Membranous nephropathy results from subepithelial antigen-antibody complex deposition along the glomerular basement membrane. Although PLA2R, THSD7A, and NELL-1 account for a majority (about 80%) of ...the target antigens, the target antigen in the remaining cases is not known. Using laser microdissection of PLA2R-negative glomeruli of patients with membranous nephropathy followed by mass spectrometry we identified a unique protein, Semaphorin 3B, in three cases. Mass spectrometry failed to detect Semaphorin-3B in 23 PLA2R-associated cases of membranous nephropathy and 88 controls. Semaphorin 3B in all three cases was localized to granular deposits along the glomerular basement membrane by immunohistochemistry. Next, an additional eight cases of Semaphorin 3B-associated membranous nephropathy were identified in three validation cohorts by immunofluorescence microscopy. In four of 11 cases, kidney biopsy also showed tubular basement membrane deposits of IgG on frozen sections. Confocal microscopy showed that both IgG and Semaphorin 3B co-localized to the glomerular basement membrane. Western blot analysis of five available sera showed reactivity to reduced Semaphorin 3B in four of four patients with active disease and no reactivity in one patient in clinical remission; there was also no reactivity in control sera. Eight of the 11 cases of Semaphorin 3B-associated membranous nephropathy were pediatric cases. Furthermore, in five cases, the disease started at or below the age of two. Thus, Semaphorin 3B-associated membranous nephropathy appears to be a distinct type of disease; more likely to be present in pediatric patients.
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Thrombotic microangiopathy in children Palma, Lilian Monteiro P.; Vaisbich-Guimarães, Maria Helena; Sridharan, Meera ...
Pediatric nephrology (Berlin, West),
09/2022, Volume:
37, Issue:
9
Journal Article
Peer reviewed
Open access
The syndrome of thrombotic microangiopathy (TMA) is a clinical-pathological entity characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ involvement. It comprises a ...spectrum of underlying etiologies that may differ in children and adults. In children, apart from ruling out shigatoxin-associated hemolytic uremic syndrome (HUS) and other infection-associated TMA like
Streptococcus pneumoniae
-HUS, rare inherited causes including complement-associated HUS, cobalamin defects, and mutations in diacylglycerol kinase epsilon gene must be investigated. TMA should also be considered in the setting of solid organ or hematopoietic stem cell transplantation. In this review, acquired and inherited causes of TMA are described with a focus on particularities of the main causes of TMA in children. A pragmatic approach that may help the clinician tailor evaluation and management is provided. The described approach will allow for early initiation of treatment while waiting for the definitive diagnosis of the underlying TMA.
The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are ...variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual’s TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.
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AKI in Children Hospitalized with Nephrotic Syndrome Rheault, Michelle N; Zhang, Lei; Selewski, David T ...
Clinical journal of the American Society of Nephrology,
12/2015, Volume:
10, Issue:
12
Journal Article
Peer reviewed
Open access
Children with nephrotic syndrome can develop life-threatening complications, including infection and thrombosis. While AKI is associated with adverse outcomes in hospitalized children, little is ...known about the epidemiology of AKI in children with nephrotic syndrome. The main objectives of this study were to determine the incidence, epidemiology, and hospital outcomes associated with AKI in a modern cohort of children hospitalized with nephrotic syndrome.
Records of children with nephrotic syndrome admitted to 17 pediatric nephrology centers across North America from 2010 to 2012 were reviewed. AKI was classified using the pediatric RIFLE definition.
AKI occurred in 58.6% of 336 children and 50.9% of 615 hospitalizations (27.3% in stage R, 17.2% in stage I, and 6.3% in stage F). After adjustment for race, sex, age at admission, and clinical diagnosis, infection (odds ratio, 2.24; 95% confidence interval, 1.37 to 3.65; P=0.001), nephrotoxic medication exposure (odds ratio, 1.35; 95% confidence interval, 1.11 to 1.64; P=0.002), days of nephrotoxic medication exposure (odds ratio, 1.10; 95% confidence interval, 1.05 to 1.15; P<0.001), and intensity of medication exposure (odds ratio, 1.34; 95% confidence interval, 1.09 to 1.65; P=0.01) remained significantly associated with AKI in children with nephrotic syndrome. Nephrotoxic medication exposure was common in this population, and each additional nephrotoxic medication received during a hospitalization was associated with 38% higher risk of AKI. AKI was associated with longer hospital stay after adjustment for race, sex, age at admission, clinical diagnosis, and infection (difference, 0.45 logdays; 95% confidence interval, 0.36 to 0.53 logdays; P<0.001).
AKI is common in children hospitalized with nephrotic syndrome and should be deemed the third major complication of nephrotic syndrome in children in addition to infection and venous thromboembolism. Risk factors for AKI include steroid-resistant nephrotic syndrome, infection, and nephrotoxic medication exposure. Children with AKI have longer hospital lengths of stay and increased need for intensive care unit admission.
The risks of iodinated contrast material administered to pediatric patients are not well defined. The purpose of this study was to examine the rates of postcontrast acute kidney injury (AKI), ...dialysis therapy, and death following administration of intravenous contrast material to pediatric patients.
Retrospective cohort study.
Pediatric (aged <18 years) patients who underwent either contrast-enhanced (contrast group) or unenhanced (noncontrast group) computed tomography (CT) at our institution from December 2001 to January 2016.
Intravenous iodinated contrast material.
Postcontrast AKI based on serum creatinine–defined KDIGO criteria, dialysis therapy, and death.
Risks for AKI, dialysis therapy, and death were compared between contrast and noncontrast group patients using a propensity score analysis incorporating clinical covariates related to contrast exposure.
2,201 pediatric patients (1,773 contrast and 428 noncontrast) were identified. Rates of AKI and dialysis therapy in the contrast group were 3.3% (59/1,773) and 0.1% (2/1,773), respectively. Following propensity score adjustment, no differences in risk for AKI (stage 1 AKI: OR, 0.75 95% CI, 0.32-1.78, P=0.5; stage 2: OR, 2.00 95% CI, 0.18-21.9, P=0.6; stage 3: OR, 0.50 95% CI, 0.05-5.48, P=0.6), dialysis therapy (OR, 1.00 95% CI, 0.06-15.9, P=0.9), or death (OR, 1.50 95% CI, 0.53-4.22, P=0.4) were observed between the contrast and noncontrast groups. All patients with post-CT stage 3 AKI diagnosed also had contrast-independent potential causes of AKI.
The study’s small sample size and low rates of postcontrast AKI, dialysis therapy, and death limited the ability to detect an effect of contrast administration on these outcomes. Unmeasured residual confounders may limit the validity of our results. Few patients had decreased kidney function at the time of CT.
Rates of postcontrast AKI, dialysis therapy, and death following contrast-enhanced CT were very low in this pediatric cohort. Although not detectably different, an effect of contrast on these outcomes could not be ruled out.
Congenital nephrotic syndrome (CNS) is a complex condition that requires multidisciplinary care. Hyperlipidemia is a characteristic feature with elevation of serum cholesterol and triglycerides. ...Little evidence is available to guide treatment of dyslipidemia in infants with CNS. We describe successful treatment of severe hypertriglyceridemia through dietary changes in a boy with CNS. A 9‐day‐old boy presented to the emergency department with lower extremity edema caused by deep venous thrombosis. Laboratory evaluation identified hypoalbuminemia, nephrotic‐range proteinuria, and a pathogenic variant of the NPHS1 gene. The initial triglyceride concentration of 369 mg/dl increased to 3096 mg/dl by 5 weeks of age, when his diet consisted of breast milk. Refrigerated breast milk was skimmed by removing the top layer after allowing it to separate for 24 h. This process was repeated prior to use. Skimmed breast milk was supplemented with medium‐chain triglyceride oil and an infant protein powder. After 2 days, the triglyceride concentration declined to 481 mg/dl and, by day 10, to 148 mg/dl. When breast milk supply decreased, a 1:1 ratio of skimmed maternal breast milk to an elemental, very low‐fat formula was utilized. The triglyceride concentration remained below 400 mg/dl for the first year of life, except when skimmed breast milk was not available during hospitalization. Severe hypertriglyceridemia caused by CNS can present in the neonatal period and be difficult to manage. In our patient, skimmed maternal breast milk was successful in reducing the triglyceride concentration and should be considered a therapeutic option for children with hyperlipidemia caused by CNS.
Thrombotic microangiopathies (TMAs) comprise a heterogeneous set of conditions linked by a common histopathologic finding of endothelial damage resulting in microvascular thromboses and potentially ...serious complications. The typical clinical presentation is microangiopathic hemolytic anemia accompanied by thrombocytopenia with varying degrees of organ ischemia. The differential diagnoses are generally broad, while the workup is frequently complex and can be confusing. This statement represents the joint recommendations from a multidisciplinary team of Mayo Clinic physicians specializing in the management of TMA. It comprises a series of evidence- and consensus-based clinical pathways developed to allow a uniform approach to the spectrum of care including when to suspect TMA, what differential diagnoses to consider, which diagnostic tests to order, and how to provide initial empiric therapy, as well as some guidance on subsequent management.
The formation of highly anisotropic organic thin films based on the designed self-assembly of mixed-stack liquid crystals is reported. A series of alkoxyanthracene donors is combined in a modular ...fashion with a naphthalenediimide acceptor to generate new charge-transfer columnar liquid crystals. Materials characterization and molecular modeling provides insight into structure–function relationships in these organic materials that lead to the striking bulk dichroic properties of certain molecular assemblies.
Background Data describing inpatient health care utilization in children with nephrotic syndrome and related severe complications are limited. Our goals were to describe the charges, length of stay ...(LOS), and number of hospitalizations among children, adolescents, and young adults with nephrotic syndrome. Study Design A cross-sectional analysis of the Kids' Inpatient Database (KID) database from the Healthcare Cost and Utilization Project (HCUP). The HCUP-KID is an all-payer database of hospital discharges for children, adolescents, and young adults in the United States compiled every 3 years by the Agency for Healthcare Research and Quality. Setting & Participants HCUP-KID data were obtained for the 2006 and 2009 cohort years. We identified patients by searching discharges for nephrotic syndrome International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Predictor Patient demographics, disease complications in children, adolescents, and young adults hospitalized with nephrotic syndrome. Outcome Number of hospitalizations, mean charges, and LOS for children, adolescents, and young adults hospitalized with nephrotic syndrome. Results There were 6,308 hospitalization discharges in children, adolescents, and young adults with a primary or secondary diagnosis of nephrotic syndrome reported by 38 and 44 states in 2006 and 2009, respectively, representing an estimated 9,934 discharges nationally. Nephrotic syndrome resulted in an estimated 48,700 inpatient days and charges totaling $259 million. The mean charge per hospitalization was ∼$26,500 (SE, $1,100) and LOS was 5 days (SE, 0.1). 16% of discharges for nephrotic syndrome had a diagnosis code for at least one severe complication, including thromboembolism (3.6%), septicemia (3.8%), peritonitis (2.6%), pneumonia (5.4%), or diabetes (2.4%). Multivariable analysis showed age 15 years or older, race, higher socioeconomic status, acute renal failure, thromboembolic disease, hypertension, and infections predicted higher mean hospitalization charges. Limitations The HCUP-KID database collects data on a hospitalization level. Consequently, health care utilization on an individual patient level or in the outpatient environment is not possible. Conclusions We present a comprehensive description of inpatient health care utilization in children, adolescents, and young adults with nephrotic syndrome. The complications of nephrotic syndrome, including thromboembolism, infection, and hypertension, contribute significantly to these charges.
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