Urinary sphingolipids in adolescents and young adults with youth-onset diabetes.

BACKGROUND: This study evaluated urinary sphingolipids as a marker of diabetic kidney disease (DKD) in adolescents and young adults with youth-onset type 1 and type 2 diabetes. METHODS: A comprehensive panel of urinary sphingolipids, including sphingomyelin (SM), glucosylceramide (GC), ceramide (Cer), and lactosylceramide (LC) species, was performed in patients with youth-onset diabetes from the SEARCH for Diabetes in Youth cohort. Sphingolipid levels, normalized to urine creatinine, were compared in 57 adolescents and young adults with type 1 diabetes, 59 with type 2 diabetes, and 44 healthy controls. The association of sphingolipids with albumin-to-creatinine (ACR) ratio and estimated glomerular filtration rate (eGFR) was evaluated. RESULTS: The median age (interquartile range [IQR]) of participants was 23.1 years (20.9, 24.9) and the median duration of diabetes was 9.3 (8.5, 10.2) years. Urinary sphingolipid concentrations in patients with and without DKD (ACR ≥ 30 mg/g) were significantly elevated compared to healthy controls. There were no significant differences in sphingolipid levels between participants with type 1 and type 2 diabetes. In multivariable analysis, many sphingolipid species were positively correlated with ACR. Most significant associations were evident for the following species: C18 SM, C24:1 SM, C24:1 GC, and C24:1 Cer (all p < 0.001). Sphingolipid levels were not associated with eGFR. However, several interaction terms (diabetes type*sphingolipid) were significant, indicating diabetes type may modify the association of sphingolipids with eGFR. CONCLUSION: Urinary sphingolipids are elevated in adolescents and young adults with youth-onset diabetes and correlate with ACR. Urinary sphingolipids may therefore represent an early biomarker of DKD.

Early microvascular complications in type 1 and type 2 diabetes: recent developments and updates.

The prevalence of youth-onset diabetes is progressing rapidly worldwide, and poor glycemic control, in combination with prolonged diabetes duration and comorbidities including hypertension, has led to the early development of microvascular complications including diabetic kidney disease, retinopathy, and neuropathy. Pediatric populations with type 1 (T1D) and type 2 (T2D) diabetes are classically underdiagnosed with microvascular complications, and this leads to both undertreatment and insufficient attention to the mitigation of risk factors that could help attenuate further progression of complications and decrease the likelihood for long-term morbidity and mortality. This narrative review aims to present a comprehensive summary of the epidemiology, risk factors, symptoms, screening practices, and treatment options, including future opportunities for treatment advancement, for microvascular complications in youth with T1D and T2D. We seek to uniquely focus on the inherent challenges of managing pediatric populations with diabetes and discuss the similarities and differences between microvascular complications in T1D and T2D, while presenting a strong emphasis on the importance of early identification of at-risk youth. Further investigation of possible treatment mechanisms for microvascular complications in youth with T1D and T2D through dedicated pediatric outcome trials is necessary to target the brief window where early pathological vascular changes may be significantly attenuated.

Diagnostic Considerations in H1N1 Influenza-induced Thrombotic Microangiopathy.

Influenza virus can trigger atypical hemolytic uremic syndrome and present with complement-driven thrombotic microangiopathy (TMA). When administered promptly, complement-blocking therapies can spare organ injury and be lifesaving. However, diagnosing TMA in the setting of a severe viral infection can be challenging, as a significant overlap of symptoms and disease complications exists. This is particularly true in influenza virus infections and more recently, Coronavirus disease 2019 (COVID-19) infections. We present a 16-year-old male with H1N1 influenza-induced atypical hemolytic uremic syndrome who quickly improved with complement-blocking therapy, highlighting an urgent need to include TMA in the differential diagnosis of severe viral infections.

Agreement between serum estimates of glomerular filtration rate (GFR) and a reference standard of radioisotopic GFR in children with cancer.

BACKGROUND: Accurate assessment of renal function is important in the care of children with cancer because renal function has implications for anti-tumor medication dosing and eligibility for clinical trials. OBJECTIVE: To characterize agreement between serum estimates of glomerular filtration rate (GFR) and a reference standard of radioisotopic GFR in a large pediatric oncology cohort. MATERIALS AND METHODS: We conducted a retrospective cross-sectional study of children who had both radioisotopic GFR (99mTc-diethylenetriaminepentaacetic acid, or 99mTc-DTPA) and serum labs (creatinine, cystatin C) obtained <7 days apart between January 2017 and August 2019. We calculated estimated GFR from serum labs using published equations and calculated agreement using intraclass correlation coefficient (ICC) and Bland-Altman analysis with univariate regression to define predictors of agreement. RESULTS: We included 272 pairs of data. Mean patient age was (mean ± standard deviation) 7.8±5.7 years. Mean radioisotopic GFR was 112±33 mL/min/1.73 m2. Absolute agreement between radioisotopic GFR and serum estimates was only fair (ICC=0.46-0.58) with a mean difference of -26.6 to +0.12 mL/min/1.73 m2. For radioisotopic GFR measurements <60 mL/min/1.73 m2, mean differences were greater, with serum estimates overestimating GFR by a mean of 21.5-39.6 mL/min/1.73 m2. In multivariable modeling, significant predictors of agreement included age, height, acute kidney injury and tumor type. Sensitivity of serum estimates was 14-29% for a GFR <60 mL/min/1.73 m2. CONCLUSION: Agreement between radioisotopic GFR and serum estimates of GFR is only fair and serum estimates of GFR have poor sensitivity for clinically relevant GFR <60 mL/min/1.73 m2. Radioisotopic measurement of GFR likely remains necessary to assess renal function in pediatric oncology patients with decreased renal function.

Composite Health Outcomes in Pediatric and Young Adult Kidney Transplant Recipients.

OBJECTIVE: To assess composite health outcomes in pediatric and young adult kidney transplant recipients following kidney transplantation. STUDY DESIGN: We conducted a cross-sectional study of all recipients at our center who had a 1-, 3-, 5-, and/or 10-year transplant anniversary visit between October 2008 and February 2015. The kidney transplant recipients were assessed at each time point according to an outcome measure consisting of 15 pass/fail criteria in 5 domains: allograft health, rejection and immunology, infection, cardiovascular health, and growth. RESULTS: We analyzed 148 patients at 231 transplantation anniversary visit time points; 52 of 82 (63%) patients assessed at 1 year had an ideal outcome, meeting at least 13 of the 15 criteria. This decreased to 37% at year 3, 40% at year 5, and 26% at year 10 (P < .01). The most common failures across all time points occurred in the domains of growth (43%-52% passing) and cardiovascular health (33%-51% passing). Allograft health declined significantly, decreasing from 74% at year 1 to 33% at year 10 (P < .01). The percentage of patients with graft failure increased from 2.4% at 1 year to 39.5% at 10 years (P < .01), and patient deaths increased from 0 to 11% (P < .01) in the same time frame. CONCLUSIONS: Ideal outcomes for pediatric kidney transplant recipients decrease over time with growth, cardiovascular health, and allograft health as the primary failure modes. Understanding the composite health of young recipients will allow primary care providers and nephrologists alike to evaluate the overall health of kidney transplant recipients and focus clinical care on the most common sequelae.

Estimating heterogeneous treatment effects for latent subgroups in observational studies.

Individuals may vary in their responses to treatment, and identification of subgroups differentially affected by a treatment is an important issue in medical research. The risk of misleading subgroup analyses has become well known, and some exploratory analyses can be helpful in clarifying how covariates potentially interact with the treatment. Motivated by a real data study of pediatric kidney transplant, we consider a semiparametric Bayesian latent model and examine its utility for an exploratory subgroup effect analysis using secondary data. The proposed method is concerned with a clinical setting where the number of subgroups is much smaller than that of potential predictors and subgroups are only latently associated with observed covariates. The semiparametric model is flexible in capturing the latent structure driven by data rather than dictated by parametric modeling assumptions. Since it is difficult to correctly specify the conditional relationship between the response and a large number of confounders in modeling, we use propensity score matching to improve the model robustness by balancing the covariates distribution. Simulation studies show that the proposed analysis can find the latent subgrouping structure and, with propensity score matching adjustment, yield robust estimates even when the outcome model is misspecified. In the real data analysis, the proposed analysis reports significant subgroup effects on steroid avoidance in kidney transplant patients, whereas standard proportional hazards regression analysis does not.

Kidney outcomes three years after bariatric surgery in severely obese adolescents.

A significant number of severely obese adolescents undergoing bariatric surgery have evidence of early kidney damage. To determine if kidney injury is reversible following bariatric surgery, we investigated renal outcomes in the Teen-Longitudinal Assessment of Bariatric Surgery cohort, a prospective multicenter study of 242 severely obese adolescents undergoing bariatric surgery. Primary outcomes of urine albumin-to-creatinine ratio and cystatin C-based estimated glomerular filtration rate (eGFR) were evaluated preoperatively and up to 3 years following bariatric surgery. At surgery, mean age of participants was 17 years and median body mass index (BMI) was 51 kg/m2. In those with decreased kidney function at baseline (eGFR under 90 mL/min/1.73m2), mean eGFR significantly improved from 76 to 102 mL/min/1.73m2 at three-year follow-up. Similarly, participants with albuminuria (albumin-to-creatinine ratio of 30 mg/g and more) at baseline demonstrated significant improvement following surgery: geometric mean of ACR was 74 mg/g at baseline and decreased to 17 mg/g at three years. Those with normal renal function and no albuminuria at baseline remained stable throughout the study period. Among individuals with a BMI of 40 kg/m2 and more at follow-up, increased BMI was associated with significantly lower eGFR, while no association was observed in those with a BMI under 40 kg/m2. In adjusted analysis, eGFR increased by 3.9 mL/min/1.73m2 for each 10-unit loss of BMI. Early kidney abnormalities improved following bariatric surgery in adolescents with evidence of preoperative kidney disease. Thus, kidney disease should be considered as a selection criteria for bariatric surgery in severely obese adolescents who fail conventional weight management.

Graft survival of pediatric kidney transplant recipients selected for de novo steroid avoidance-a propensity score-matched study.

BACKGROUND: Steroid-avoidance protocols have gained popularity in pediatric kidney transplant recipients at low immunologic risk. The long-term safety of steroid avoidance in children with immunologic risk factors remains unknown. METHODS: Pediatric kidney transplant recipients from 2004 to 2014 in the Organ Procurement and Transplantation Network database who received tacrolimus and mycophenolate immunosuppression were investigated. Propensity score matching was used to compare graft survival in 1624 children who received steroid avoidance with 1624 children who received steroid-based immunosuppression. The effect of steroid avoidance on graft failure among immunologic risk strata was estimated using Cox proportional hazards regression in this propensity score-matched cohort. RESULTS: It was observed that 5-year graft survival was mildly improved in children receiving steroid avoidance (84.8% versus 81.2%, P = 0.03). This improvement in graft survival occurred in the first 2 years following transplant, when the hazard ratio (HR) for allograft failure in children receiving steroid avoidance was 0.62 [95% confidence interval (CI) 0.45-0.86]. In contrast, steroid avoidance was not associated with improved allograft survival during Years 2-10 following transplant (HR = 0.93; 95% CI 0.75-1.15). During this time period, HRs (95% CIs) for allograft failure within immunologic risk strata were not significantly different from the null value of 1: repeat kidney transplants, 1.84 (0.84-4.05); African-Americans, 1.02 (0.67-1.56); sensitized recipients, 1.24 (0.63-2.43); recipients of deceased donor kidneys, 1.02 (0.79-1.32); recipients of completely human leukocyte antigen-mismatched kidneys, 0.80 (0.47-1.37); and recipients with pretransplant glomerular disease, 0.94 (0.71-1.23). CONCLUSIONS: In pediatric kidney transplant recipients receiving tacrolimus- and mycophenolate-based immunosuppression, steroid avoidance can be safely practiced in children with immunologic risk factors.

Masked hypertension and allograft function in pediatric and young adults kidney transplant recipients.

Masked hypertension is a common complication of pediatric kidney transplantation. While office hypertension is known to be associated with worse short- and long-term graft function, the role of masked hypertension in allograft dysfunction is not clear. We conducted a retrospective cross-sectional analysis of 77 consecutive pediatric kidney transplant recipients who had routine 24-h ambulatory blood pressure monitoring with the aims to estimate the prevalence of masked hypertension and examine its association with allograft function. Masked hypertension was defined as a 24-h systolic or diastolic blood pressure load ≥25%. Twenty-nine percent of patients had masked hypertension. Patients with masked hypertension had significantly lower allograft function estimated using the creatinine-based Schwartz-Lyon formula, a cystatin C-based formula, and combined cystatin C and creatinine-based formulas than patients with normal blood pressure (all p values <0.05). In a multivariable analysis, masked hypertension remained independently associated with worse allograft function after adjustment for age, sex, race, time post-transplant, rejection history, antihypertensive treatment, and hemoglobin level. We conclude that in young kidney transplant recipients, masked hypertension is common and is associated with worse allograft function. These results support the case for routine ambulatory blood pressure monitoring as the standard of care in these patients to detect and treat masked hypertension.

Kidney transplantation in children with decreased left ventricular systolic function: a Midwest Pediatric Nephrology Consortium study.

BACKGROUND: Left ventricular (LV) systolic dysfunction is a relatively uncommon but serious complication of pediatric chronic kidney disease, and may be related to uremia and uncontrolled hypertension. There is limited information on the strategy for managing these children. In some cases, combined heart-kidney transplant may be considered or kidney transplant delayed until cardiac function improves. It is unknown whether these patients are at increased risk for poor outcomes after kidney transplantation. METHODS: We conducted a retrospective, multicenter study on the outcomes of children with severe and symptomatic cardiomyopathy who underwent kidney transplantation. RESULTS: Eleven patients receiving maintenance dialysis with systolic dysfunction underwent kidney transplantation without simultaneous heart transplant. Nine patients had congestive heart failure in the pre-transplant period. There were no identified complications post-transplant related to the underlying cardiac dysfunction. LV systolic function normalized in all patients and the mean shortening fraction increased from 19.0 ± 4.6 % to 32.0 ± 4.4 % (p < 0.0001). CONCLUSIONS: Kidney transplantation should be considered for children receiving maintenance dialysis with severe LV dysfunction.

Performance of cystatin C-based equations in a pediatric cohort at high risk of kidney injury.

BACKGROUND: Limited data exist on the performance of cystatin C-based glomerular filtration rate (GFR) equations in pediatric transplant recipients and other high-risk patients. The aim of our study was therefore to evaluate the performance of current cystatin C-based equations in this population. METHODS: This was a retrospective, cross-sectional study of 141 consecutive patients (58 % post-transplant) who received a nuclear medicine GFR (NucGFR) examination using (99m)Tc- diethylenetriaminepentaacetic acid at our institution. Subjects included children receiving liver, kidney or hematopoietic stem cell transplants and patients with oncologic or urologic disease. GFR estimates using published GFR estimating equations, including those based on cystatin C (Filler, Zappitelli, Larsson, Hoek, Rule and Le Bricon equations, respectively) and on both cystatin C and creatinine (Zappitelli, Bouvet and Schwartz equations, respectively), were evaluated and compared to the NucGFR measurement using Bland-Altman analysis. RESULTS: The mean NucGFR was 95 (interquartile range 76-111) ml/min/1.73 m(2). Of the cystatin C-based equations, the Rule, Hoek, Zappitelli and Schwartz (2009 CKiD equation) formulas provided the closest agreement to the NucGFR estimate. All other formulas overestimated the GFR in our cohort. CONCLUSION: Cystatin C-based GFR formulas can provide an accurate estimation of NucGFR in a pediatric population with a high proportion of transplant recipients and oncology patients.

GFR Estimation After Cystatin C Reference Material Change.

INTRODUCTION: Glomerular filtration rate (GFR) is routinely estimated with cystatin C. In June 2010, the International Federation of Clinical Chemistry (IFCC) released a certified cystatin C reference material (ERM-DA471/IFCC), and new cystatin C glomerular filtration rate estimation (eGFR) equations were developed with the IFCC standard. Early in 2018, Siemens discontinued their nonstandardized cystatin C reagent kits and replaced them with IFCC-calibrated kits in the US market. The aim of the current study was to assess the effect of IFCC calibration on cystatin C values and corresponding GFR estimations. METHODS: Cystatin C concentration was measured in 81 pediatric patients using a plasma sample from their nuclear GFR measurement with 99mTc-diethylenetriaminepentaaccetic acid. Calibration curves were generated using Siemens nonstandardized and IFCC-standardized kits to measure paired cystatin C concentrations in each sample. GFR-estimating equations using pre-IFCC and IFCC cystatin C values were compared using Bland-Altman analyses. RESULTS: The IFCC-standardized assay resulted in a mean increase in the measured cystatin C value of 24%. Estimating equations consistently overestimated GFR prior to IFCC standardization. Following incorporation of the IFCC standard, the Full Age Spectrum equation demonstrated the best overall performance, whereas the Chronic Kidney Disease in Children (CKiD) equation was more accurate in children with decreased GFR. CONCLUSION: Incorporation of the IFCC standard significantly increased cystatin C values and affected the performance of GFR estimating equations. Clinical laboratories and providers may need to update the equation used for cystatin C-based estimation of GFR following adoption of the IFCC reference standard.

Ambulatory Blood Pressure Control in Children and Young Adults After Kidney Transplantation.

BACKGROUND: Ambulatory blood pressure (BP) monitoring (ABPM) is the preferred method to characterize BP status, and its use in kidney transplant recipients is increasing. Data on longitudinal ambulatory BP (ABP) trends in pediatric and young adult kidney transplant recipients are limited. METHODS: Retrospective review of a large cohort of children and young adults following kidney transplantation and evaluation of their ABP status over time and its associations with any patient and clinical characteristics. RESULTS: Two hundred and two patients had baseline ABPM available for analysis, and 123 of them had a follow up (median time 2.3 years) ABPM. At the time of follow up, more patients were treated for hypertension (80% vs. 72%, P = 0.02), and less patients had ambulatory hypertension (36% vs. 54%, P = 0.005), uncontrolled or untreated, compared with baseline, with 45% of all patients classified as having controlled hypertension (compared to 26% at baseline, P = 0.002). Prevalence of ambulatory hypertension decreased only in patients who were less than 18 years old at baseline. High baseline mean 24-hour systolic BP was independently associated with persistent hypertension. CONCLUSIONS: In young kidney transplant recipients followed by ABPM, the prevalence of ambulatory hypertension decreases over time, mainly due to the increased number of patients with controlled hypertension.

Ambulatory Blood Pressure, Left Ventricular Hypertrophy, and Allograft Function in Children and Young Adults After Kidney Transplantation.

BACKGROUND: Hypertension is a common complication and is an important risk factor for graft loss and adverse cardiovascular outcomes in pediatric kidney transplantation. Ambulatory blood pressure monitoring (ABPM) is the preferred method to characterize blood pressure status. METHODS: We conducted a retrospective review of a large cohort of children and young adults with kidney transplant to estimate the prevalence of abnormal ambulatory blood pressure (ABP), assess factors associated with abnormal ABP, and examine whether ambulatory hypertension is associated with worse allograft function and left ventricular hypertrophy (LVH). RESULTS: Two hundred twenty-one patients had ABPM, and 142 patients had echocardiographic results available for analysis. One third of the patients had masked hypertension, 32% had LVH, and 38% had estimated glomerular filtration rate less than 60 mL/min per 1.73 m. African-American race/Hispanic ethnicity and requirement for more than 1 antihypertensive medication were independently associated with having masked hypertension. In a multivariate analysis, abnormal blood pressure (masked or sustained hypertension combined) was an independent predictor for LVH among patients not receiving antihypertensive treatment (P = 0.025). In a separate analysis, the use of antihypertensive medications was independently associated with worse allograft function (P = 0.002) although abnormal blood pressure was not a significant predictor. CONCLUSIONS: In young kidney transplant recipients, elevated ABP is frequently unrecognized and undertreated. The high prevalence of abnormal ABP, including masked hypertension, and its association with LVH supports the case for routine ABPM and cardiac structure evaluation as the standard of care in these patients.

Pharmacokinetics of meropenem in children receiving continuous renal replacement therapy: Validation of clinical trial simulations.

Meropenem is frequently prescribed in critically ill children receiving continuous renal replacement therapy (CRRT). We previously used clinical trial simulations to evaluate dosing regimens of meropenem in this population and reported that a dose of 20 mg/kg every 12 hours optimizes target attainment. Meropenem pharmacokinetics were investigated in this prospective, open-label study to validate our previous in silico predictions. Seven patients received meropenem (13.8-22 mg/kg) administered intravenously every 12 hours as part of standard care. A mean dose of 18.6 mg/kg of meropenem was administered, resulting in a mean peak concentration of 80.1 µg/mL. Meropenem volume of distribution was 0.35 ± 0.085 L/kg. CRRT clearance was 40.2 ± 6.6 mL/(min · 1.73 m(2) ) and accounted for 63.4% of the total clearance of 74.8 ± 36.9 mL/(min · 1.73 m(2) ). Simulations demonstrated that a dose of 20 mg/kg every 12 hours resulted in a time above the minimum inhibitory concentration (%fT > MIC) of 100% in 5 out of 7 subjects, with a %fT > MIC of 93% and 43% in the remaining 2 subjects. We conclude that CRRT contributed significantly to the total clearance of meropenem. A dosing regimen of 20 mg/kg achieved good target attainment in critically ill children receiving CRRT, which is consistent with our previously published in silico predictions.

Meropenem in children receiving continuous renal replacement therapy: clinical trial simulations using realistic covariates.

Meropenem is frequently prescribed in children receiving continuous renal replacement therapy (CRRT). Fluid overload is often present in critically ill children and affects drug disposition. The purpose of this study was to develop a pharmacokinetic model to (1) evaluate target attainment of meropenem dosing regimens against P. aeruginosa in children receiving CRRT and (2) estimate the effect of fluid overload on target attainment. Clinical trial simulations were employed to evaluate target attainment of meropenem in various age groups and degrees of fluid overload in children receiving CRRT. Pharmacokinetic parameters were extracted from published literature, and 287 patients from the prospective pediatric CRRT registry database provided realistic clinical covariates including patient weight, fluid overload, and CRRT prescription characteristics. Target attainment at 40% and 75% time above the minimum inhibitory concentration was evaluated. Clinical trial simulations demonstrated that children greater than 5 years of age achieved acceptable target attainment with a dosing regimen of 20 mg/kg every 12 hours. In children less than 5, however, increased dosing of 20 mg/kg every 8 hours was needed to optimize target attainment. Fluid overload did not affect target attainment. These in silico model predictions will need to be verified in vivo in children receiving meropenem and CRRT.

Focal segmental glomerulosclerosis in children: multivariate analysis indicates that donor type does not alter recurrence risk.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS), the second leading cause of end stage renal disease in children, appears to be increasing. Moreover, posttransplantation FSGS recurrence is a major problem, and there is concern that children receiving kidneys from living donors (LD) have increased recurrence risk. METHODS: Data from the United Network for Organ Sharing from 1988 to 2008 were analyzed for number of de novo transplant recipients with a primary diagnosis of FSGS in children 1 to 20 years of age. Poisson regression was used for trend analysis. Univariate and multivariable logistic regression analyses were performed to examine the association of gender, race, human leukocyte antigen matching, age, and donor type with recurrence. RESULTS: Trend analysis of kidney transplantations for FSGS in children (n=2157) showed an increase in cases of 5.8% per year or 209% over 20 years (P<0.0001). Recurrence was reported in 327 (15%) cases overall, with a preponderance for white recipients (P<0.001) in younger age subgroups (P<0.01). Donor type was significant (P=0.02), with recurrence reported in 17% versus 14% of recipients of kidneys from LDs versus deceased donors. Using multivariate analysis, recipients' young age (P=0.02) and white race (P<0.001) were identified as significant risk factors for recurrence, whereas receiving a LD kidney became insignificant. CONCLUSIONS: FSGS as a cause of pediatric end-stage renal disease leading to transplantation is on the rise. FSGS recurrence is highest in young, white children, whereas receiving a LD kidney is not independently associated with increased risk of recurrence.