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Changes in plasma suPAR levels across pregnancy and in relation to hypertensive disorders [Letter]

Cowell, Whitney; Limaye, Meghana; Brubaker, Sara G; Kahn, Linda G; Reiser, Jochen; Silverstein, Jenna; Malaga-Dieguez, Laura; Mehta-Lee, Shilpi S; Trasande, Leonardo
OBJECTIVE:, suggesting that elevated suPAR levels may reflect a heightened inflammatory response in preeclamptic pregnancies rather than serving as a pre-clinical indicator. No data currently exist on the trajectory of suPAR across pregnancy. In the present study, we investigated if and how plasma suPAR levels change across gestation and examined whether this change and the levels in each trimester varied between women with and without HDP. STUDY DESIGN/METHODS:Participants included pregnant individuals enrolled in the [study name removed for blinding], a prospective birth cohort designed to study an array of exposures and conditions relevant to maternal and child health. Maternal blood was collected at up to three time points during pregnancy and plasma suPAR levels were analyzed by enzyme-linked immunosorbent assay. Information on maternal HDP was abstracted from electronic medical records. Study participants with suPAR data in any trimester and information about HDP were eligible for inclusion (n=393); 64 non-HDP participants who had chronic hypertension (n=5), gestational diabetes mellitus (n=55), lupus (n=1), type 1 diabetes (n=1) or type 2 diabetes (n=2) were excluded, resulting in a final analytic sample of 329. The study was approved by the Institutional Review Board of the [institution removed for blinding] and all participants provided written informed consent. We first regressed suPAR levels on gestational age at the time of sample collection to assess change over the course of pregnancy. We did this for the sample overall and stratified by HDP status. Among the subset of participants with repeated measures, we used paired Wilcoxon signed-rank tests to assess the within-person change in suPAR across trimesters in both groups. Finally, we used Wilcoxon signed-rank tests to assess whether suPAR levels in each trimester and averaged over pregnancy were different among participants with and without HDP. RESULTS:and ranged from 16.8-50.1; 44% of the sample was overweight or obese defined by a BMI ≥ 25. The majority had at least a high school degree (90.1%) and reported never smoking cigarettes (92.9%). Participants with HDP (n=44) were older and had higher BMI; other participant characteristics did not significantly vary by HDP status. suPAR levels did not significantly differ between those with and without HDP at any gestational timepoint (Table 1), although the association was marginal when considering the third trimester such that those with HDP had higher suPAR levels (2.43 ng/mL vs. 2.12 ng/mL, p=0.11). In the sample overall, suPAR levels decreased by 1.1% per week of advancing gestation (p-value< 0.001); however, when stratified by HDP status, suPAR levels only significantly decreased among those without HDP (1.2% per week, p<0.001), while remaining more stable among the cases (0.8% per week, p=0.17) (Figure 1). This finding was also apparent when examining the subset of participants with repeated measures. Among those with paired samples that did not have HDP, the median suPAR level in early gestation (2.79 ng/mL) was significantly higher than late gestation (2.30 ng/mL) with a p-value <0.001 and large effect size r=0.634. In contrast, among those with paired samples and HDP, the median suPAR level in early gestation (2.37 ng/mL) was not significantly different than late gestation (2.45 ng/mL) with a p-value=0.578 and small effect size r=0.256. It is notable however that the sample size of participants with repeated measures and HDP was small (n=7) and the timing of HDP onset was variable across participants. CONCLUSIONS:Although HDP is a primary cause of morbidity and mortality in pregnancy, predictive biomarkers are lacking. suPAR levels decrease with advancing gestation among healthy women, but remain stable in women with HDP, which may reflect a heightened inflammatory state. Additional research is needed to understand how suPAR correlates with other biomarkers of HDP and whether stable suPAR levels can predict HDP accurately in clinical practice.
PMID: 36775198
ISSN: 2589-9333
CID: 5448002

Elevated Levels of Urinary Biomarkers TIMP-2 and IGFBP-7 Predict Acute Kidney Injury in Neonates after Congenital Heart Surgery

Ramírez, Michelle; Chakravarti, Sujata; Busovsky-McNeal, Melissa; McKinstry, Jaclyn; Al-Qaqaa, Yasir; Sahulee, Raj; Kumar, T K Susheel; Li, Xiaochun; Goldberg, Judith D; Gefen, Ashley M; Malaga-Dieguez, Laura
PMID: 35734207
ISSN: 2146-4618
CID: 5282022

Catheter-Directed Thrombolysis for Neonatal IVC and Bilateral Renal Vein Thrombosis: A Case Report

Guichet, Phillip L; Jasinski, Sylwia; Malaga-Dieguez, Laura; De Los Reyes, Francis A; Ahuja, Tania; Bride, Karen L; Patel, Amish
Renal vein thrombosis is the most common non-catheter-associated venous thromboembolism event in neonates, accounting for up to 20% of cases. Although mortality rates are lower than a variety of other forms of pediatric thrombosis, renal vein thrombi are associated with significant short-term and long-term sequelae. This report presents the case of a full-term neonate presenting with bilateral renal vein thrombosis with inferior vena cava involvement treated with catheter-directed thrombolysis. This case report intends to highlight the value of a multidisciplinary approach to pediatric venous thromboembolism and to outline relevant procedural details and current laboratory and imaging monitoring of catheter-directed thrombolysis.
PMID: 32569035
ISSN: 1536-3678
CID: 4492822

Pulmonary Manifestations of Renal Disorders in Children

Malaga-Dieguez, Laura; Trachtman, Howard; Giusti, Robert
The causes of kidney disease in pediatric patients are evenly divided between congenital abnormalities of the kidney and urinary tract and acquired disorders. Nearly 10% to 15% of adults in the United States have chronic kidney disease (CKD); there are no comparable data in children. Regardless of patient age, CKD is a systemic problem that affects every organ system, including the lung. We review the tests used to diagnose and evaluate kidney disease and the main clinical syndromes that are likely to be encountered to aid the pulmonology consultant who is asked to evaluate patients with kidney disease.
PMID: 33228933
ISSN: 1557-8240
CID: 4680392

Center Volume and Kidney Transplant Outcomes in Pediatric Patients

Contento, Marissa N; Vercillo, Rachel N; Malaga-Dieguez, Laura; Pehrson, Laura Jane; Wang, Yuyan; Liu, Mengling; Stewart, Zoe; Montgomery, Robert; Trachtman, Howard
Rationale & Objectives/UNASSIGNED:Recent data demonstrate that center volume is not a factor in the outcomes of adult kidney transplant recipients. This study assessed whether center volume affects graft survival in pediatric patients who received a kidney transplant. Study Design/UNASSIGNED:Case-cohort study. Setting & Participants/UNASSIGNED:Kidney transplantation centers, recipients younger than 18 years. Results/UNASSIGNED: = 0.02. Although outcomes for deceased donor kidney recipients were similar in the 3 volume categories, outcomes in patients who received a living kidney donation were better in the high-volume centers. Low household income was associated with poorer outcomes. However, 3-year graft survival was similar in the 3 center volume categories in high and low mean household income states. Limitations/UNASSIGNED:Lack of information for complications and individual family household income of recipients. Conclusions/UNASSIGNED:Transplantation outcomes are worse in pediatric patients treated at lower-volume centers. The difference was more pronounced for patients receiving living versus deceased donor kidneys. The distribution of household income in pediatric transplant recipients may also be a factor that contributes to lower 3-year graft survival in low-volume centers.
PMID: 32734249
ISSN: 2590-0595
CID: 4540722

The Psychosocial Impact of a Diagnosis of Hypertension in Pediatric Patients

Bieber, Amy Kalowitz; Pehrson, Laura Jane; Vento, Suzanne; Malaga-Dieguez, Laura; Spruill, Tanya M; Trachtman, Howard
PMID: 32043037
ISSN: 2468-0249
CID: 4303892

Hypokalemia Associated With a Claudin 10 Mutation: A Case Report

Meyers, Nicole; Nelson-Williams, Carol; Malaga-Dieguez, Laura; Kaufmann, Horacio; Loring, Erin; Knight, James; Lifton, Richard P; Trachtman, Howard
Hypokalemia of renal origin can arise from genetic abnormalities in a variety of transporters or channel proteins that mediate tubular handling of potassium. Recently, mutations in claudin 10 have been documented in patients with hypokalemia in association with a range of other electrolyte abnormalities and skin and sweat gland manifestations. We report a 12-year-old Hispanic boy who presented with anhydrosis, aptyalism, alacrima, hypokalemia, and hypocalciuria, in whom we detected a homozygous mutation in the claudin 10 gene. During the 4-year follow-up period, he developed hypermagnesemia and a decline in estimated glomerular filtration rate to 59mL/min/1.73m2. His unaffected parents and siblings were heterozygous for the mutation. We summarize the clinical phenotype encountered in patients with claudin 10 mutations. It is characterized by significant heterogeneity in electrolyte and extrarenal abnormalities and is associated with a risk for progressive loss of kidney function in up to 33% of cases. Awareness of this association between claudin 10 mutations and electrolyte abnormalities, namely hypokalemia and hypermagnesemia, sheds new light on the physiology of potassium and magnesium handling along the nephron and increases the likelihood of identifying the underlying tubular mechanism in patients with newly diagnosed hypokalemia with or without concomitant hypermagnesemia.
PMID: 30482581
ISSN: 1523-6838
CID: 3657872

Infection-associated glomerulonephritis

Chapter by: Malaga-Dieguez, Laura
in: Glomerulonephritis by
[S.l. : s.n.], 2019
pp. 437-450
ISBN: 9783319493787
CID: 3857182

Immune cell profiles in children with essential hypertension (EH) [Meeting Abstract]

Trachtman, H; Pehrson, L J; Malaga-Dieguez, L; Alexandre, J M; Chattopadhyay, P K
Background: There is growing evidence that sodium is stored in a non-osmotic form in the interstitial compartment of skin and muscle. In these sites, sodium may contribute to the development of EH by altering the immune system. These effects may be reflected in peripheral blood (PB). We tested PB of children with EH to examine the diversity of immunophenotypes, and to test whether disease treatment changed circulating cells. We deployed high parameter flow cytometry, which allowed detailed characterization of T-cell subsets.
Method(s): Eight pediatric patients with EH were enrolled. PB was collected at baseline for all patients, and after 4 and 16 weeks of anti-hypertensive treatment for 3 patients. We designed a 24-parameter flow cytometry panel to enumerate various T-cell subsets, including naive, memory, dividing, exhausted, regulatory, and suppressive cells. We analyzed data using t-sne, a dimension reduction algorithm that provides a broad overview of the landscape of T-cell immunophenotypes, and applied bivariate difference gating to identify the cell populations uniquely altered with treatment.
Result(s): At baseline, 7 of 8 patients showed the expected diversity in T-cells subsets. There were dominant populations that differed by patient, suggesting heterogeneity that might be linked to clinical outcome. The 8th patient had a striking polarization in T-cell phenotype at baseline, with two major subpopulations and very few other cells. Her "skewed" T-cell landscape resolved with treatment, and we could precisely identify the cells lost. Cells were uniformly CD4+CD45RA+CD127+CD25-CD38+CCR4-Ki67-LAG3+CTLA4-CD39-IDO-HELIOS-FoxP 3-CXCR3-GITR+. This phenotype represents a class of naive, non-classical regulatory (i.e., suppressive) T-cells. Subsets also expressed other suppressive markers like LAP, GARP, and CD73. Interestingly, the other two patients also showed loss of cells expressing LAG3, CD73, LAP, and/or GARP with treatment.
Conclusion(s): Children with EH have heterogeneous regulatory T-cell subsets. Successful control of blood pressure with anti-hypertensive drugs re-shapes the T-cell landscape in PB, reducing the number of suppressive T-cells. Our approach-to precisely identify specific cell types altered with disease-is well-suited to identifying biomarkers, and can provide detailed mechanistic information that informs treatment approaches
ISSN: 1533-3450
CID: 4755042

Efficacy of a gluten-free diet (GFD) in children with difficult-to-manage nephrotic syndrome (NS) [Meeting Abstract]

Trachtman, H; Pehrson, L J; Vento, S M; Malaga-Dieguez, L; Gipson, D S; Lemley, K V; Dell, K M; Srivastava, T; Kaskel, F J; Meyers, K E; Faul, C
Background: Zonulin (ZON) increases gut permeability after exposure to gliadin in children with celiac disease. Plasma zonulin levels are increased in children with NS. Protease activated receptor-2, which mediates ZON effect in enterocytes, is present on podocytes. Thus, gluten-induced elevations in ZON may affect glomerular permeability and mediate proteinuria in children with NS. We conducted this study to assess the efficacy of a GFD in controlling disease in children with difficult-to-manage NS.
Method(s): This multicenter, open-label trial tested the efficacy of a GFD in children with steroid-responsive, difficult-to-manage NS. The Treatment Period was 6 months. A positive response was defined as >=50% reduction in relapse rate versus the prior 6 months or discontinuation of >=1 immunosuppressive medication. The following data were tabulated: age, gender, race/ethnicity, serum creatinine, proteinuria, histopathology if available, and treatment. Serum was collected prior to and at completion of the Treatment Period to assess the effect on the glomerular cytoskeleton in vitro. Data are provided as mean+/-SD.
Result(s): 14 children (8F:6M) were enrolled, age 7.8+/-4.6 yr, baseline serum creatinine 0.46+/-0.12 mg/dl, and Up/c 0.45+/-0.49 (mg:mg). There were 11 Whites, 1 Black and 3 other racial groups and 2 children were Hispanic/Latino. The underlying disease was MCD in 10 and FSGS in 4 cases. At the end of the Treatment Period, 4 participants had a positive response (2 reduced relapse rate and 2 reduced medication burden), 5 had no benefit (2 withdrew before 6 months), 3 patients are in the 6-month Treatment Period, and 1 child was lost to follow-up. One adolescent had no change in relapse rate but responded to corticosteroids more rapidly on the GFD. Baseline plasma zonulin concentration was 19.4+/-1.7 vs 13.4+/-0.9 pg/mL in non-responders (n=4) vs GFD responders (n=2), respectively, P=0.01.
Conclusion(s): Up to a third of patients with difficult-to-manage NS have a favorable response to implementation of a GFD. An elevated plasma zonulin level may predict a poor response to the maneuver. A trial of this dietary intervention may be warranted in children with frequently relapsing or steroid dependent NS to minimize the need for immunosuppressive agents
ISSN: 1533-3450
CID: 4755162