Responding to the workforce crisis: consensus recommendations from the Second Workforce Summit of the American Society of Pediatric Nephrology.

IMPORTANCE: Pediatric patients with complex medical problems benefit from pediatric sub-specialty care; however, a significant proportion of children live greater than 80 mi. away from pediatric sub-specialty care. OBJECTIVE: To identify current knowledge gaps and outline concrete next steps to make progress on issues that have persistently challenged the pediatric nephrology workforce. EVIDENCE REVIEW: Workforce Summit 2.0 employed the round table format and methodology for consensus building using adapted Delphi principles. Content domains were identified via input from the ASPN Workforce Committee, the ASPN's 2023 Strategic Plan survey, the ASPN's Pediatric Nephrology Division Directors survey, and ongoing feedback from ASPN members. Working groups met prior to the Summit to conduct an organized literature review and establish key questions to be addressed. The Summit was held in-person in November 2023. During the Summit, work groups presented their preliminary findings, and the at-large group developed the key action statements and future directions. FINDINGS: A holistic appraisal of the effort required to cover inpatient and outpatient sub-specialty care will help define faculty effort and time distribution. Most pediatric nephrologists practice in academic settings, so work beyond clinical care including education, research, advocacy, and administrative/service tasks may form a substantial amount of a faculty member's time and effort. An academic relative value unit (RVU) may assist in creating a more inclusive assessment of their contributions to their academic practice. Pediatric sub-specialties, such as nephrology, contribute to the clinical mission and care of their institutions beyond their direct billable RVUs. Advocacy throughout the field of pediatrics is necessary in order for reimbursement of pediatric sub-specialist care to accurately reflect the time and effort required to address complex care needs. Flexible, individualized training pathways may improve recruitment into sub-specialty fields such as nephrology. CONCLUSIONS AND RELEVANCE: The workforce crisis facing the pediatric nephrology field is echoed throughout many pediatric sub-specialties. Efforts to improve recruitment, retention, and reimbursement are necessary to improve the care delivered to pediatric patients.

Safety and infectious outcomes in pediatric kidney transplant recipients after COVID-19 vaccination: A pediatric nephrology research consortium study.

BACKGROUND: Adult kidney transplant recipients (KTRs) fully vaccinated against COVID-19 have substantial morbidity and mortality related to SARS-CoV-2 infection compared with the general population. However, little is known regarding the safety and efficacy of the COVID-19 vaccination series in pediatric KTRs. METHODS: A multicenter, retrospective observational study was performed across nine pediatric transplantation centers. Eligible KTRs fully vaccinated against COVID-19 were enrolled and data were collected pertaining to SARS-CoV-2 infection incidence and severity, graft outcomes and post-vaccination safety profile, as well as overall patient survival. RESULTS: A total of 247 patients were included in this investigation with a median age at transplantation of 11 years (IQR 5-15). SARS-CoV-2 infection was observed in 30/110 (27.27%) of fully vaccinated patients, tested post-transplant, within the defined follow-up period. Of these patients, 6/30 (18.18%) required hospitalization and 3/30 (12.12%) required reduction in immunosuppression, with no reported deaths. De novo donor-specific antibodies (DSAs) were found in 8/86 (9.30%) of DSA-tested patients with two experiencing rejection and subsequent graft loss. The overall incidence of rejection and graft loss among the total cohort was 11/247 (4.45%) and 6/247 (3.64%), respectively. A 100% patient survival was observed. CONCLUSIONS: Observationally, infectious outcomes of SARS-CoV-2 in fully vaccinated pediatric KTRs are excellent, with a low incidence of infection requiring hospitalization and no associated deaths. Though de novo DSAs were observed, there was minimal graft rejection and graft loss reported in the total cohort.

Pharmacological management of youth with type 2 diabetes and diabetic kidney disease: a comprehensive review of current treatments and future directions.

INTRODUCTION: Diabetic kidney disease (DKD) is a leading cause of mortality in people with type 2 diabetes (T2D), and over 50% of individuals with youth-onset T2D will develop DKD as a young adult. Diagnosis of early-onset DKD remains a challenge in young persons with T2D secondary to a lack of available biomarkers for early DKD, while the injuries may still be reversible. Furthermore, multiple barriers exist to initiate timely prevention and treatment strategies for DKD, including a lack of Food and Drug Administration approval of medications in pediatrics; provider comfort with medication prescription, titration, and monitoring; and medication adherence. AREAS COVERED: Therapies that have promise for slowing DKD progression in youth with T2D include metformin, renin-angiotensin-aldosterone system inhibitors, glucagon-like peptide-1 receptor agonists, sodium glucose co-transporter 2 inhibitors, thiazolidinediones, sulfonylureas, endothelin receptor agonists, and mineralocorticoid antagonists. Novel agents are also in development to act synergistically on the kidneys with the aforementioned medications. We comprehensively review the available pharmacologic strategies for DKD in youth-onset T2D including mechanisms of action, potential adverse effects, and kidney-specific effects, with an emphasis on published pediatric and adult trials. EXPERT OPINION: Large clinical trials evaluating pharmacologic interventions targeting the treatment of DKD in youth-onset T2D are strongly needed.

Rates of Cardiovascular Disease and CKD Progression in Young Adults with CKD across Racial and Ethnic Groups.

Background: Significant racial and ethnic disparities in cardiovascular (CV) and kidney function outcomes in older adults with chronic kidney disease (CKD) have been reported. However, little is known about the extent to which these disparities exist in patients with CKD during the foundational period of young adulthood. The objective of this study was to determine risk factors and rates of CV disease and CKD progression in young adults with CKD across racial and ethnic groups. Methods: We studied all participants aged 21-40 years of age enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study (n=317). Baseline CV risk factors were described across racial and ethnic groups. Results: Outcomes included CV events or death (first incidence of heart failure, myocardial infarction, and stroke or death) and CKD progression (>50% decline in eGFR from baseline or end stage kidney disease [ESKD]). Incidence rate ratios (IRRs) were compared as a secondary analysis for participants identifying as Black or Hispanic with those identifying as White or another race and ethnicity. Adjusted models included age, sex, and per APOL1 high-risk allele. CV risk factors were higher in Black and Hispanic participants, including mean SBP, BMI, median UACr, and LDL. Black and Hispanic participants had higher incidence rates of HF (17.5 versus 5.1/1000 person-years), all-cause mortality (15.2 versus 7.1/1000 person-years), and CKD progression (125 versus 59/1000 person-years). Conclusions: In conclusion, we found a higher prevalence of CV risk factors, some modifiable, in young adults with CKD who identify as Black or Hispanic. Future strategies to ameliorate the racial and ethnic inequality in health outcomes earlier in life for patients with CKD should be prioritized.

Major adverse kidney events after acute kidney injury in the pediatric intensive care unit: a propensity score-matched cohort study.

BACKGROUND: Acute kidney injury (AKI) in patients admitted to the pediatric intensive care unit (PICU) is associated with poor short-term and long-term outcomes. Greater awareness of long-term AKI-associated outcomes is needed to optimally plan follow-up and management after ICU discharge. We used propensity score methods to study associations between pediatric AKI and major adverse kidney outcomes, including mortality. METHODS: We included all children 6 months-18 years admitted to PICU at Seattle Children's Hospital from 7/1/2009 to 12/31/2018. Our primary outcome measure was Major Adverse Kidney Events at 30 days (MAKE30): creatinine > 200% of baseline, eGFR < 60 mL/min/1.73 m2, dialysis dependence, or mortality. Propensity scores for AKI development in PICU were generated using demographic, medical history, admission, and PICU hospitalization variables. Patients with AKI were matched to control patients without AKI. Logistic regression was used to test association between AKI status and MAKE30. RESULTS: In the unmatched cohort (n = 878), patients with AKI had lower platelet count (160 vs. 222) and higher PRISM III score (11 vs. 3.5). After propensity score matching, those with AKI vs. no AKI had similar PRISM III scores (9 vs. 10) and platelet count (163 vs. 159). AKI was significantly associated with MAKE30 after propensity score matching (OR: 2.97; 95% CI 1.82-4.84). CONCLUSIONS: Propensity score matching significantly reduced imbalance in baseline characteristics between those with and without AKI. After matching, AKI remained significantly associated with MAKE30. Patients who developed AKI were more likely to have abnormal kidney function at 30 and 90 days after ICU admission and may be at high risk for developing CKD in the future. A higher resolution version of the Graphical abstract is available as Supplementary information.

Considerations and possibilities for sodium-glucose cotransporter 2 inhibitors in pediatric CKD.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) were originally developed as glucose-lowering agents. These medications function by inhibiting glucose and sodium reabsorption in the S1 segment of the proximal tubule. Early clinical trials in adults with type 2 diabetes mellitus (T2DM) suggested a significant improvement in kidney and cardiovascular outcomes with SGLT2i therapy. Since then, SGLT2is have become a mainstay treatment for adult patients with CKD. A growing body of research has explored deploying these medications in new clinical contexts and investigated the mechanisms underlying their physiologic effects. However, patients under the age of 18 years have been largely excluded from all major trials of SGLT2i. This review aims to summarize the available clinical evidence, physiology, and mechanisms relating to SGLT2is to inform discussions about their implementation in pediatrics.

BP in Young Adults with CKD and Associations with Cardiovascular Events and Decline in Kidney Function.

BACKGROUND: BP is an important modifiable risk factor for cardiovascular events and CKD progression in middle-aged or older adults with CKD. However, studies describing the relationship between BP with outcomes in young adults with CKD are limited. METHODS: In an observational study, we focused on 317 young adults (aged 21-40 years) with mild to moderate CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Exposures included baseline systolic BP evaluated continuously (per 10 mm Hg increase) and in categories (<120, 120-129, and ≥130 mm Hg). Primary outcomes included cardiovascular events (heart failure, myocardial infarction, stroke, or all-cause death) and CKD progression (50% decline of eGFR or ESKD). We used Cox proportional hazard models to test associations between baseline systolic BP with cardiovascular events and CKD progression. RESULTS: Cardiovascular events occurred in 52 participants and 161 had CKD progression during median follow-up times of 11.3 years and 4.1 years, respectively. Among those with baseline systolic BP ≥130 mm Hg, 3%/yr developed heart failure, 20%/yr had CKD progression, and 2%/yr died. In fully adjusted models, baseline systolic BP ≥130 mm Hg (versus systolic BP<120 mm Hg) was significantly associated with cardiovascular events or death (hazard ratio [HR], 2.13; 95% confidence interval [95% CI], 1.05 to 4.32) and CKD progression (HR, 1.68; 95% CI, 1.10 to 2.58). CONCLUSIONS: Among young adults with CKD, higher systolic BP is significantly associated with a greater risk of cardiovascular events and CKD progression. Trials of BP management are needed to test targets and treatment strategies specifically in young adults with CKD.

Association of circulating cardiac biomarkers with electrocardiographic abnormalities in chronic kidney disease.

BACKGROUND: Among patients with chronic kidney disease (CKD), the circulating cardiac biomarkers soluble ST2 (SST2), galectin-3, growth differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin-T (hsTnT) possibly reflect pathophysiologic processes and are associated with clinical cardiovascular disease. Whether these biomarkers are associated with electrocardiographic findings is not known. The aim of this study was to test the association between serum cardiac biomarkers and the presence of electrocardiographic changes potentially indicative of subclinical myocardial disease in patients with CKD. METHODS: We performed a cross-sectional analysis using 3048 participants from the Chronic Renal Insufficiency Cohort (CRIC) without atrial fibrillation, atrioventricular block, bundle branch block or a pacemaker at the baseline visit. Using logistic regression, we tested the association of each of the five cardiac biomarkers with baseline electrocardiogram (ECG) findings: PR interval >200 ms, QRS interval >100 ms and a prolonged QTc interval. Models were adjusted for demographic variables, measures of kidney function, prevalent cardiovascular disease and cardiovascular risk factors. RESULTS: In adjusted models, hsTnT levels associated with prolonged PR {odds ratio [OR] 1.23 [95% confidence interval (CI) 1.08-1.40]}, QRS [OR 1.28 (95% CI 1.16-1.42)] and QTc [OR 1.94 (95% CI 1.50-2.51)] intervals. NT-proBNP levels were associated with prolonged QRS [OR 1.11 (95% CI 1.06-1.16)] and QTc [OR 1.82 (95% CI 1.58-2.10)] intervals. SST2, galectin-3 and GDF-15 were not significantly associated with any of the ECG parameters. CONCLUSIONS: hsTnT and NT-proBNP were associated with ECG measures indicative of subclinical myocardial dysfunction. These results may support future research investigating the significance of myocardial ischemia and volume overload in the pathogenesis of dysfunctional myocardial conduction in CKD.

The Impact of Donor and Recipient Renal Dysfunction on Cardiac Allograft Survival: Insights Into Reno-Cardiac Interactions.

BACKGROUND: Renal dysfunction (RD) is a potent risk factor for death in patients with cardiovascular disease. This relationship may be causal; experimentally induced RD produces findings such as myocardial necrosis and apoptosis in animals. Cardiac transplantation provides an opportunity to investigate this hypothesis in humans. METHODS AND RESULTS: Cardiac transplantations from the United Network for Organ Sharing registry were studied (n = 23,056). RD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m(2). RD was present in 17.9% of donors and 39.4% of recipients. Unlike multiple donor characteristics, such as older age, hypertension, or diabetes, donor RD was not associated with recipient death or retransplantation (age-adjusted hazard ratio [HR] = 1.00, 95% confidence interval [CI] 0.94-1.07, P = .92). Moreover, in recipients with RD the highest risk for death or retransplantation occurred immediately posttransplant (0-30 day HR = 1.8, 95% CI 1.54-2.02, P < .001) with subsequent attenuation of the risk over time (30-365 day HR = 0.92, 95% CI 0.77-1.09, P = .33). CONCLUSIONS: The risk for adverse recipient outcomes associated with RD does not appear to be transferrable from donor to recipient via the cardiac allograft, and the risk associated with recipient RD is greatest immediately following transplant. These observations suggest that the risk for adverse outcomes associated with RD is likely primarily driven by nonmyocardial factors.

Influence of Titration of Neurohormonal Antagonists and Blood Pressure Reduction on Renal Function and Decongestion in Decompensated Heart Failure.

BACKGROUND: Reduction in systolic blood pressure (SBP reduction) during the treatment of acute decompensated heart failure is strongly and independently associated with worsening renal function. Our objective was to determine whether SBP reduction or titration of oral neurohormonal antagonists during acute decompensated heart failure treatment negatively influences diuresis and decongestion. METHODS AND RESULTS: SBP reduction was evaluated from admission to discharge in consecutive acute decompensated heart failure admissions (n=656). Diuresis and decongestion were examined across a range of parameters, such as diuretic efficiency, fluid output, hemoconcentration, and diuretic dose. The average reduction in SBP was 14.4 ± 19.4 mm Hg, and 77.6% of the population had discharge SBP lower than admission. SBP reduction was strongly associated with worsening renal function (odds ratio, 1.9; 95% confidence interval, 1.2-2.9; P=0.004), a finding that persisted after adjusting for parameters of diuresis and decongestion (odds ratio, 2.0; 95% confidence interval, 1.3-3.2; P=0.002). However, SBP reduction did not negatively affect diuresis or decongestion (P ≥ 0.25 for all parameters). Uptitration of neurohormonal antagonists occurred in >50% of admissions and was associated with a modest additional reduction in blood pressure (≤ 5.6 mm Hg). Notably, worsening renal function was not increased, and diuretic efficiency was significantly improved with the uptitration of neurohormonal antagonists. CONCLUSIONS: Despite a higher rate of worsening renal function, blood pressure reduction was not associated with worsening of diuresis or decongestion. Furthermore, titration of oral neurohormonal antagonists was actually associated with improved diuresis in this cohort. These results provide reassurance that the guideline-recommended titration of chronic oral medication during acute decompensated heart failure hospitalization may not be antagonistic to the short-term goal of decongestion.

Evidence of Mild Liver Dysfunction Identifies Stable Heart Failure Outpatients with Reversible Renal Dysfunction.

BACKGROUND: In decompensated heart failure (HF), reversible renal dysfunction (RD) is more frequently observed in patients with mild liver dysfunction likely due to the shared pathophysiologic factors involved. The objective of this study was to determine if these findings also apply to stable HF outpatients. METHODS: Patients in the Beta-Blocker Evaluation of Survival Trial (BEST) were studied. Improvement in renal function (IRF) was defined as a 20% improvement in the estimated glomerular filtration rate from baseline to 3 months. RESULTS: Elevated bilirubin (BIL), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were significantly associated with signs of congestion or poor perfusion. IRF occurred in 12.0% of all patients and was more common in those with elevated BIL (OR = 1.5, p = 0.003), ALT (OR = 1.4, p = 0.01), and AST (OR = 1.4, p = 0.01). In a model containing all 3 liver parameters and baseline characteristics, including markers of congestion/poor perfusion, BIL (OR = 1.6, p = 0.001) and ALT (OR = 1.7, p < 0.001) were independently associated with IRF. CONCLUSIONS: Biochemical evidence of mild liver dysfunction is significantly associated with IRF in stable HF outpatients. Given the widespread availability and low cost of these markers, additional research is necessary to determine the utility of these parameters in identifying patients with reversible RD who may benefit from cardiorenal interventions.

A combined-biomarker approach to clinical phenotyping renal dysfunction in heart failure.

BACKGROUND: Differentiating heart failure (HF) induced renal dysfunction (RD) from intrinsic kidney disease is challenging. It has been demonstrated that biomarkers such as B-type natriuretic peptide (BNP) or the blood urea nitrogen to creatinine ratio (BUN/creat) can identify high- vs low-risk RD. Our objective was to determine if combining these biomarkers could further improve risk stratification and clinical phenotyping of patients with RD and HF. METHODS AND RESULTS: A total of 908 patients with a discharge diagnosis of HF were included. Median values were used to define elevated BNP (>1296 pg/mL) and BUN/creat (>17). In the group without RD, survival was similar regardless of BNP and BUN/creat (n = 430, adjusted P = .52). Similarly, in patients with both a low BNP and BUN/creat, RD was not associated with mortality (n = 250, adjusted hazard ratio [HR] = 1.0, 95% confidence interval [CI] 0.6-1.6, P = .99). However, in patients with both an elevated BNP and BUN/creat those with RD had a cardiorenal profile characterized by venous congestion, diuretic resistance, hypotension, hyponatremia, longer length of stay, greater inotrope use, and substantially worse survival compared with patients without RD (n = 249, adjusted HR = 1.8, 95% CI 1.2-2.7, P = .008, P interaction = .005). CONCLUSIONS: In the setting of decompensated HF, the combined use of BNP and BUN/creat stratifies patients with RD into groups with significantly different clinical phenotypes and prognosis.

Influence of age-related versus non-age-related renal dysfunction on survival in patients with left ventricular dysfunction.

Normal aging results in a predictable decrease in glomerular filtration rate (GFR), and low GFR is associated with worsened survival. If this survival disadvantage is directly caused by the low GFR, as opposed to the disease causing the low GFR, the risk should be similar regardless of the underlying mechanism. Our objective was to determine if age-related decreases in estimated GFR (eGFR) carry the same prognostic importance as disease-attributable losses in patients with ventricular dysfunction. We analyzed the Studies Of Left Ventricular Dysfunction limited data set (n = 6,337). The primary analysis focused on determining if the eGFR-mortality relation differed by the extent to which the eGFR was consistent with normal aging. Mean eGFR was 65.7 ml/min/1.73 m(2) (SD = 19.0). Across the range of age in the population (27 to 80 years), baseline eGFR decreased by 0.67 ml/min/1.73 m(2)/year (95% confidence interval [CI] 0.63 to 0.71). The risk of death associated with eGFR was strongly modified by the degree to which the low eGFR could be explained by aging (p for interaction <0.0001). For example, in a model incorporating the interaction, uncorrected eGFR was no longer significantly related to mortality (adjusted hazard ratio 1.0 per 10 ml/min/1.73 m(2), 95% CI 0.97 to 1.1, p = 0.53), whereas a disease-attributable decrease in eGFR above the median carried significant risk (adjusted hazard ratio 2.8, 95% CI 1.6 to 4.7, p <0.001). In conclusion, in the setting of left ventricular dysfunction, renal dysfunction attributable to normal aging had a limited risk for mortality, suggesting that the mechanism underlying renal dysfunction is critical in determining prognosis.