Search

Background: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1’s natural absence in laboratory animals makes studying its pathobiology challenging. Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR

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.

BackgroundClassification of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies. This approach does not reflect underlying disease biology, limiting the ability to predict progression or treatment response.MethodsSystems biology approaches were used to categorize patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) based on kidney biopsy tissue transcriptomics across three cohorts and assessed association with clinical outcomes. Patient-level tissue pathway activation scores were generated using differential gene expression. Then, functional enrichment and non-invasive urine biomarker candidates were identified. Biomarkers were validated in kidney organoid models and single nucleus RNA-seq (snRNAseq) from kidney biopsies.ResultsTranscriptome-based categorization identified three subgroups of patients with shared molecular signatures across independent North American, European and African cohorts. One subgroup demonstrated worse longterm outcomes (HR 5.2, p = 0.001) which persisted after adjusting for diagnosis and clinical measures (HR 3.8, p = 0.035) at time of biopsy. This subgroup’s molecular profile was largely (48%) driven by tissue necrosis factor (TNF) activation and could be predicted based on levels of TNF pathway urinary biomarkers TIMP-1 and MCP-1 and clinical features (correlation 0.63, p ConclusionsMolecular profiling identified a patient subgroup within nephrotic syndrome with poor outcome and kidney TNF pathway activation. Clinical trials using non-invasive biomarkers of pathway activation to target therapies are currently being evaluated.Significance StatementMechanistic, targeted therapies are urgently needed for patients with nephrotic syndrome. The inability to target an individual’s specific disease mechanism using currently used diagnostic parameters leads to potential treatment failure and toxicity risk. Patients with focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) were grouped by kidney tissue transcriptional profiles and a subgroup associated with poor outcomes defined. The segregation of the poor outcome group was driven by tumor necrosis factor (TNF) pathway activation and could be identified by urine biomarkers, MCP1 and TIMP1. Based on these findings, clinical trials utilizing non-invasive biomarkers of pathway activation to target therapies, improve response rates and facilitate personalized treatment in nephrotic syndrome have been initiated.

Limited information is available regarding the relationship between ambulatory blood pressure monitoring (ABPM) and cardiac geometry in hypertensive children. ABPM and 2D‐echocardiography were retrospectively reviewed in children and adolescents

Introduction Recurrent focal and segmental glomerulosclerosis (FSGS) in kidney transplant recipients is associated with lower graft survival and increased morbidity. There are limited data to guide the decision to re-transplant patients with transplant failure due to FSGS recurrence. We aimed to evaluate outcomes in patients re-transplanted after having initial graft failure due to recurrent FSGS and to study physician attitudes and practice patterns. Methods Retrospective data from 10 centers were collected on 20 patients transplanted between January 1997 and September 2018. A survey was sent to nephrologist members of the Pediatric Nephrology Research Consortium. Results Mean patient age (years) was 9.8 ± 4.8 at first transplant and 15.9 ± 4.9 at re-transplantation. Pre-transplant plasmapheresis was used in 1 (5.3%) primary transplant vs. 7 (38.9%) re-transplants (p = .03). Nephrotic syndrome recurred in 14 patients (70%) after re-transplantation and was severe in 21.1% vs. 64.7% after first transplant (p = .04). Graft survival was significantly higher in the second transplant (p .009) with 70% having functioning grafts at a median of 25.2 months. Thirty-one physicians from 21 centers completed the survey, 94% indicated they would re-transplant such patients, 44.4% preferred a minimum waiting period before re-transplantation, 36.4% preferred living donors, and 22.2% indicated having protocols for re-transplantation at their centers. Conclusions Consideration for re-transplantation is high among pediatric nephrologists. Pre-transplant plasmapheresis was more frequent in re-transplanted patients. Nephrotic syndrome recurrence was less severe, with better graft survival. More data and a larger population are necessary to further evaluate outcome determinants and best practices in this special population.

Acute severe hypertension in otherwise healthy children with acute illness requiring hospitalization for BP management is uncommon and warrants immediate evaluation. We describe 10 cases of children presenting with acute gastroenteritis and found to have acute severe hypertension. They required admission to the hospital for antihypertensive treatment, including 2 to the intensive care unit, but all had normalization of BP and were able to stop treatment with resolution of the acute illness. All patients had thorough testing for secondary causes of hypertension and for signs of end-target organ damage, which were unremarkable. To our knowledge, acute severe hypertension in the setting of acute gastroenteritis without underlying kidney pathology and with complete resolution after illness has not been previously described. The mechanism of this association is not clear, although activation of the sympathetic nervous system is suspected. These cases illustrate the importance of thoroughly assessing BP in the acute setting.

BACKGROUND AND OBJECTIVES: Hypertension is highly prevalent in pediatric kidney transplant recipients and contributes to cardiovascular death and graft loss. Improper blood pressure (BP) measurement limits the ability to control hypertension in this population. Here, we report multicenter efforts from the Improving Renal Outcomes Collaborative (IROC) to standardize and improve appropriate BP measurement in transplant patients. METHODS: Seventeen centers participated in structured quality improvement activities facilitated by IROC, including formal training in quality improvement methods. The primary outcome measure was the proportion of transplant clinic visits with appropriate BP measurement according to published guidelines. Prospective data were analyzed over a 12-week pre-intervention period and a 20-week active intervention period for each center and then aggregated as of the program-specific start date. We used control charts to quantify improvements across IROC centers. We applied thematic analysis to identify patterns and common themes of successful interventions. RESULTS: We analyzed data from 5392 clinic visits. At baseline, BP was measured and documented appropriately at 11% of visits. Center-specific interventions for improving BP measurement included educating clinic staff, assigning specific team member roles, and creating BP tracking tools and alerts. Appropriate BP measurement improved throughout the 20-week active intervention period to 78% of visits. CONCLUSIONS: We standardized appropriate BP measurement across 17 pediatric transplant centers using the infrastructure of the IROC learning health system and substantially improved the rate of appropriate measurement over 20 weeks. Accurate BP assessment will allow further interventions to reduce complications of hypertension in pediatric kidney transplant recipients.

COVID-19 is the illness caused by infection with the novel coronavirus SARS-CoV-2. Although myalgia is common in adults, it has not been noted as a common symptom in children. There have been a few reported cases of COVID-19-associated rhabdomyolysis in adults. This case report describes a 16-year-old boy who presented with fever, myalgias, mild shortness of breath with exertion, and dark-colored urine. COVID-19 PCR was positive. His initial creatinine kinase (CK) level was 427,656 U/L. Serum creatinine was normal for age. He was treated with isotonic intravenous fluids containing sodium bicarbonate to maintain urine output of 100–200 mL/h and urine pH > 7.0. His serum creatinine remained normal throughout the hospital stay and he was discharged on hospital day 12 with a CK of 6526 U/L. To our knowledge, no pediatric cases of COVID-19-associated rhabdomyolysis have been previously reported. Adult cases of rhabdomyolysis have been reported and a few reports have noted patients with elevated CK levels without rhabdomyolysis. Given this pediatric case of COVID-19-associated rhabdomyolysis, pediatric clinicians should be aware of this complication and manage fluids appropriately in order to prevent acute kidney injury.

Background Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS). Methods FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied. Results There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (−7.6 points, P = 0.02) and mobility (−4.2, P = 0.02), the number of reported symptoms was associated with worse depression (−2.7 per symptom, P = 0.009) and anxiety (−2.3, P = 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (−2.8 per visit, P Conclusions PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes.

Low nephron number has been shown to be a risk factor for hypertension (HTN) in adulthood. Kidney volume may serve as a surrogate marker for nephron mass. The relationship between kidney volume and ambulatory blood pressure (BP) in the pediatric population is not known. A retrospective chart review of children younger than 21 years who were evaluated for HTN was performed. Twenty‐four‐hour BP and ultrasonography data were obtained. Multiple regression was used to examine associations between BP and kidney volume. Of 84 children (mean age 13.87 years, 72.6% males), 54 had HTN. Systolic BP index during the awake, sleep, and 24‐hour periods (all P≤.05) was found to be positively correlated with total kidney volume. Greater total kidney volume was found to be a positive predictor of 24‐hour and sleep systolic index (P≤.05). It failed to serve as a predictor of HTN, pre‐HTN, or white‐coat HTN. Contrary to expectation, total kidney volume was positively associated with systolic BP indices.

Hypertension affects approximately 30% of all US adults1 and is the leading risk factor for cardiovascular morbidity and mortality.2 Although antihypertensive medication is the mainstay of blood pressure (BP) control, dietary sodium restriction has been widely recommended as a public health measure for both prevention and treatment of hypertension.3 Sodium restriction has been found to lower mean BP,4–6 with a recent Cochrane review indicating an average systolic BP (SBP) reduction of 3.5% in hypertensive patients when sodium intake was reduced by 125 mmol/day.7 At the same time, controversy exists on whether this sodium–BP effect actually translates to cardioprevention because intensive sodium restriction may have adverse effects on insulin resistance, triglycerides, and sympathetic nervous system activation.7,8 Studies directly examining the association between sodium intake and cardiovascular outcomes have produced conflicting results, with some finding a direct association, some showing an inverse or J-shaped curve, and others finding no relation to cardiovascular disease mortality. The lack of a consistent association is highlighted by the recent Institute of Medicine report,9 which concluded that the available data preclude a recommendation to restrict sodium to

Background: Studies linking sodium intake and mortality have produced conflicting results, with some showing an inverse or J-shaped relationship. An earlier assessment of this population (mean 3.8 years follow-up) revealed an inverse association of sodium to CVD morbidity and mortality. We now report the association with all-cause and cardiovascular mortality during an average 18.4 years of follow-up. METHODS: Subjects participated in a worksite hypertension program between 1980-1995. Entry criteria were SBP≥140, DBP≥90, or receiving antihypertensive medications. Sodium intake was assessed with 24-hour urine collection. Antihypertensives were discontinued 3-4 weeks prior to collection, and individuals with BP Results: Of 2983 individuals, 66% were male; mean(±sd) age 52.2 (±9.5) years; mean sodium intake 3023 (±1584) mg/day. Mean follow-up time was 18.4 (±5.9) years. There were 878 deaths, including 351 (40%) due to cardiovascular causes. HR and 95% CI (QI vs QIV) for all-cause and CV mortality respectively were 1.24 (1.02, 1.49), p=0.03 and 1.68 (1.20, 2.35), p=0.003 in unadjusted models, and 0.76 (0.61, 0.95), p=0.02, and 0.86 (0.60, 1.25), p=0.44 in adjusted models. Subgroup analysis limited to MI, heart failure and ischemic heart disease also revealed a non-significant direct relationship (p=0.15). Conclusions: We observed a direct association between sodium intake and all-cause mortality, and a similar but non-significant trend with cardiovascular mortality. These are in contrast both to unadjusted models and to an earlier study in the same population. Absence of clinical information after 1998, and the gap between sodium determination and follow-up, limits ability to explain these contrasting findings. Studies that obtain prolonged information on dietary intake and clinical experience over time will be required to better assess long-term associations between sodium intake and health outcomes.