Racial and Ethnic Disparities in Acute Care Utilization Among Patients With Glomerular Disease.

RATIONALE & OBJECTIVE: The effects of race, ethnicity, socioeconomic status (SES), and disease severity on acute care utilization in patients with glomerular disease are unknown. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,456 adults and 768 children with biopsy-proven glomerular disease enrolled in the Cure Glomerulonephropathy (CureGN) cohort. EXPOSURE: Race and ethnicity as a participant-reported social factor. OUTCOME: Acute care utilization defined as hospitalizations or emergency department visits. ANALYTICAL APPROACH: Multivariable recurrent event proportional rate models were used to estimate associations between race and ethnicity and acute care utilization. RESULTS: Black or Hispanic participants had lower SES and more severe glomerular disease than White or Asian participants. Acute care utilization rates were 45.6, 29.5, 25.8, and 19.2 per 100 person-years in Black, Hispanic, White, and Asian adults, respectively, and 55.8, 42.5, 40.8, and 13.0, respectively, for children. Compared with the White race (reference group), Black race was significantly associated with acute care utilization in adults (rate ratio [RR], 1.76 [95% CI, 1.37-2.27]), although this finding was attenuated after multivariable adjustment (RR, 1.31 [95% CI, 1.03-1.68]). Black race was not significantly associated with acute care utilization in children; Asian race was significantly associated with lower acute care utilization in children (RR, 0.32 [95% CI 0.14-0.70]); no significant associations between Hispanic ethnicity and acute care utilization were identified. LIMITATIONS: We used proxies for SES and lacked direct information on income, household unemployment, or disability. CONCLUSIONS: Significant differences in acute care utilization rates were observed across racial and ethnic groups in persons with prevalent glomerular disease, although many of these difference were explained by differences in SES and disease severity. Measures to combat socioeconomic disadvantage in Black patients and to more effectively prevent and treat glomerular disease are needed to reduce disparities in acute care utilization, improve patient wellbeing, and reduce health care costs.

Case report: Diarrhea-associated hemolytic uremic syndrome in the Era of COVID-19.

Over the past two years, a growing number of SARS-CoV-2 infection-associated clinical pediatric phenotypes have been identified, including a hemolytic uremic syndrome (HUS) form of thrombotic microangiopathy. Oregon's high prevalence of Shiga toxin-producing Escherichia coli (STEC) infections gives it a unique perspective to discuss the impact of COVID-19 and HUS. We seek to highlight SARS-CoV-2 as a potential new infectious etiology of severe diarrhea-associated HUS, based on two cases from Portland, Oregon, occurring in non-COVID-19 immunized children. The first case is a previously healthy ten-year-old who presented with SARS-CoV-2 infection and bloody diarrhea after an appendectomy, followed by full-blown oligo-anuric HUS. Second is a previously healthy six-year-old who presented with short-lived bloody diarrhea, rapidly evolving to HUS, and who tested positive for COVID-19 via polymerase chain reaction and STEC toxins one and two. These two cases highlight two main points. First, SARS-CoV-2 must be included in the differential diagnosis of diarrhea-associated HUS, either as the sole agent or concurrent with a STEC infection. Second, when managing STEC gastroenteritis the recommendation has been to maintain excellent hydration as a strategy to prevent the progression to oligo-anuric acute kidney injury and HUS. This strategy may need to be re-evaluated in a patient with SARS-CoV-2 infection or co-infection.

Pathology findings in pediatric patients with COVID-19 and kidney dysfunction.

BACKGROUND: Acute kidney injury (AKI) is seen in one-fifth of pediatric patients with COVID-19 requiring hospital admission, and is associated with increased morbidity, mortality, and residual kidney impairment. The majority of kidney pathology data in patients with COVID-19 is derived from adult case series and there is an overall lack of histologic data for most pediatric patients with COVID-19. METHODS: We assembled a multi-institutional cohort of five unvaccinated pediatric patients with COVID-19 and associated kidney dysfunction with available histology. RESULTS: Three complex patients with current or prior SARS-CoV-2 infection had multifactorial thrombotic microangiopathy with clinical features of hemolytic uremic syndrome (in two) or disseminated intravascular coagulation (in one); one died and another developed chronic kidney disease stage 5. Two with recently preceding SARS-CoV-2 infection presented with nephrotic syndrome; one had IgA vasculitis and one had minimal change disease. Within a short follow-up time, none has returned to baseline kidney function. CONCLUSION: Although uncommon, COVID-19-associated kidney injury can have significant morbidity in the unvaccinated pediatric and adolescent population. A higher resolution version of the Graphical abstract is available as Supplementary information.

Racial-ethnic differences in health-related quality of life among adults and children with glomerular disease.

INTRODUCTION: Disparities in health-related quality of life (HRQOL) have been inadequately studied in patients with glomerular disease. The aim of this study was to identify relationships between race/ethnicity, socioeconomic status, disease severity, and HRQOL in an ethnically and racially diverse cohort of patients with glomerular disease. METHODS: Cure Glomerulonephropathy (CureGN) is a multinational cohort study of patients with biopsy-proven glomerular disease. Associations between race/ethnicity and HRQOL were determined by the following: 1. Missed school or work due to kidney disease; 2. Responses to Patient Reported Outcomes Measurement Information System (PROMIS) questionnaires. We adjusted for demographics, socioeconomic status, and disease characteristics using multivariable logistic and linear regression. RESULTS: Black and Hispanic participants had worse socioeconomic status and more severe glomerular disease than White or Asian participants. Black adults missed work or school most frequently due to kidney disease (30% versus 16-23% in the other three groups, p=0.04), and had the worst self-reported global physical health (median score 44.1 versus 48.0-48.2, p<0.001) and fatigue (53.8 versus 48.5-51.1, p=0.002), compared to other racial/ethnic groups. However, these findings were not statistically significant with adjustment for socioeconomic status and disease severity, both of which were strongly associated with HRQOL in adults. Among children, disease severity but not race/ethnicity or socioeconomic status were associated with HRQOL. CONCLUSIONS: Among patients with glomerular disease enrolled in CureGN, the worse HRQOL reported by Black adults was attributable to lower socioeconomic status and more severe glomerular disease. No racial/ethnic differences in HRQOL were observed in children.

Elimination of Intravenous Di-2-Ethylhexyl Phthalate Exposure Abrogates Most Neonatal Hypertension in Premature Infants with Bronchopulmonary Dysplasia.

(1) Background: The incidence of hypertension in very low birthweight (VLBW) infants in a single neonatal intensive care unit (NICU) dropped markedly during a 2-year period when the IV fluid (IVF) in both the antenatal unit and the NICU temporarily changed to a di-2-ethylhexyl phthalate (DEHP)-free formulation. The objective of the current report is to document this observation and demonstrate the changes in incidence of hypertension were not associated with the variation in risk factors for hypertension; (2) Methods: The charts of all VLBW infants born in a single NICU during a 7-year span were reviewed. This time includes 32 months of baseline, 20 months of DEHP-free IVF, 20 months of IVF DEHP re-exposure, and two 4-month washout intervals. The group of interest was limited to VLBW infants with bronchopulmonary dysplasia (BPD). Chi-square analysis was used to compare incidence of hypertension among periods. Vermont Oxford NICU Registry data were examined for variation in maternal and neonatal risk factors for hypertension; Results: Incidence of hypertension in VLBW infants with BPD decreased from 7.7% (baseline) to 1.4% when IVF was DEHP-free, rising back to 10.1% when DEHP-containing IVF returned to use. Risk factors for neonatal hypertension were stable across the 3 study periods in the NICU's group of VLBW infants; (3) Conclusions: Serendipitous removal of IVF containing DEHP resulted in near elimination of hypertension in one NICU-an effect entirely reversed after the same brand of DEHP-containing IVF returned to clinical use. These results suggest that DEHP exposure from IVF plays a major role in neonatal hypertension.

Phthalate-associated hypertension in premature infants: a prospective mechanistic cohort study.

BACKGROUND: Phthalates are associated with increased blood pressure in children. Large exposures to di-(2-ethylhexyl) phthalate (DEHP) among premature infants have been a cause for concern. METHODS: We conducted a prospective observational cohort study to determine if DEHP exposures are related to systolic blood pressure (SBP) in premature infants, and if this exposure is associated with activation of the mineralocorticoid receptor (MR). Infants were monitored longitudinally for 8 months from birth. Those who developed idiopathic hypertension were compared with normotensive infants for DEHP exposures. Appearance of urinary metabolites after exposure was documented. Linear regression evaluated the relationship between DEHP exposures and SBP index and whether urinary cortisol/cortisone ratio (a surrogate marker for 11ß-HSD2 activity) mediated those relationships. Urinary exosomes were quantified for sodium transporter/channel expression and interrogated against SBP index. RESULTS: Eighteen patients met the study criteria, nine developed transient idiopathic hypertension at a postmenstrual age of 40.6 ± 3.4 weeks. The presence of urinary DEHP metabolites was associated with prior IV and respiratory tubing DEHP exposures (p < 0.05). Both IV and respiratory DEHP exposures were greater in hypertensive infants (p < 0.05). SBP index was related to DEHP exposure from IV fluid (p = 0.018), but not respiratory DEHP. Urinary cortisol/cortisone ratio was related to IV DEHP and SBP index (p < 0.05). Sodium transporter/channel expression was also related to SBP index (p < 0.05). CONCLUSIONS: Increased blood pressure and hypertension in premature infants are associated with postnatal DEHP exposure. The mechanism of action appears to be activation of the MR through inhibition of 11ß-HSD2.

Diagnosis, Treatment, and Outcomes in Children With Congenital Nephrogenic Diabetes Insipidus: A Pediatric Nephrology Research Consortium Study.

Background and Objectives: Congenital or primary nephrogenic diabetes insipidus (NDI) is a rare genetic disorder that severely impairs renal concentrating ability, resulting in massive polyuria. There is limited information about prognosis or evidence guiding the management of these patients, either in the high-risk period after diagnosis, or long-term. We describe the clinical presentation, genetic etiology, treatment and renal outcomes in a large group of children <21 years with NDI. Design: A multi-center retrospective chart review. Results: We report on 66 subjects from 16 centers. They were mainly male (89%) and white (67%). Median age at diagnosis was 4.2 months interquartile range (IQR 1.1, 9.8). A desmopressin acetate loading test was administered to 46% of children at a median age of 4.8 months (IQR 2.8, 7.6); only 15% had a water restriction test. Genetic testing or a known family history was present in 70% of the patients; out of those genetically tested, 89 and 11% had mutations in AVPR2 and AQP2, respectively. No positive family history or genetic testing was available for 30%. The most common treatments were thiazide diuretics (74%), potassium-sparing diuretics (67%) and non-steroidal anti-inflammatory drugs (42%). At the time of first treatment, 70 and 71% of children were below -2 standard deviations (SD) for weight and height, respectively. At last follow-up, median age was 72.3 months (IQR 40.9, 137.2) and the percentage below -2 SD improved to 29% and 38% for weight and height, respectively. Adverse outcomes included inpatient hospitalizations (61%), urologic complications (37%), and chronic kidney disease (CKD) stage 2 or higher in 23%. Conclusion: We found the majority of patients were treated with thiazides with either a potassium sparing diuretic and/or NSAIDs. Hospitalizations, urologic complications, short stature, and CKD were common. Prospective trials to evaluate different treatment strategies are needed to attempt to improve outcomes.

Clinical Characteristics and Treatment Patterns of Children and Adults With IgA Nephropathy or IgA Vasculitis: Findings From the CureGN Study.

INTRODUCTION: The Cure Glomerulonephropathy Network (CureGN) is a 66-center longitudinal observational study of patients with biopsy-confirmed minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (IgAN), including IgA vasculitis (IgAV). This study describes the clinical characteristics and treatment patterns in the IgA cohort, including comparisons between IgAN versus IgAV and adult versus pediatric patients. METHODS: Patients with a diagnostic kidney biopsy within 5 years of screening were eligible to join CureGN. This is a descriptive analysis of clinical and treatment data collected at the time of enrollment. RESULTS: A total of 667 patients (506 IgAN, 161 IgAV) constitute the IgAN/IgAV cohort (382 adults, 285 children). At biopsy, those with IgAV were younger (13.0 years vs. 29.6 years, P < 0.001), more frequently white (89.7% vs. 78.9%, P = 0.003), had a higher estimated glomerular filtration rate (103.5 vs. 70.6 ml/min per 1.73 m2, P < 0.001), and lower serum albumin (3.4 vs. 3.8 g/dl, P < 0.001) than those with IgAN. Adult and pediatric individuals with IgAV were more likely than those with IgAN to have been treated with immunosuppressive therapy at or prior to enrollment (79.5% vs. 54.0%, P < 0.001). CONCLUSION: This report highlights clinical differences between IgAV and IgAN and between children and adults with these diagnoses. We identified differences in treatment with immunosuppressive therapies by disease type. This description of baseline characteristics will serve as a foundation for future CureGN studies.

Alemtuzumab induction with tacrolimus monotherapy in 25 pediatric renal transplant recipients.

ALA induction in transplantation has been shown to reduce the need for maintenance immunosuppression. We report the outcome of 25 pediatric renal transplants between 2007 and 2010 using ALA induction followed by tacrolimus maintenance monotherapy. Patient ages were 1-19 yr (mean 14 ± 4.1 yr). Time of follow-up was 7-51 months (mean 26 ± 13 months). Tacrolimus monotherapy was maintained in 48% of patients, and glucocorticoids were avoided in 80% of recipients. Mean plasma creatinine and GFR at one yr post-transplant were 0.88 ± 0.3 mg/dL and 104.4 ± 25 mL/min/1.73m(2) , respectively. One, two, and three-yr actuarial patient and graft survival rates were 100%. The incidence of early AR (<12 months after transplantation) was 12%, while the incidence of late AR (after 12 months) was 16%. Forty-four percent of the recipients recovered normal, baseline renal function after an episode of AR, and 44% had persistent renal dysfunction (plasma creatinine 1.0-1.8 mg/dL). One graft was lost four yr after transplantation due to medication non-compliance. Four (16%) patients developed BK or CMV infection. In our experience, ALA induction with tacrolimus monotherapy resulted in excellent short- and mid-term patient and graft survival in low-immunologic risk pediatric renal transplant recipients.

Hepatosplenomegaly and reticulocytopenia as prominent features of atypical hemolytic uremic syndrome.

This is a case of atypical hemolytic uremic syndrome (HUS) due to invasive pneumococcal disease in which the prominent clinical features were reticulocytopenia and hepatosplenomegaly, leading to the incorrect initial diagnosis of acute leukemia. Delayed diagnosis of HUS, especially in atypical cases, can lead to increased morbidity and mortality. Atypical HUS must be part of the differential diagnosis of children who present with clinical characteristics suggestive of a hematologic malignancy with associated renal injury.

Leptospirosis mimicking hemolytic uremic syndrome: a case report.

Leptospirosis was diagnosed in a child presenting with acute kidney injury, anemia, and thrombocytopenia. Initial symptoms included abdominal pain and nonbloody diarrhea, followed by fever, vomiting, and skin rash. Leptospirosis was suspected and eventually confirmed. Although leptospirosis is uncommon in temperate climates, it is occurring in increasing numbers of participants in water sports, making it a consideration in the differential diagnosis of hemolytic uremic syndrome.

Simple multicystic dysplastic kidney disease: end points for subspecialty follow-up.

Simple multicystic dysplastic kidney (MCDK) disease, defined as unilateral MCDK without other genitourinary tract involvement, portends an excellent prognosis. Nevertheless, its long-term management remains undefined. This study aims to provide subspecialty discharge recommendations for these patients. We identified eighty patients with simple MCDK disease by renal ultrasound between 1996 and 2006. Their charts were reviewed for growth of the contralateral kidney, involution of the MCDK, and incidence of complications, specifically hypertension, chronic renal insufficiency (CRI), urinary tract infection (UTI), and malignancy. Mean follow-up was 5 years. At approximately 1 year, 59% of unaffected kidneys were hypertrophied (>or=95th percentile for age/height) and 100% were >50th percentile. With continued follow-up, 80.3% of unaffected kidneys were hypertrophied. Likewise, at 1 year, 71.2% of MCDKs assessed were either involuting or had disappeared; on further follow-up, this increased to 89.6%. No patient had hypertension, CRI, or malignancy. Four patients (5%) developed nonrecurrent UTIs, none leading to renal scarring or growth impairment. These data suggest that subspecialty follow-up may be discontinued once contralateral hypertrophy and ipsilateral involution occur, assuming that the patient has not experienced hypertension, CRI, or UTI. These criteria are often met by 1 year of age, which would preclude repeated visits, uncomfortable investigations, and unnecessary costs.

The risk of cardiovascular disease in adults who have had childhood nephrotic syndrome.

While increased risk of cardiovascular disease (CVD) in patients with hyperlipidemia, chronic kidney disease (CKD), or end-stage renal disease (ESRD) is well documented, transient hyperlipidemia or intermittent renal disease as a consequence of relapsing nephrotic syndrome (NS) has not been studied. To investigate this enigma, 62 patients, between 25 and 53 years of age, who had steroid-responsive/dependent NS during childhood, were identified from the records of the Division of Pediatric Nephrology at Yale School of Medicine. Forty patients were located and contacted to ascertain symptoms or occurrences of CVD via a telephone interview. At the time of follow-up, 23-46 years after cessation of NS, none of these patients had ESRD or CKD. Three patients had experienced a myocardial infarction (MI): a 32-year-old male with a family history of CVD; a 41-year-old male with a history of heavy smoking, hypertension, diabetes mellitus, and elevated cholesterol; a 31-year-old male after a cocaine overdose. The occurrence of events (8%) and mortality from CVD (none) in this cohort of patients is comparable to patients of a similar age in the general population and is lower than that of patients of the same age who are on dialysis. The data suggest that relapsing NS during childhood does not place patients at increased risk for CVD mortality or morbidity compared with the general population. Consequently, it would appear that factors related to persistent proteinuria or renal insufficiency, rather than transient proteinuria and renal disease, contribute to the CVD documented in patients with CKD or ESRD.