACKGROUND: There are limited long-term outcome data in eculizumab-treated patients with atypical hemolytic uremic syndrome (aHUS). We report final results from the largest prospective, observational, multicenter study of patients with aHUS treated with eculizumab. METHODS: Patients with aHUS who participated in any of five parent eculizumab trials and received at least one eculizumab infusion were eligible for enrollment in a long-term follow-up study. Rates of thrombotic microangiopathy (TMA) manifestations off versus on eculizumab were evaluated. Additional endpoints included change from baseline estimated glomerular filtration rate (eGFR), long-term renal outcomes, and serious targeted treatment-emergent adverse events. RESULTS: Among 93 patients (0-80 years of age), 51 (55%) remained on eculizumab and 42 (45%) discontinued; for those who discontinued, 21 (50%) reinitiated therapy. Patients who reinitiated eculizumab had similar baseline clinical characteristics to patients who remained on eculizumab, with higher likelihood of genetic/autoimmune complement abnormalities, more prior TMAs, and longer disease course versus those who did not reinitiate. Mean eGFR improved rapidly and remained stable for up to 6 years on eculizumab. In patients who discontinued, there was a trend toward decreasing renal function over time from discontinuation. Additionally, off-treatment TMA manifestation rates were higher in those aged < 18 years at diagnosis, with identified genetic/autoimmune complement abnormalities, or history of multiple TMAs prior to eculizumab initiation. The safety profile was consistent with previous studies. Three definite and one possible meningococcal infections related to eculizumab were reported and resolved with treatment. Three deaths unrelated to eculizumab were reported. CONCLUSIONS: The current study confirms the efficacy and safety of eculizumab in aHUS, particularly with regard to long-term renal function and TMA events. Pediatric age at disease onset and presence of genetic or autoimmune complement abnormalities are risk factors for TMA events off treatment. Overall, patients who discontinue eculizumab may be at risk for additional TMA manifestations and renal function decreases. Discontinuation of eculizumab, with careful monitoring, is an option in select patients with consideration of patient preference, organ function normalization, and risk factors for relapse, including mutational analysis, age of onset, and history of multiple TMA episodes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01522170 , January 31, 2012.


Assuntos
Anticorpos Monoclonais Humanizados , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Efeitos Adversos de Longa Duração , Microangiopatias Trombóticas , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Síndrome Hemolítico-Urêmica Atípica/complicações , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/epidemiologia , Criança , Inativadores do Complemento/administração & dosagem , Inativadores do Complemento/efeitos adversos , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Cooperação Internacional , Efeitos Adversos de Longa Duração/diagnóstico , Efeitos Adversos de Longa Duração/epidemiologia , Efeitos Adversos de Longa Duração/etiologia , Masculino , Conduta do Tratamento Medicamentoso , Avaliação de Processos e Resultados em Cuidados de Saúde , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/epidemiologia , Microangiopatias Trombóticas/etiologia
20.
Clin Kidney J ; 12(2): 196-205, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30976396

RESUMO

Background: Eculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). Methods: In five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. Post hoc analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated. Results: Of 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P = 0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P = 0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment. Conclusions: As expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment.

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