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Pediatric chronic disease impacts the affected child and their family structure. There is limited literature investigating the psychosocial impact of nephrotic syndrome on families.Caregivers of children with nephrotic syndrome completed two validated surveys: (1) Impact on Family (IOF) that evaluates the family impact (degree to which family is affected by a pediatric chronic illness) and (2) Coping Health Inventory for Parents (CHIP) that examines the coping patterns used by caregivers. Linear regression models were utilized to determine predictors of perceived family impact and coping patterns.Seventy-five caregivers of a child with nephrotic syndrome completed the surveys. On a scale from low impact to significant impact to very serious impact, results indicated that nephrotic syndrome had a significant impact on families (mean revised IOF total score 33.04 ± 9.38). Families in the steroid-resistant nephrotic syndrome (SRNS) group reported a higher financial impact compared to the steroid-sensitive nephrotic syndrome (SSNS) group (p = 0.03). Families in the frequently relapsing group (FRNS) reported a higher impact on the caregiver's ability to cope with the child's condition compared to the SRNS group (p = 0.02). Tacrolimus use was associated with increasing the perceived family impact (β = 4.76, p = 0.046). CHIP scores indicated that caregivers did not cope well with family integration (component I) but coped well with social support (component II) and communication (component III).Childhood nephrotic syndrome has a significant overall perceived impact on the family, and caregivers did not cope well regarding strengthening their family life. These findings can be used as outcome measures for future intervention studies to find solutions that would decrease the perceived family burden. A higher resolution version of the Graphical abstract is available as Supplementary information.

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

Successful outcomes in pediatric kidney transplantation require the involvement of the transplant team as well as recipients and their caregivers. Enhancing patient and family understanding of the disease and of post-transplant care can result in improved adherence and outcomes. Educational strategies should aim to be broad, understandable, innovative, and inclusive while maintaining a tailored approach to individualized care. Teaching should not be viewed as a one-time event but rather as an ongoing conversation throughout the duration of care, emphasizing different aspects throughout the patient's various developmental stages. The following review article discusses the content and methods of post-transplant education.

We report follow-up data from an ongoing prospective cohort study of COVID-19 in pediatric kidney transplantation through the Improving Renal Outcomes Collaborative (IROC).Patient-level data from the IROC registry were combined with testing, indication, and outcomes data collected to describe the epidemiology of COVID testing, treatment, and clinical outcomes; determine the incidence of a positive COVID-19 test; describe rates of COVID-19 testing; and assess for clinical predictors of a positive COVID-19 test.From September 2020 to February 2021, 21 centers that care for 2690 patients submitted data from 648 COVID-19 tests on 465 patients. Most patients required supportive care only and were treated as outpatients, 16% experienced inpatient care, and 5% experienced intensive care. Allograft complications were rare, with acute kidney injury most common (7%). There was 1 case of respiratory failure and 1 death attributed to COVID-19. Twelve centers that care for 1730 patients submitted complete testing data on 351 patients. The incidence of COVID-19 among patients at these centers was 4%, whereas the incidence among tested patients was 19%. Risk factors to predict a positive COVID-19 test included age 12 years, symptoms consistent with COVID-19, and close contact with a confirmed case of COVID-19.Despite the increase in testing and positive tests over this study period, the incidence of allograft loss or death related to COVID-19 remained extremely low, with allograft loss or death each occurring in 1% of COVID-19-positive patients and in less than 0.1% of all transplant patients within the IROC cohort. A higher resolution version of the Graphical abstract is available as Supplementary information.

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.

BACKGROUND Focal segmental glomerulosclerosis (FSGS) predisposes patients for risk of recurrent disease in allografts. METHODS We report a case of a recipient of an unrelated living donor renal transplant and discuss considerations for utilization of ofatumumab and eplerenone in treatment for recurrent FSGS. RESULTS The recipient was initially managed with scheduled plasmapheresis, intravenous immunoglobulin (IVIG), and rituximab post-transplant during index hospitalization. With notable recurrence of FSGS noted on kidney transplant biopsy, she was initially treated with additional plasmapheresis sessions leading to downtrend in proteinuria. The patient was then transitioned to LDL-A pheresis, which resulted again in uptrend in proteinuria. This prompted return to scheduled plasmapheresis sessions weekly, leading again to a downtrend in proteinuria. Albumin levels remained within normal range throughout her course. Following initiation of eplerenone and ofatumumab, the patient demonstrated normalization of urine protein:creatinine ratio and remission of FSGS recurrence without need for additional apheresis. CONCLUSIONS With notable risk of recurrence of FSGS in kidney transplants leading to allograft failure, the use of ofatumumab and eplerenone in conjunction should be considered for management to induce remission.

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

BACKGROUND Literature supports equivalent kidney transplant outcomes in adults with systemic lupus erythematosus (SLE) compared with those without SLE. However, there are conflicting and scant data on kidney transplant outcomes, as well as controversy over optimal timing of transplantation, in children and adolescents with SLE. METHODS Analysis included kidney-only transplant recipients aged 2-21 years from 2000 to 2017 enrolled in the Organ Procurement and Transplant Network (OPTN). The relationship between diagnosis (SLE n = 457, non-SLE glomerular disease n = 4492, and non-SLE non-glomerular disease n = 5605) and transplant outcomes was evaluated. The association between dialysis time and outcomes was analyzed in the SLE group only. RESULTS In adjusted models, SLE had higher mortality compared with non-SLE glomerular recipients (HR 1.24 CI 1.07-1.44) and non-glomerular recipients (HR 1.42 CI 1.20-1.70). SLE was associated with higher graft failure compared with non-SLE glomerular (HR 1.42 CI 1.20-1.69) and non-glomerular disease (HR 1.67 CI 1.22-2.28). SLE had a higher risk of acute rejection at 1 year compared with non-glomerular disease (HR 1.39 CI 1.03-1.88). There was a decreased risk of delayed graft function compared with non-SLE glomerular disease (HR 0.54, CI 0.36-0.82). There were no significant associations between dialysis time and transplant outcomes in the SLE group. CONCLUSION SLE in children and adolescents is associated with worse patient and graft survival compared with non-SLE diagnoses. Outcomes in children and adolescents with SLE are not associated with dialysis time. Further studies are needed to assess implications of potential earlier transplantation and shorter time on dialysis prior to transplantation.

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.

Objective To compare pediatric ambulatory blood pressure monitoring (ABPM) criteria with adult ABPM criteria for the diagnosis of hypertension and detection of left ventricular hypertrophy (LVH) in adolescents. Study design ABPM and echocardiography reports from adolescents age 13-21 years from 2015 to 2019 were analyzed. The concordance of hypertension based on pediatric criteria (American Heart Association 2014) was compared with adult criteria from American College of Cardiology/American Heart Association 2017 (overall BP ≥125/75 mm Hg, wake BP ≥130/80 mm Hg, sleep BP ≥110/65 mm Hg) using the Cohen kappa statistic. Logistic regression, adjusted for body mass index z score, and receiver operating characteristic curves (ROCs) compared pediatric criteria vs adult criteria in predicting LVH (left ventricular mass index >95th percentile reference values and left ventricular mass index >51 g/m2.7). Results Of 306 adolescents, 140 (45.8%) had hypertension based on pediatric criteria vs 228 (74.5%) based on adult criteria; the agreement was poor (59.3%, n = 137, kappa = 0.41). A higher prevalence of LVH was captured by adult criteria only (n = 91) compared with pediatric criteria only (n = 3). Logistic regression found no significant differences between pediatric and adult criteria in the detection of LVH >95th percentile (OR 1.24, CI 0.66, 2.31, P = .51) or >51 g/m2.7 (OR 1.06, CI 0.47, 2.40, P = .89). ROCs for pediatric criteria were not significant for detecting LVH >95th percentile (0.50, P = .91) or >51 g/m2.7 (0.55, P = .45), whereas the ROC for adult criteria was significant for detecting LVH >95th percentile (0.59, P = .045) but not >51 g/m2.7 (0.63, P = .07). Although all individuals with LVH >51 g/m2.7 were hypertensive by adult criteria, 8 of these individuals were missed by pediatric criteria. Conclusions Adult criteria captured a higher prevalence of LVH and appeared to predict better LVH than pediatric criteria. A consideration to align ABPM criteria for diagnosing hypertension in adolescents with adult guidelines is warranted.

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 Deceased donor kidneys with acute kidney injury (AKI) and donation after circulatory death (DCD) kidneys are viable sources of organs. The outcomes of renal transplantation from DCD donors with AKI are not known. METHODS A retrospective review of deceased donor renal transplants performed from 2006 to 2016 was conducted using the United Network for Organ Sharing dataset. Donors were stratified by DCD or brain dead status and by AKI stage. Recipients were followed until graft failure or the end of study. Cox regression was used to adjust for donor, recipient, and transplant covariates known to affect the incidence of delayed graft function and graft survival. RESULTS A total of 135 644 patients were included in the study. The odds of delayed graft function among DCD recipients were significantly higher across all donor AKI stages. The unadjusted risk of overall and death-censored graft failure were similar between the 2 groups. After adjusting for covariates, there was a significant increase in the risk of overall graft failure in recipients of DCD allografts from donors with stage 2 AKI. There was also a higher risk of death-censored graft failure among stage 1 and 2 AKI DCD recipients. CONCLUSIONS DCD renal allografts from donors experiencing stage 1 and 2 AKI have a higher adjusted risk of death-censored graft failure than AKI stage-matched donation after brain death renal allografts. Their use, however, is still associated with improved outcomes compared with waitlist mortality.

A 7-year-old boy with a history of febrile illness-related epilepsy syndrome presented with proteinuria and elevated creatinine. His severe epileptic disorder has been treated since age 2 with multiple antiepileptic medications, including valproic acid. More recently, he was noted to have features of Fanconi syndrome with acidosis, hypophosphatemia, hypokalemia, glucosuria, and nephrotic-range proteinuria. This was managed with supplements; however, in the setting of rising creatinine and prominent proteinuria, a kidney biopsy was performed. Renal cortex revealed markedly decreased expression of proximal tubule markers and increased expression of markers of distal nephron differentiation. Such findings have been described in several genetic and acquired conditions, including renal tubular dysgenesis, severe hypoxic injury following renal artery stenosis, and toxic injury related to in utero exposure to angiotensin-converting-enzyme inhibitors. Such changes have not been reported before in valproic acid-associated Fanconi syndrome, although in general, morphologic findings in this condition have not been well established in the literature.

Obesity is a risk factor for poor transplant outcomes in the adult population. The effect of pre-transplant weight on pediatric kidney transplantation is conflicting in the existing literature. Data was collected from the Organ Procurement and Transplantation Network (OPTN) database on recipients aged 2–21 years who received a kidney-only transplant from 1987 to 2017. Recipients were categorized into underweight, normal, overweight, and obese cohorts. Using adjusted regression models, the relationship between recipient weight and various graft outcomes (delayed graft function [DGF], acute rejection, prolonged hospitalization, graft failure, mortality) was examined. 18,261 transplant recipients (mean age 14.1 ± 5.5 years) were included, of which 8.7% were underweight, 14.8% were overweight, and 15% were obese. Obesity was associated with greater odds of DGF (OR 1.3 95% CI 1.13–1.49, p

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.

It is well established that racial differences exist in kidney transplant outcomes; however, there are no studies which focus on the role of race in transplant outcomes specifically in children diagnosed with FSGS. Associations between race and transplant outcomes in FSGS children were evaluated using the Organ Procurement and Transplantation Network database from 2000 to 2012. Recipients aged 2-21 years who received a kidney-only transplant were included. Multivariate regression models were used to evaluate transplant outcomes by race. Five hundred and thirty-six recipients (59.7% male, 15.6±3.9 years) were black and 1134 (55.7% male, 14.3±5.0 years) were non-black. Graft survival was significantly shorter in the black group (4.2±3.1 vs 4.6±3.3 years, P=.005). Black race was associated with significantly higher risk of graft failure (HR 1.34, 95% CI=1.21-1.49, P

The ambulatory arterial stiffness index (AASI) and the symmetric ambulatory arterial stiffness index (s-AASI) have been shown to correlate to arterial stiffness in adults. This study assesses these indices with anthropometric and blood pressure (BP) measures in children. A total of 102 children at a pediatric hypertension clinic who had ambulatory blood pressure monitoring (ABPM) done from 2009 to 2013 were included (75% males, 7-22yo, 47% hypertensive, 24% prehypertensive, and 34% white-coat hypertensives). AASI is 1 minus the regression slope of diastolic BP values on systolic BP values from a 24-hour ambulatory blood pressure monitoring. s-AASI is the symmetric regression of AASI. Obese patients had a significantly higher AASI. s-AASI correlated with systolic BP variability. In multivariable regression, BP variability independently correlated with AASI and s-AASI. s-AASI is related to systolic dipping.AASI and s-AASI are highly dependent on BP variability in children. Further studies are necessary to assess their utility.

This study examined the efficacy of an adjunctive traumafocused art therapy intervention in reducing chronic child posttraumatic stress disorder (PTSD) symptoms in an inpatient psychiatric facility...

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.