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BACKGROUND: Minimal change disease and primary focal segmental glomerulosclerosis in adults, along with idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies that lead to nephrotic syndrome. Autoantibodies targeting nephrin have been found in patients with minimal change disease, but their clinical and pathophysiological roles are unclear. METHODS: We conducted a multicenter study to analyze antinephrin autoantibodies in adults with glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, antineutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis, as well as in children with idiopathic nephrotic syndrome and in controls. We also created an experimental mouse model through active immunization with recombinant murine nephrin. RESULTS: The study included 539 patients (357 adults and 182 children) and 117 controls. Among the adults, antinephrin autoantibodies were found in 46 of the 105 patients (44%) with minimal change disease, 7 of 74 (9%) with primary focal segmental glomerulosclerosis, and only in rare cases among the patients with other conditions. Of the 182 children with idiopathic nephrotic syndrome, 94 (52%) had detectable antinephrin autoantibodies. In the subgroup of patients with active minimal change disease or idiopathic nephrotic syndrome who were not receiving immunosuppressive treatment, the prevalence of antinephrin autoantibodies was as high as 69% and 90%, respectively. At study inclusion and during follow-up, antinephrin autoantibody levels were correlated with disease activity. Experimental immunization induced a nephrotic syndrome, a minimal change disease-like phenotype, IgG localization to the podocyte slit diaphragm, nephrin phosphorylation, and severe cytoskeletal changes in mice. CONCLUSIONS: In this study, circulating antinephrin autoantibodies were common in patients with minimal change disease or idiopathic nephrotic syndrome and appeared to be markers of disease activity. Their binding at the slit diaphragm induced podocyte dysfunction and nephrotic syndrome, which highlights their pathophysiological significance. (Funded by Deutsche Forschungsgemeinschaft and others.).
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Autoanticorpos , Proteínas de Membrana , Síndrome Nefrótica , Podócitos , Proteínas de Membrana/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Humanos , Animais , Camundongos , Criança , Podócitos/imunologia , Adulto , Síndrome Nefrótica/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Modelos Animais de Doenças , Adolescente , Nefrose Lipoide/imunologia , Pré-Escolar , Glomerulosclerose Segmentar e Focal/imunologia , Adulto Jovem , IdosoRESUMO
Focal segmental glomerular sclerosis (FSGS) is 1 of the primary causes of nephrotic syndrome in both pediatric and adult patients, which can lead to end-stage kidney disease. Recurrence of FSGS after kidney transplantation significantly increases allograft loss, leading to morbidity and mortality. Currently, there are no consensus guidelines for identifying those patients who are at risk for recurrence or for the management of recurrent FSGS. Our work group performed a literature search on PubMed/Medline, Embase, and Cochrane, and recommendations were proposed and graded for strength of evidence. Of the 614 initially identified studies, 221 were found suitable to formulate consensus guidelines for recurrent FSGS. These guidelines focus on the definition, epidemiology, risk factors, pathogenesis, and management of recurrent FSGS. We conclude that additional studies are required to strengthen the recommendations proposed in this review.
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Glomerulosclerose Segmentar e Focal , Transplante de Rim , Síndrome Nefrótica , Adulto , Humanos , Criança , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/epidemiologia , Glomerulosclerose Segmentar e Focal/etiologia , Esclerose/complicações , Transplante de Rim/efeitos adversos , Transplante Homólogo/efeitos adversos , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/terapia , Recidiva , PlasmafereseRESUMO
RATIONALE & OBJECTIVE: Patients with glomerular disease (GN) may be at increased risk of severe COVID-19, yet concerns over vaccines causing disease relapse may lead to vaccine hesitancy. We examined the associations of COVID-19 with longitudinal kidney function and proteinuria and compared these with similar associations with COVID-19 vaccination. STUDY DESIGN: Observational cohort study from July 1, 2021, to January 1, 2023. SETTING & PARTICIPANTS: A prospective observational study network of 71 centers from North America and Europe (CureGN) with children and adults with primary minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy. EXPOSURE: COVID-19 and COVID-19 vaccination. OUTCOME: Repeated measure of estimated glomerular filtration rate (eGFR); recurrent time-to-event outcome of GN disease worsening as defined by doubling of the urinary protein-creatinine ratio (UPCR) to at least 1.5g/g or increase in dipstick urine protein by 2 ordinal levels to 3+(300mg/dL) or above. ANALYTICAL APPROACH: Interrupted time series analysis for eGFR. Prognostic matched sequential stratification recurrent event analysis for GN disease worsening. RESULTS: Among 2,055 participants, 722 (35%) reported COVID-19 infection; of these, 92 (13%) were hospitalized, and 3 died (<1%). The eGFR slope before COVID-19 infection was-1.40mL/min/1.73m2 (± 0.29 SD); within 6 months after COVID-19 infection, the eGFR slope was-4.26mL/min/1.73m2 (± 3.02 SD), which was not significantly different (P=0.34). COVID-19 was associated with increased risk of worsening GN disease activity (HR, 1.35 [95% CI, 1.01-1.80]). Vaccination was not associated with a change in eGFR (-1.34mL/min/1.73m2±0.15 SD vs-2.16mL/min/1.73m2±1.74 SD; P=0.6) or subsequent GN disease worsening (HR 1.02 [95% CI, 0.79-1.33]) in this cohort. LIMITATIONS: Infrequent or short follow-up. CONCLUSIONS: Among patients with primary GN, COVID-19 infection was severe for 1 in 8 cases and was associated with subsequent worsening of GN disease activity, as defined by proteinuria. By contrast, vaccination against COVID-19 was not associated with change in disease activity or kidney function decline. These results support COVID-19 vaccination for patients with GN. PLAIN-LANGUAGE SUMMARY: In this cohort study of 2,055 patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy, COVID-19 resulted in hospitalization or death for 1 in 8 cases and was associated with a 35% increase in risk for worsening proteinuria. By contrast, vaccination did not appear to adversely affect kidney function or proteinuria. Our data support vaccination for COVID-19 in patients with glomerular disease.
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COVID-19 , Glomerulonefrite por IGA , Glomerulonefrite Membranosa , Glomerulosclerose Segmentar e Focal , Nefrose Lipoide , Adulto , Criança , Humanos , Estudos de Coortes , COVID-19/complicações , COVID-19/epidemiologia , Vacinas contra COVID-19/efeitos adversos , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/urina , Glomérulos Renais , Proteinúria/epidemiologia , Vacinação , Estudos ProspectivosRESUMO
BACKGROUND: Although congenital abnormalities of the kidney and urinary tract (CAKUT) is the leading cause of childhood onset chronic kidney disease (CKD) and kidney failure, comprehensive information on the disease burden among children and adolescents globally is lacking. We aim to report the trends and socioeconomic inequality of CAKUT burden for people aged 0-24 years from 1990 to 2019·. METHODS: We reported the prevalence, mortality and disability-adjusted life-years (DALYs) for CAKUT based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, quantified the association of disease burden and socio-demographic index (SDI), calculated the slope index of inequality (SII) the relative index of inequality (RII) and concentration index. RESULTS: In 2019, the global prevalence, mortality, and DALYs of CAKUT among individuals aged 0-24 years were 167.11 (95%Confident Interval 166.97, 167.25), 0.30 (0.29, 0.30), and 32.22 (32.16, 32.29) per 100 000 population. The greatest prevalence, mortality and DALYs were recorded in the 0-4 year age group. The greatest mortality and DALYs were recorded in low SDI countries and territories. During 1990 to 2019, the prevalence, mortality and DALYs decreased globally, while in low and low-middle countries and territories the reduction was much less slower. India, Nigeria and Pakistan had the highest DALYs. Saudi Arabia and China exhibited a markedly decrease of CAKUT burden. Globally for every 0.1 increase in SDI, there was a 20.53% reduction in mortality, a 16.31% decrease in DALYs, but a 0.38% rise in prevalence. CONCLUSIONS: Inequality for disease burden of varying SDI was increasing globally. Thus, specific preventive and health service measures are needed to reduce the global burden from CAKUT.
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BACKGROUND: Recurrence of focal segmental glomerulosclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS) after kidney transplant leads to significant morbidity and potentially earlier allograft loss. To date however, reported rates, risk factors and treatment outcomes have varied widely. METHODS: We applied computational phenotypes to a multicenter aggregation of electronic health records data from 7 large pediatric health systems in the USA, to identify recurrence rates, risk factors, and treatment outcomes. We refined the data collection by chart review. RESULTS: From > 7 million patients, we compared children with primary FSGS/SRNS who received a kidney transplant between 2009 and 2020 and who either developed recurrence (n = 67/165; 40.6%) or did not (n = 98/165). Serum albumin level at time of transplant was significantly lower and recipient HLA DR7 presence was significantly higher in the recurrence group. By 36 months post-transplant, complete remission occurred in 58.2% and partial remission in 17.9%. Through 6 years post-transplant, no remission after recurrence was associated with an increased risk of allograft loss over time (p < 0.0001), but any remission showed similar allograft survival and function decline to those with no recurrence. Since treatments were used in non-random fashion, using spline curves and multivariable non-linear analyses, complete + partial remission chance was significantly higher with greater plasmapheresis sessions, CTLA4-Ig doses or LDL-apheresis sessions. Only treatment with anti-CD20, CTLA4-Ig agents, or LDL-apheresis sessions were associated with complete remission. Excluding 25 patients with mutations did not significantly change our results. CONCLUSIONS: Our contemporary high-risk cohort had higher favorable response rates than most prior reports, from combinations of agents.
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INTRODUCTION: Tonsillectomies are among the most common surgical procedures in children, with over 500 000 cases annually in the United States. Despite universal administration of intraoperative opioid analgesia, three out of five children undergoing tonsillectomy report moderate-to-severe pain upon recovering from anesthesia. The underlying molecular mechanisms of post-tonsillectomy pain are not well understood, limiting the development of targeted treatment strategies. Our study aimed to identify candidate serum metabolites associated with varying severity of post-tonsillectomy pain. METHODS: Venous blood samples and pain scores were obtained from 34 children undergoing tonsillectomy ± adenoidectomy, and metabolomic analysis was performed. Supervised orthogonal projections to latent structures discriminant analysis were employed to identify differentially expressed metabolites between children with severe and mild pain, as well as between moderate and mild pain. RESULTS: Pain scores differentiated children as mild (n = 6), moderate (n = 14), or severe (n = 14). Four metabolites (fatty acid 18:0(OH), thyroxine, phosphatidylcholine 38:5, and branched fatty acids C27H54O3) were identified as candidate biomarkers that differentiated severe vs. mild post-tonsillectomy pain, the combination of which yielded an AUC of 0.91. Similarly, four metabolites (sebacic acid, dicarboxylic acids C18H34O4, hydroxy fatty acids C18H34O3, and myristoleic acid) were identified as candidate biomarkers that differentiated moderate vs. mild post-tonsillectomy pain, with AUC values ranging from 0.85 to 0.95. CONCLUSION: This study identified novel candidate biomarker panels that effectively differentiated varying severity of post-tonsillectomy pain. Further research is needed to validate these data and to explore their clinical implications for personalized pain management in children undergoing painful surgeries.
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Biomarcadores , Metabolômica , Dor Pós-Operatória , Tonsilectomia , Humanos , Dor Pós-Operatória/sangue , Feminino , Masculino , Criança , Biomarcadores/sangue , Pré-Escolar , Estudo de Prova de Conceito , Medição da Dor/métodos , Adenoidectomia , AdolescenteRESUMO
BACKGROUND AND HYPOTHESIS: Glucocorticoids are the treatment of choice for proteinuric patients with minimal-change disease (MCD) and primary focal and segmental glomerulosclerosis (FSGS). Immunosuppressive as well as direct effects on podocytes are believed to mediate their actions. In this study, we analyzed the anti-proteinuric effects of inhibition of the glucocorticoid receptor (GR) in glomerular epithelial cells, including podocytes. METHODS: We employed genetic and pharmacological approaches to inhibit the GR. Genetically, we used Pax8-Cre/GRfl/fl mice to specifically inactivate the GR in kidney epithelial cells. Pharmacologically, we utilized a glucocorticoid antagonist called mifepristone. RESULTS: Genetic inactivation of GR, specifically in kidney epithelial cells, using Pax8-Cre/GRfl/fl mice, ameliorated proteinuria following protein overload. We further tested the effects of pharmacological GR inhibition in three models and species: the puromycin-aminonucleoside-induced nephrosis model in rats, the protein overload model in mice and the inducible transgenic NTR/MTZ zebrafish larvae with specific and reversible podocyte injury. In all three models, both pharmacological GR activation and inhibition consistently and significantly ameliorated proteinuria. Additionally, we translated our findings to humans, where three nephrotic adult patients with MCD or primary FSGS with contraindications or insufficient responses to corticosteroids, were treated with mifepristone. This treatment resulted in a clinically relevant reduction of proteinuria. CONCLUSIONS: Thus, across multiple species and proteinuria models, both genetic and pharmacological GR inhibition was at least as effective as pronounced GR activation. While, the mechanism remains perplexing, GR inhibition may be a novel and targeted therapeutic approach to treat glomerular proteinuria potentially bypassing adverse actions of steroids.
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BACKGROUND: Nephrotic syndrome (NS) is a common pediatric kidney disease, yet current treatments for complicated NS are only partially effective and have significant toxicity. There is no Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-approved safe and effective treatment for NS. Thiazolidinediones (TZDs) have been shown to reduce proteinuria in both diabetic and non-diabetic kidney disease and in preclinical studies to directly protect podocytes from injury and reduce proteinuria. Here, we report on the potential utility of the addition of the TZD pioglitazone (PIO) to enhance proteinuria reduction in 8 children and young adults with steroid dependent NS and steroid resistant NS. METHODS: Clinical data were analyzed in comparable time periods before and after the addition of PIO to their medical regimens. Eight NS patients with minimal change NS (n = 2), focal segmental glomerulosclerosis (FSGS) (n = 4), or collapsing FSGS (n = 2) were evaluated. RESULTS: Prior to PIO initiation, all children and young adults had already received multiple immunosuppressive medications (mean = 3.75). Five of eight patients (63%; "Responders") had notable proteinuria reduction within 1 month of PIO initiation (62% reduction; P = 0.04) and normalization within 6 months (97% reduction; P = 0.04). PIO-related benefits among the responders included notable increases in serum albumin (2.5 to 3.7 g/dl; P = 0.08), dramatic reductions in hospitalizations for IV albumin infusions and diuresis (11 to 0; P < 0.01), and considerable reduction in total immunosuppression (43% reduction; P > 0.1). Importantly, no patients experienced any adverse events attributable to PIO during a total of 136 patient-months of treatment. CONCLUSIONS: While confirmatory safety and efficacy studies are needed, these findings suggest pioglitazone (a non-immunosuppressive drug) may be useful to enhance proteinuria reduction in some children and young adults with complicated NS. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Glomerulosclerose Segmentar e Focal , Síndrome Nefrótica , Adulto Jovem , Humanos , Criança , Síndrome Nefrótica/complicações , Síndrome Nefrótica/tratamento farmacológico , Pioglitazona/uso terapêutico , Glomerulosclerose Segmentar e Focal/complicações , Proteinúria/etiologia , Proteinúria/complicações , Esteroides/uso terapêuticoRESUMO
BACKGROUND: IgA vasculitis is the most common vasculitis in children and is often complicated by acute nephritis (IgAVN). Risk of chronic kidney disease (CKD) among children with IgAVN remains unknown. This study aimed to describe the clinical management and kidney outcomes in a large cohort of children with IgAVN. METHODS: This observational cohort study used the PEDSnet database to identify children diagnosed with IgAV between January 1, 2009, and February 29, 2020. Demographic and clinical characteristics were compared among children with and without kidney involvement. For children followed by nephrology, clinical course, and management patterns were described. Patients were divided into four categories based on treatment: observation, renin-angiotensin-aldosterone system (RAAS) blockade, corticosteroids, and other immunosuppression, and outcomes were compared among these groups. RESULTS: A total of 6802 children had a diagnosis of IgAV, of whom 1139 (16.7%) were followed by nephrology for at least 2 visits over a median follow-up period of 1.7 years [0.4,4.2]. Conservative management was the most predominant practice pattern, consisting of observation in 57% and RAAS blockade in 6%. Steroid monotherapy was used in 29% and other immunosuppression regimens in 8%. Children receiving immunosuppression had higher rates of proteinuria and hypertension compared to those managed with observation (p < 0.001). At the end of follow-up, 2.6 and 0.5% developed CKD and kidney failure, respectively. CONCLUSIONS: Kidney outcomes over a limited follow-up period were favorable in a large cohort of children with IgAV. Immunosuppressive medications were used in those with more severe presentations and may have contributed to improved outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Vasculite por IgA , Nefrite , Insuficiência Renal Crônica , Humanos , Criança , Vasculite por IgA/complicações , Vasculite por IgA/diagnóstico , Vasculite por IgA/tratamento farmacológico , Imunoglobulina A , Nefrite/etiologia , Insuficiência Renal Crônica/complicações , Progressão da DoençaRESUMO
BACKGROUND: Children with glomerular disease have unique risk factors for compromised bone health. Studies addressing skeletal complications in this population are lacking. METHODS: This retrospective cohort study utilized data from PEDSnet, a national network of pediatric health systems with standardized electronic health record data for more than 6.5 million patients from 2009 to 2021. Incidence rates (per 10,000 person-years) of fracture, slipped capital femoral epiphysis (SCFE), and avascular necrosis/osteonecrosis (AVN) in 4598 children and young adults with glomerular disease were compared with those among 553,624 general pediatric patients using Poisson regression analysis. The glomerular disease cohort was identified using a published computable phenotype. Inclusion criteria for the general pediatric cohort were two or more primary care visits 1 year or more apart between 1 and 21 years of age, one visit or more every 18 months if followed >3 years, and no chronic progressive conditions defined by the Pediatric Medical Complexity Algorithm. Fracture, SCFE, and AVN were identified using SNOMED-CT diagnosis codes; fracture required an associated x-ray or splinting/casting procedure within 48 hours. RESULTS: We found a higher risk of fracture for the glomerular disease cohort compared with the general pediatric cohort in girls only (incidence rate ratio [IRR], 1.6; 95% CI, 1.3 to 1.9). Hip/femur and vertebral fracture risk were increased in the glomerular disease cohort: adjusted IRR was 2.2 (95% CI, 1.3 to 3.7) and 5 (95% CI, 3.2 to 7.6), respectively. For SCFE, the adjusted IRR was 3.4 (95% CI, 1.9 to 5.9). For AVN, the adjusted IRR was 56.2 (95% CI, 40.7 to 77.5). CONCLUSIONS: Children and young adults with glomerular disease have significantly higher burden of skeletal complications than the general pediatric population.
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Necrose da Cabeça do Fêmur , Nefropatias , Escorregamento das Epífises Proximais do Fêmur , Criança , Humanos , Necrose da Cabeça do Fêmur/diagnóstico por imagem , Necrose da Cabeça do Fêmur/epidemiologia , Necrose da Cabeça do Fêmur/etiologia , Estudos Retrospectivos , Resultado do Tratamento , Escorregamento das Epífises Proximais do Fêmur/diagnóstico , Escorregamento das Epífises Proximais do Fêmur/diagnóstico por imagem , Radiografia , Nefropatias/complicaçõesRESUMO
Chronic kidney disease (CKD) can progress to kidney failure and require dialysis or transplantation, while early diagnosis can alter the course of disease and lead to better outcomes in both pediatric and adult patients. Significant CKD comorbidities include the manifestation of cardiovascular disease, heart failure, coronary disease, and hypertension. The pathogenesis of chronic kidney diseases can present as subtle and especially difficult to distinguish between different glomerular pathologies. Early detection of adult and pediatric CKD and detailed mechanistic understanding of the kidney damage can be helpful in delaying or curtailing disease progression via precise intervention toward diagnosis and prognosis. Clinically, serum creatinine and albumin levels can be indicative of CKD, but often are a lagging indicator only significantly affected once kidney function has severely diminished. The evolution of proteomics and mass spectrometry technologies has begun to provide a powerful research tool in defining these mechanisms and identifying novel biomarkers of CKD. Many of the same challenges and advances in proteomics apply to adult and pediatric patient populations. Additionally, proteomic analysis of adult CKD patients can be transferred directly toward advancing our knowledge of pediatric CKD as well. In this review, we highlight applications of proteomics that have yielded such biomarkers as PLA2R, SEMA3B, and other markers of membranous nephropathy as well as KIM-1, MCP-1, and NGAL in lupus nephritis among other potential diagnostic and prognostic markers. The potential for improving the clinical toolkit toward better treatment of pediatric kidney diseases is significantly aided by current and future development of proteomic applications.
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Nefropatias , Insuficiência Renal Crônica , Adulto , Biomarcadores , Criança , Taxa de Filtração Glomerular , Humanos , Nefropatias/diagnóstico , Proteômica , Diálise RenalRESUMO
BACKGROUND: The revised 2018 ISN/RPS Classification System for lupus nephritis (LN) includes calculations for both activity index (A.I.) and chronicity index (C.I.). Unchanged were the thresholds of < 25%, 25-50%, and > 50% crescents to distinguish between mild, moderate, and severe activity/chronicity. We aimed to evaluate these thresholds for percent crescents in childhood-onset LN. METHODS: Eighty-six subjects < 21 years of age were enrolled from the Pediatric Glomerulonephritis with Crescents Registry, a retrospective multi-center cohort sponsored by the Pediatric Nephrology Research Consortium. Thresholds of 10%, 25%, and 50% for both cellular/fibrocellular and fibrous crescents were interrogated for primary outcomes of kidney failure, eGFR, and eGFR slope. RESULTS: Median age at time of initial biopsy was 14 years (range 1-21). Median follow-up time was 3 years (range 1-11). Cumulative incidence of kidney failure was 6% at 1 year and 10% at latest follow-up. Median eGFR slope was - 18 mL/1.73 m2/min (IQR - 51 to + 8) at 1 year and - 3 mL/min/1.73 m2/year (IQR - 19 to + 6) at latest follow-up. We found no difference in kidney failure at the proposed < 25% and 25-50% cellular crescents thresholds, and thus added a new provisional threshold of 10% that better predicted outcomes in children. Moreover, use of 10% and 25% thresholds for fibrous crescents showed a fourfold and sevenfold increase in risk of kidney failure. CONCLUSIONS: In children with crescentic LN, use of 10% and 25% thresholds for cellular crescents better reflects disease activity, while these thresholds for fibrous crescents better discriminates kidney disease outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Nefrite Lúpica , Nefrologia , Insuficiência Renal , Humanos , Criança , Lactente , Pré-Escolar , Adolescente , Adulto Jovem , Adulto , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/epidemiologia , Glomérulos Renais/patologia , Rim/patologiaRESUMO
Best treatments for initial presentation and relapses in children with nephrotic syndrome (NS) are still to be defined. The PROPINE study, published in this issue of Kidney International, demonstrates for relapse of childhood NS, the non-inferiority of a short taper (over 36 days) after remission with steroids. This study reinforces the need for more well-designed studies and the incorporation of predictive biomarkers, genetic studies, and other details to personalize treatment for each child with idiopathic NS.
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Síndrome Nefrótica , Criança , Epinefrina/análogos & derivados , Humanos , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/tratamento farmacológico , Prednisona , RecidivaRESUMO
As the nation implements SARS-CoV-2 vaccination in adults at an unprecedented scale, it is now essential to focus on the prospect of SARS-CoV-2 vaccinations in pediatric populations. To date, no children younger than 12 years have been enrolled in clinical trials. Key challenges and knowledge gaps that must be addressed include (1) rationale for vaccines in children, (2) possible effects of immune maturation during childhood, (3) ethical concerns, (4) unique needs of children with developmental disorders and chronic conditions, (5) health inequities, and (6) vaccine hesitancy. Because COVID-19 is minimally symptomatic in the vast majority of children, a higher acceptable risk threshold is required when evaluating pediatric clinical trials. Profound differences in innate and adaptive immunity during childhood and adolescence are known to affect vaccine responsiveness for a variety of childhood diseases. COVID-19 and the accompanying social disruption, such as the school shutdowns, has been disproportionately damaging to minority and low-income children. In this commentary, we briefly address each of these key issues, specify research gaps, and suggest a broader learning health system approach to accelerate testing and clinical trial development for an ethical and effective strategy to implement a pediatric SARS-CoV-2 vaccine as rapidly and safely as possible. IMPACT: As the US begins an unprecedented implementation of SARS-CoV-2 vaccination, substantial knowledge gaps have yet to be addressed regarding vaccinations in the pediatric population. Maturational changes in the immune system during childhood have influenced the effectiveness of pediatric vaccines for other diseases and conditions, and could affect SARS-CoV-2 vaccine responsiveness in children. Given that COVID-19 disease is far milder in the majority of children than in adults, the risk-benefit of a pediatric SARS-CoV-2 vaccine must be carefully weighed. The needs of children with developmental disabilities and with chronic disease must be addressed. Minority and low-income children have been disproportionately adversely affected by the COVID-19 pandemic; care must be taken to address issues of health equity regarding pediatric SARS-CoV-2 vaccine trials and allocation. Research and strategies to address general vaccine hesitancy in communities must be addressed in the context of pediatric SARS-CoV-2 vaccines.
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Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Ensaios Clínicos como Assunto , Pediatria , Projetos de Pesquisa , SARS-CoV-2/patogenicidade , Vacinação , Fatores Etários , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/efeitos adversos , Ensaios Clínicos como Assunto/ética , Interações Hospedeiro-Patógeno , Humanos , Imunogenicidade da Vacina , Segurança do Paciente , Pediatria/ética , Opinião Pública , Medição de Risco , Fatores de Risco , SARS-CoV-2/imunologia , Resultado do Tratamento , Vacinação/efeitos adversos , Hesitação Vacinal , Eficácia de VacinasRESUMO
Glomerular diseases are often chronic or recurring and thus associated with a tremendous physical, psychological, and economic burden. Their etiologies are often unknown, and their pathogeneses are frequently poorly understood. The diagnoses and management of these diseases are therefore based on clinical features, traditional laboratory markers, and, often, kidney pathology. However, the clinical presentation can be highly variable, the kidney pathology may not establish a definitive diagnosis, and the therapeutic responses and resulting clinical outcomes are often unpredictable. To try to address these challenges, significant research efforts have been made over the last decade to identify potential biomarkers that can help clinicians optimize the diagnosis and prognosis at clinical presentation, as well as help predict long-term outcomes. Unfortunately, these efforts have to date only identified a single biomarker for glomerular disease that has been fully validated and developed for widespread clinical use (anti-PLA2R antibodies to diagnose membranous nephropathy). In this manuscript, we review the definitions and development of biomarkers, as well as the current knowledge on both historical and novel candidate biomarkers of glomerular disease, with an emphasis on those associated with idiopathic nephrotic syndrome.
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Glomerulonefrite Membranosa , Síndrome Nefrótica , Anticorpos/sangue , Biomarcadores/sangue , Criança , Glomerulonefrite Membranosa/diagnóstico , Humanos , Síndrome Nefrótica/diagnóstico , Receptores da Fosfolipase A2/imunologiaRESUMO
Gross et al. present results of the EARLY PRO-TECT trial, a randomized controlled trial of ramipril versus placebo in children with early-stage Alport syndrome. Although under-enrolled and not a positive trial in the traditional sense, EARLY PRO-TECT does provide strong supportive evidence for both long-term safety and a clinical benefit of early treatment with angiotensin-converting enzyme inhibitors in slowing the progression of both albuminuria and estimated glomerular filtration rate decline in children with Alport syndrome.
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Nefrite Hereditária , Albuminúria , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Criança , Taxa de Filtração Glomerular , Humanos , Nefrite Hereditária/tratamento farmacológico , Ramipril/efeitos adversosRESUMO
Children with steroid-resistant nephrotic syndrome (SRNS) are exposed to multiple cardiovascular risk factors predisposing them to accelerated atherosclerosis. This risk is negligible in steroid-sensitive nephrotic syndrome, but a substantial proportion of children with SRNS progress to chronic kidney disease, exacerbating the already existing cardiovascular risk. While dyslipidemia is an established modifiable risk factor for cardiovascular disease in adults with NS, it is uncertain to what extent analogous risks exist for children. There is increasing evidence of accelerated atherosclerosis in children with persistently high lipid levels, especially in refractory NS. Abnormalities of lipid metabolism in NS include hypertriglyceridemia and hypercholesterolemia due to elevated apolipoprotein B-containing lipoproteins, decreased lipoprotein lipase and hepatic lipase activity, increased hepatic PCSK9 levels, and reduced hepatic uptake of high-density lipoprotein. Existing guidelines for the management of dyslipidemia in children may be adapted to target lower lipid levels in children with NS, but they will most likely require both lifestyle modifications and pharmacological therapy. While there is a lack of data from randomized controlled trials in children with NS demonstrating the benefit of lipid-lowering drugs, therapies including statins, bile acid sequestrants, fibrates, ezetimibe, and LDL apheresis have all been suggested and/or utilized. However, concerns with the use of lipid-lowering drugs in children include unclear side effect profiles and unknown long-term impacts on neurological development and puberty. The recent introduction of anti-PCSK9 monoclonal antibodies and other therapies targeted to the molecular mechanisms of lipid transport disrupted in NS holds promise for the future treatment of dyslipidemia in NS.
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Dislipidemias/fisiopatologia , Síndrome Nefrótica/fisiopatologia , Adolescente , Adulto , Aterosclerose/etiologia , Aterosclerose/prevenção & controle , Criança , Dislipidemias/tratamento farmacológico , Dislipidemias/etiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Lipoproteínas/sangue , Lipoproteínas/efeitos dos fármacos , Síndrome Nefrótica/complicações , Síndrome Nefrótica/tratamento farmacológico , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: The rarity of pediatric glomerular disease makes it difficult to identify sufficient numbers of participants for clinical trials. This leaves limited data to guide improvements in care for these patients. METHODS: The authors developed and tested an electronic health record (EHR) algorithm to identify children with glomerular disease. We used EHR data from 231 patients with glomerular disorders at a single center to develop a computerized algorithm comprising diagnosis, kidney biopsy, and transplant procedure codes. The algorithm was tested using PEDSnet, a national network of eight children's hospitals with data on >6.5 million children. Patients with three or more nephrologist encounters (n=55,560) not meeting the computable phenotype definition of glomerular disease were defined as nonglomerular cases. A reviewer blinded to case status used a standardized form to review random samples of cases (n=800) and nonglomerular cases (n=798). RESULTS: The final algorithm consisted of two or more diagnosis codes from a qualifying list or one diagnosis code and a pretransplant biopsy. Performance characteristics among the population with three or more nephrology encounters were sensitivity, 96% (95% CI, 94% to 97%); specificity, 93% (95% CI, 91% to 94%); positive predictive value (PPV), 89% (95% CI, 86% to 91%); negative predictive value, 97% (95% CI, 96% to 98%); and area under the receiver operating characteristics curve, 94% (95% CI, 93% to 95%). Requiring that the sum of nephrotic syndrome diagnosis codes exceed that of glomerulonephritis codes identified children with nephrotic syndrome or biopsy-based minimal change nephropathy, FSGS, or membranous nephropathy, with 94% sensitivity and 92% PPV. The algorithm identified 6657 children with glomerular disease across PEDSnet, ≥50% of whom were seen within 18 months. CONCLUSIONS: The authors developed an EHR-based algorithm and demonstrated that it had excellent classification accuracy across PEDSnet. This tool may enable faster identification of cohorts of pediatric patients with glomerular disease for observational or prospective studies.
Assuntos
Registros Eletrônicos de Saúde , Glomerulonefrite , Síndrome Nefrótica , Seleção de Pacientes , Algoritmos , Área Sob a Curva , Biópsia , Criança , Controle de Formulários e Registros , Glomerulonefrite/diagnóstico , Glomerulonefrite/epidemiologia , Glomerulonefrite/patologia , Glomerulonefrite/cirurgia , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Serviços de Informação , Classificação Internacional de Doenças , Rim/patologia , Transplante de Rim , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/epidemiologia , Síndrome Nefrótica/patologia , Síndrome Nefrótica/cirurgia , Estudos Observacionais como Assunto , Estudos Prospectivos , Curva ROC , Método Simples-CegoRESUMO
There is scant literature describing the effect of glomerular disease on health-related quality of life (HRQOL). The Cure Glomerulonephropathy study (CureGN) is an international longitudinal cohort study of children and adults with four primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy). HRQOL is systematically assessed using items from the Patient-Reported Outcomes Measurement Informative System (PROMIS). We assessed the relationship between HRQOL and demographic and clinical variables in 478 children and 1115 adults at the time of enrollment into CureGN. Domains measured by PROMIS items included global assessments of health, mobility, anxiety, fatigue, and sleep impairment, as well as a derived composite measure incorporating all measured domains. Multivariable models were created that explained 7 to 32% of variance in HRQOL. Patient-reported edema consistently had the strongest and most robust association with each measured domain of HRQOL in multivariable analysis (adjusted ß [95% CI] for composite PROMIS score in children, -5.2 [-7.1 to -3.4]; for composite PROMIS score in adults, -6.1 [-7.4 to -4.9]). Female sex, weight (particularly obesity), and estimated glomerular filtration rate were also associated with some, but not all, domains of HRQOL. Primary diagnosis, disease duration, and exposure to immunosuppression were not associated with HRQOL after adjustment. Sensitivity analyses and interaction testing demonstrated no significant association between disease duration or immunosuppression and any measured domain of HRQOL. Thus, patient-reported edema has a consistent negative association with HRQOL in patients with primary glomerular diseases, with substantially greater impact than other demographic and clinical variables.
Assuntos
Edema/etiologia , Glomerulonefrite/complicações , Qualidade de Vida , Adolescente , Adulto , Idoso , Criança , Edema/psicologia , Feminino , Glomerulonefrite/psicologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Autorrelato/estatística & dados numéricosRESUMO
RATIONALE & OBJECTIVES: Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death. STUDY DESIGN: Multicenter prospective cohort study. SETTING & PARTICIPANTS: Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded. EXPOSURES: Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year. OUTCOMES: Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events. ANALYTICAL APPROACH: The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years' initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year. LIMITATIONS: Current follow-up can only detect large differences in ESKD and death outcomes. CONCLUSIONS: Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.