Patient-Reported Outcomes Over 24 Months in Pediatric CKD: Findings From the MyKidneyHealth Cohort Study.

2023

03/2023

1523-6838

RATIONALE AND OBJECTIVE: The lived experience of children with chronic kidney disease (CKD) is poorly characterized. We examined the associations between patient-reported outcomes (PROs) measuring children's fatigue, sleep health, psychological distress, family relationships, and global health with clinical outcomes over time in children with CKD and investigated how PROs of children with CKD compare with those of other children.

STUDY DESIGN: Prospective cohort study.

SETTING AND PARTICIPANTS: 212 children 8-21 years-old with CKD and their parents recruited from 16 nephrology programs across North America.

PREDICTORS: CKD stage, disease etiology, sociodemographic and clinical variables.

OUTCOMES: PROs over 2 years.

ANALYTICAL APPROACH: We compared PROs in the CKD sample with a nationally representative general pediatric population. Change of PROs over time and association of sociodemographic and clinical variables with PROs were assessed using multivariable regression models.

RESULTS: 84% parents and 77% children completed PROs at all time points. Baseline PRO scores for children with CKD revealed higher burden of fatigue, sleep-related impairment, psychological distress, impaired global health, and poorer family relationships compared with the general pediatric population, with median score differences ≥ one standard deviation for fatigue and global health. Baseline PRO scores did not differ by CKD stage or glomerular vs. non-glomerular etiology. Over two years, PROs were stable with < 1-point annual change on average on each measure and intraclass correlation coefficients ranging 0.53 to 0.79, indicating high stability. Hospitalization and parent-reported sleep problems were associated with worse fatigue, psychological health and global health scores (all p<0.04).

LIMITATIONS: Unable to assess responsiveness to change with dialysis or transplant.

CONCLUSIONS: Children with CKD experience high, yet stable burden of impairment across numerous PRO measures, especially fatigue and global health, independent of disease severity. These findings underscore the importance of assessing PRO, including fatigue and sleep measures, in this vulnerable population.

10.1053/j.ajkd.2022.12.014

Am J Kidney Dis

36889426

Evaluating Kidney Function Decline in Children with Chronic Kidney Disease Using a Multi-Institutional Electronic Health Record Database.

2023

173-182

02/2023

1555-905X

BACKGROUND: The objectives of this study were to use electronic health record data from a US national multicenter pediatric network to identify a large cohort of children with CKD, evaluate CKD progression, and examine clinical risk factors for kidney function decline.

METHODS: This retrospective cohort study identified children seen between January 1, 2009, to February 28, 2022. Data were from six pediatric health systems in PEDSnet. We identified children aged 18 months to 18 years who met criteria for CKD: two eGFR values <90 and ≥15 ml/min per 1.73 m2 separated by ≥90 days without an intervening value ≥90. CKD progression was defined as a composite outcome: eGFR <15 ml/min per 1.73 m2, ≥50% eGFR decline, long-term dialysis, or kidney transplant. Subcohorts were defined based on CKD etiology: glomerular, nonglomerular, or malignancy. We assessed the association of hypertension (≥2 visits with hypertension diagnosis code) and proteinuria (≥1 urinalysis with ≥1+ protein) within 2 years of cohort entrance on the composite outcome.

RESULTS: Among 7,148,875 children, we identified 11,240 (15.7 per 10,000) with CKD (median age 11 years, 50% female). The median follow-up was 5.1 (interquartile range 2.8-8.3) years, the median initial eGFR was 75.3 (interquartile range 61-83) ml/min per 1.73 m2, 37% had proteinuria, and 35% had hypertension. The following were associated with CKD progression: lower eGFR category (adjusted hazard ratio [aHR] 1.44 [95% confidence interval (95% CI), 1.23 to 1.69], aHR 2.38 [95% CI, 2.02 to 2.79], aHR 5.75 [95% CI, 5.05 to 6.55] for eGFR 45-59 ml/min per 1.73 m2, 30-44 ml/min per 1.73 m2, 15-29 ml/min per 1.73 m2 at cohort entrance, respectively, when compared with eGFR 60-89 ml/min per 1.73 m2), glomerular disease (aHR 2.01 [95% CI, 1.78 to 2.28]), malignancy (aHR 1.79 [95% CI, 1.52 to 2.11]), proteinuria (aHR 2.23 [95% CI, 1.89 to 2.62]), hypertension (aHR 1.49 [95% CI, 1.22 to 1.82]), proteinuria and hypertension together (aHR 3.98 [95% CI, 3.40 to 4.68]), count of complex chronic comorbidities (aHR 1.07 [95% CI, 1.05 to 1.10] per additional comorbid body system), male sex (aHR 1.16 [95% CI, 1.05 to 1.28]), and younger age at cohort entrance (aHR 0.95 [95% CI, 0.94 to 0.96] per year older).

CONCLUSIONS: In large-scale real-world data for children with CKD, disease etiology, albuminuria, hypertension, age, male sex, lower eGFR, and greater medical complexity at start of follow-up were associated with more rapid decline in kidney function.

10.2215/CJN.0000000000000051

Clin J Am Soc Nephrol

36754006

Using Machine Learning to Identify Metabolomic Signatures of Pediatric Chronic Kidney Disease Etiology.

2022

375-386

2022 Feb

1533-3450

<p><strong>BACKGROUND: </strong>Untargeted plasma metabolomic profiling combined with machine learning (ML) may lead to discovery of metabolic profiles that inform our understanding of pediatric CKD causes. We sought to identify metabolomic signatures in pediatric CKD based on diagnosis: FSGS, obstructive uropathy (OU), aplasia/dysplasia/hypoplasia (A/D/H), and reflux nephropathy (RN).</p>

<p><strong>METHODS: </strong>Untargeted metabolomic quantification (GC-MS/LC-MS, Metabolon) was performed on plasma from 702 Chronic Kidney Disease in Children study participants (: FSGS=63, OU=122, A/D/H=109, and RN=86). Lasso regression was used for feature selection, adjusting for clinical covariates. Four methods were then applied to stratify significance: logistic regression, support vector machine, random forest, and extreme gradient boosting. ML training was performed on 80% total cohort subsets and validated on 20% holdout subsets. Important features were selected based on being significant in at least two of the four modeling approaches. We additionally performed pathway enrichment analysis to identify metabolic subpathways associated with CKD cause.</p>

<p><strong>RESULTS: </strong>ML models were evaluated on holdout subsets with receiver-operator and precision-recall area-under-the-curve, F1 score, and Matthews correlation coefficient. ML models outperformed no-skill prediction. Metabolomic profiles were identified based on cause. FSGS was associated with the sphingomyelin-ceramide axis. FSGS was also associated with individual plasmalogen metabolites and the subpathway. OU was associated with gut microbiome-derived histidine metabolites.</p>

<p><strong>CONCLUSION: </strong>ML models identified metabolomic signatures based on CKD cause. Using ML techniques in conjunction with traditional biostatistics, we demonstrated that sphingomyelin-ceramide and plasmalogen dysmetabolism are associated with FSGS and that gut microbiome-derived histidine metabolites are associated with OU.</p>

10.1681/ASN.2021040538

J Am Soc Nephrol

35017168

Decreased Neural Connectivity in the Default Mode Network Among Youth and Young Adults With Chronic Kidney Disease.

2021

455-461

2021 Sep

1558-4488

<p>An increasing amount of literature has indicated that chronic kidney disease (CKD) is associated with cognitive deficits that increase with worsening disease severity. Although abnormalities in brain structure have been widely documented, few studies to date have examined the functioning of brain areas associated with the specific cognitive domains affected by CKD (namely, attention and executive functions). Furthermore, few studies have examined functional connectivity among CKD youth who are relatively early in the course of the disease. The present study used functional magnetic resonance imaging to examine the resting state connectivity in 67 youth with CKD (mean age, 17 y) and 58 age-matched healthy controls. Using seed-based multiple regression, decreased connectivity was observed within the anterior cingulate portion of the default mode network. In addition, decreased connectivity within the dorsolateral prefrontal cortex, paracingulate gyrus, and frontal pole were correlated significantly with disease severity. These data indicate that connectivity deficits in circuits implementing attentional processes may represent an early marker for cognitive decline in CKD.</p>

10.1016/j.semnephrol.2021.09.008

Semin Nephrol

34916007

Using a Multi-Institutional Pediatric Learning Health System to Identify Systemic Lupus Erythematosus and Lupus Nephritis: Development and Validation of Computable Phenotypes.

2021

2021 Nov 03

1555-905X

<p><strong>BACKGROUND AND OBJECTIVES: </strong>Performing adequately powered clinical trials in pediatric diseases, such as SLE, is challenging. Improved recruitment strategies are needed for identifying patients.</p>

<p><strong>DESIGN, SETTING, PARTICIPANTS, &amp; MEASUREMENTS: </strong>Electronic health record algorithms were developed and tested to identify children with SLE both with and without lupus nephritis. We used single-center electronic health record data to develop computable phenotypes composed of diagnosis, medication, procedure, and utilization codes. These were evaluated iteratively against a manually assembled database of patients with SLE. The highest-performing phenotypes were then evaluated across institutions in PEDSnet, a national health care systems network of &gt;6.7 million children. Reviewers blinded to case status used standardized forms to review random samples of cases (=350) and noncases (=350).</p>

<p><strong>RESULTS: </strong>Final algorithms consisted of both utilization and diagnostic criteria. For both, utilization criteria included two or more in-person visits with nephrology or rheumatology and ≥60 days follow-up. SLE diagnostic criteria included absence of neonatal lupus, one or more hydroxychloroquine exposures, and either three or more qualifying diagnosis codes separated by ≥30 days or one or more diagnosis codes and one or more kidney biopsy procedure codes. Sensitivity was 100% (95% confidence interval [95% CI], 99 to 100), specificity was 92% (95% CI, 88 to 94), positive predictive value was 91% (95% CI, 87 to 94), and negative predictive value was 100% (95% CI, 99 to 100). Lupus nephritis diagnostic criteria included either three or more qualifying lupus nephritis diagnosis codes (or SLE codes on the same day as glomerular/kidney codes) separated by ≥30 days or one or more SLE diagnosis codes and one or more kidney biopsy procedure codes. Sensitivity was 90% (95% CI, 85 to 94), specificity was 93% (95% CI, 89 to 97), positive predictive value was 94% (95% CI, 89 to 97), and negative predictive value was 90% (95% CI, 84 to 94). Algorithms identified 1508 children with SLE at PEDSnet institutions (537 with lupus nephritis), 809 of whom were seen in the past 12 months.</p>

<p><strong>CONCLUSIONS: </strong>Electronic health record-based algorithms for SLE and lupus nephritis demonstrated excellent classification accuracy across PEDSnet institutions.</p>

10.2215/CJN.07810621

Clin J Am Soc Nephrol

34732529

Urine Biomarkers of Kidney Tubule Health, Injury, and Inflammation are Associated with Progression of CKD in Children.

2021

2021 Sep 20

1533-3450

<p><strong>BACKGROUND: </strong>Novel urine biomarkers may improve identification of children at greater risk of rapid kidney function decline, and elucidate the pathophysiology of CKD progression.</p>

<p><strong>METHODS: </strong>We investigated the relationship between urine biomarkers of kidney tubular health (EGF and -1 microglobulin), tubular injury (kidney injury molecule-1; KIM-1), and inflammation (monocyte chemoattractant protein-1 [MCP-1] and YKL-40) and CKD progression. The prospective CKD in Children Study enrolled children aged 6 months to 16 years with an eGFR of 30-90ml/min per 1.73m. Urine biomarkers were assayed a median of 5 months [IQR: 4-7] after study enrollment. We indexed the biomarker to urine creatinine by dividing the urine biomarker concentration by the urine creatinine concentration to account for the concentration of the urine. The primary outcome was CKD progression (a composite of a 50% decline in eGFR or kidney failure) during the follow-up period.</p>

<p><strong>RESULTS: </strong>Overall, 252 of 665 children (38%) reached the composite outcome over a median follow-up of 6.5 years. After adjustment for covariates, children with urine EGF concentrations in the lowest quartile were at a seven-fold higher risk of CKD progression versus those with concentrations in the highest quartile (fully adjusted hazard ratio [aHR], 7.1; 95% confidence interval [95% CI], 3.9 to 20.0). Children with urine KIM-1, MCP-1, and -1 microglobulin concentrations in the highest quartile were also at significantly higher risk of CKD progression versus those with biomarker concentrations in the lowest quartile. Addition of the five biomarkers to a clinical model increased the discrimination and reclassification for CKD progression.</p>

<p><strong>CONCLUSIONS: </strong>After multivariable adjustment, a lower urine EGF concentration and higher urine KIM-1, MCP-1, and -1 microglobulin concentrations were each associated with CKD progression in children.</p>

10.1681/ASN.2021010094

J Am Soc Nephrol

34544821

Potential benefits of functional magnetic resonance urography (fMRU) over MAG3 renal scan in children with obstructive uropathy.

2021

2021 Jul 10

1873-4898

<p><strong>INTRODUCTION: </strong>Functional renal imaging, most commonly with MAG3 nuclear medicine renal scan, is recommended in the evaluation of children with urinary tract dilation (UTD) suspected of obstructive uropathy. Alternatively, renal function can be evaluated with functional Magnetic Resonance Urography (fMRU), which has superior anatomic detail. However, there are not enough data comparing both methods' equivalency. In this study, we compare the functional and obstruction parameters of fMRU and MAG3 in a pediatric cohort presenting with obstructive uropathy.</p>

<p><strong>STUDY DESIGN: </strong>This is an IRB-approved retrospective review of all children undergoing fMRU at a single, free-standing children's hospital between May 2008 and September 2017. Patients who also underwent a MAG3 renal scan within 6 months and who had no interval surgical intervention were included in the study. Bladder catheterization was performed prior to both imaging studies.</p>

<p><strong>RESULTS: </strong>735 children had 988 fMRU studies performed during the study period. 37 unique patients (13 girls and 24 boys) with median age of 6 months (range: 2 mo-19&nbsp;y) were included in the final sample. Median time interval between studies was 70 days (range 6-179 days). The majority of participants (26/37, 70.3%) presented with UTD P3 and had diagnosis of uretero-pelvic junction obstruction (UPJO) in 21/37. Differential renal function (DRF) was used to group 10 fMRU and 9 MAG3 patients as normal; 9 fMRU and 11 MAG3 as mild; 11 fMRU and 6 MAG3 as moderate; and 7 fMRU and 6 MAG3 as severe; Wilcoxon signed-rank test (p&nbsp;=&nbsp;0.5106). Results were similar for DRF among patients with and without duplex kidneys. In the analysis of obstruction, using reference standard T½ MAG3&nbsp;≥&nbsp;20&nbsp;min, a greater or equal than 6&nbsp;min renal transit time (RTT) from fMRU showed a specificity of 94%, a sensitivity of 62%, and an AUC of 0.827.</p>

<p><strong>DISCUSSION AND CONCLUSIONS: </strong>The differential renal function determined by MAG3 and fMRU in children was not statistically different, therefore we concluded that it was similar and potentially equivalent. Better correlation was shown in patients who had normal split kidney function. While the tests are clinically equivalent, the variability of DRF within each clinical category (i.e., normal, mild, moderate, severe) is not surprising, because MAG3 does not clearly differentiate the dilated collecting system from the functional parenchymal tissue, while fMRU does. Using MAG3 as the gold standard, fMRU was 94.74% specific and 5% more sensitive in detecting UPJO with a RTT of 6min vs. 8min.</p>

10.1016/j.jpurol.2021.07.005

J Pediatr Urol

34426090

Race and Ethnicity Predict Bone Markers and Fracture in Pediatric Patients With Chronic Kidney Disease.

2021

298-304

2021 02

1523-4681

<p>Studies in healthy children have shown racial-ethnic differences in bone markers and bone outcomes including fractures. At present, limited studies have evaluated the impact of race and ethnicity on bone markers and fractures within the pediatric chronic kidney disease (CKD) population. In a cohort study of 762 children between the ages of 1.5 years and 18 years, with CKD stages 1 to 4 from the CKD in children (CKiD) cohort, the relationship between racial-ethnic group and bone markers (parathyroid hormone [PTH], 25-hydroxyvitamin D [25-OHD], 1,25-dihydroxyvitamin D [1,25(OH) D], and C-terminal fibroblast growth factor [FGF23]) was determined using linear mixed models. Additionally, logistic regression was used to evaluate racial-ethnic differences in prevalent fracture upon study entry. Black race was associated with 23% higher PTH levels (confidence interval [CI], 2.5% to 47.7%; p = .03), 33.1% lower 25-OHD levels (CI, -39.7% to -25.7%; p &lt; .0001), and no difference in C-terminal FGF23 or 1,25(OH) D levels when compared to whites. Hispanic ethnicity was associated with 15.9% lower C-terminal FGF23 levels (CI, -28.3% to -1.5%; p = .03) and 13.8% lower 25-OHD levels (CI, -22.2% to -4.5%; p = .005) when compared to whites. Black and Hispanic children had 74% (odds ratio [OR] 0.26; CI, 0.14 to 0.49; p = .001) and 66% (OR 0.34; CI, 0.17 to 0.65; p &lt; .0001) lower odds of any fracture than white children at study entry, respectively. Race and ethnicity are associated with differences in bone markers and despite lower 25-OHD levels, both black and Hispanic children with CKD reported a lower prevalent fracture history than white children. The current findings in the CKD population are similar to racial-ethnic differences described in healthy children. Additional studies are needed to better understand how these differences might impact the management of pediatric CKD-MBD. © 2020 American Society for Bone and Mineral Research (ASBMR).</p>

10.1002/jbmr.4182

J Bone Miner Res

32960469

Metabolite Biomarkers of CKD Progression in Children.

2021

1178-1189

2021 Aug

1555-905X

<p><strong>BACKGROUND AND OBJECTIVES: </strong>Metabolomics facilitates the discovery of biomarkers and potential therapeutic targets for CKD progression.</p>

<p><strong>DESIGN, SETTING, PARTICIPANTS, &amp; MEASUREMENTS: </strong>We evaluated an untargeted metabolomics quantification of stored plasma samples from 645 Chronic Kidney Disease in Children (CKiD) participants. Metabolites were standardized and logarithmically transformed. Cox proportional hazards regression examined the association between 825 nondrug metabolites and progression to the composite outcome of KRT or 50% reduction of eGFR, adjusting for age, sex, race, body mass index, hypertension, glomerular versus nonglomerular diagnosis, proteinuria, and baseline eGFR. Stratified analyses were performed within subgroups of glomerular/nonglomerular diagnosis and baseline eGFR.</p>

<p><strong>RESULTS: </strong>Baseline characteristics were 391 (61%) male; median age 12 years; median eGFR 54 ml/min per 1.73 m; 448 (69%) nonglomerular diagnosis. Over a median follow-up of 4.8 years, 209 (32%) participants developed the composite outcome. Unique association signals were identified in subgroups of baseline eGFR. Among participants with baseline eGFR ≥60 ml/min per 1.73 m, two-fold higher levels of seven metabolites were significantly associated with higher hazards of KRT/halving of eGFR events: three involved in purine and pyrimidine metabolism (N6-carbamoylthreonyladenosine, hazard ratio, 16; 95% confidence interval, 4 to 60; 5,6-dihydrouridine, hazard ratio, 17; 95% confidence interval, 5 to 55; pseudouridine, hazard ratio, 39; 95% confidence interval, 8 to 200); two amino acids, C-glycosyltryptophan, hazard ratio, 24; 95% confidence interval 6 to 95 and lanthionine, hazard ratio, 3; 95% confidence interval, 2 to 5; the tricarboxylic acid cycle intermediate 2-methylcitrate/homocitrate, hazard ratio, 4; 95% confidence interval, 2 to 7; and gulonate, hazard ratio, 10; 95% confidence interval, 3 to 29. Among those with baseline eGFR &lt;60 ml/min per 1.73 m, a higher level of tetrahydrocortisol sulfate was associated with lower risk of progression (hazard ratio, 0.8; 95% confidence interval, 0.7 to 0.9).</p>

<p><strong>CONCLUSIONS: </strong>Untargeted plasma metabolomic profiling facilitated discovery of novel metabolite associations with CKD progression in children that were independent of established clinical predictors and highlight the role of select biologic pathways.</p>

10.2215/CJN.00220121

Clin J Am Soc Nephrol

34362785

Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

2021

115-126

2021 01

1533-3450

<p><strong>BACKGROUND: </strong>Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals.</p>

<p><strong>METHODS: </strong>In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of &lt;60 ml/min per 1.73 m at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change.</p>

<p><strong>RESULTS: </strong>Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline.</p>

<p><strong>CONCLUSIONS: </strong>Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.</p>

10.1681/ASN.2020040487

J Am Soc Nephrol

33122288