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Accurate detection of hypertension is crucial for clinical management of pediatric chronic kidney disease (CKD). The 2017 American Academy of Pediatrics childhood hypertension guidelines included new normative blood pressure (BP) values and revised definitions of BP categories. In this study, we examined the effect of applying these changes to the Chronic Kidney Disease in Children (CKiD) cohort compared to use of the 2004 Fourth Report normative data and definitions.Observational cohort study.Children and adolescents in the CKiD cohort.Clinic blood pressure measurements.Blood pressure percentiles and hypertension stages calculated using the 2017 and 2004 guidelines.Agreement analysis compared the estimated percentile and prevalence of high blood pressure based on the 2017 and 2004 guidelines to clinic and combined ambulatory blood pressure readings.The proportion of children classified as having normal clinic blood pressure was similar using the 2017 and 2004 guidelines, but the use of the 2017 normative data classified more participants as having hypertensive-range blood pressure (22% vs. 11%) with marginal reproducibility (kappa= 0.569, 95%CI: 0.538, 0.599). Those identified as hypertensive by the 2017 guidelines had higher levels of proteinuria compared to those identified using the 2004 guidelines. There were substantially more participants with white coat and ambulatory hypertension when using the 2017 guidelines (3.5% vs. 1.5%; and 15.5% vs. 7.9%, respectively). The proportion with masked hypertension was lower using the 2017 guidelines (40.2% vs. 47.8%, respectively) with good reproducibility (kappa= 0.799, 95%CI: 0.778, 0.819), and the percentage of participants with normal ambulatory blood pressure was similar (40.9% vs. 42.9%, respectively), LIMITATIONS: Relationship with long-term progression and target organ damage was not assessed.A greater percentage of children with CKD were identified as hypertensive based on both clinic and ambulatory blood pressure when using the 2017 vs. the 2004 guidelines, and the 2017 guidelines better discriminated those with higher levels of proteinuria. The substantial differences in the classification of hypertension when using the 2004 vs. 2017 guidelines should inform clinical care.

Recent reassessment of the use of race in estimated glomerular filtration rate (eGFR) in adults has instigated questions about the role of race in eGFR expressions for children. Little research has examined the associations of self-reported race with measured GFR (mGFR) adjusting for serum creatinine or cystatin C in children and young adults with chronic kidney disease (CKD). This study examined these associations and evaluated the performance of the previously published "U25" (under the age of 25 years) eGFR equations in a large cohort of children and young adults with CKD.Observational cohort study.Participants in the Chronic Kidney Disease in Children (CKiD) study including 190 Black and 675 non-Black participants contributing 473 and 1,897 annual person-visits, respectively.Self- or parental-reported race (Black, non-Black). Adjustment for serum creatinine or cystatin C, body size, and socioeconomic status.mGFR based on iohexol clearance.Linear regression with generalized estimating equations, stratified by age (6, 6-12, 12-18, and ≥18 years) incorporating serum creatinine or serum cystatin C. Contrasting performance in different self-reported racial groups of the U25 eGFR equations.Self-reported Black race was significantly associated with 12.8% higher mGFR among children in regression models including serum creatinine. Self-reported Black race was significantly associated with 3.5% lower mGFR after adjustment for cystatin C overall but was not significant for those over 12 years. The results were similar after adjustment for body size and socioeconomic factors. The average of creatinine- and cystatin C-based U25 equations was unbiased by self-reported race groups.Small number of children 6 years; lean body mass was estimated.Differences in the creatinine-mGFR relationship by self-reported race were observed in children and young adults with CKD and were consistent with findings in adults. Smaller and opposite differences were observed for the cystatin C-mGFR relationship, especially in the younger age group. We recommend inclusion of children for future investigations of biomarkers to estimate GFR. Importantly, for GFR estimation among those under 25 years of age, the average of the new U25 creatinine and cystatin C equations without race coefficients yields unbiased estimates of mGFR.

RATIONALE & OBJECTIVE: The KDIGO (Kidney Disease: Improving Global Outcomes) guideline on CKD presented an international classification system that ranks patients' risk for CKD progression. Few data on children informed guideline development STUDY DESIGN: Observational cohort study SETTINGS AND PARTICIPANTS: Children aged 1-18 years enrolled in the North American Chronic Kidney Disease in Children (CKiD) cohort study and the European Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) trial. PREDICTOR: Level of estimated glomerular filtration rate (eGFR) and proteinuria (urine protein-creatinine ratio (mg/mg)) at study entry OUTCOME: A composite event of renal replacement therapy, 50% reduction of estimated GFR (eGFR), or eGFR 2.0 at study entry. Six ordered stages with varying combinations of eGFR categories (60-89, 45-59, 30-44 and 15-29 ml/min/1.73m(2)) and UPCR categories (2.0) described the risk continuum. Median times to event ranged from >10 years for eGFR 45-90 and UPCR 2. Children with glomerular disease were estimated to have a 43% shorter time to event than children with nonglomerular disease. Cross-validation demonstrated risk patterns that were consistent across the ten subsample validation models. LIMITATIONS: Observational study, utilized cross validation rather than external validation CONCLUSION: CKD staged by level of eGFR and proteinuria characterizes the timeline of progression and can guide management strategies in children.

Middle-molecules (MM) are not monitored in children on hemodialysis (HD), but are accumulated and increase the risk of cardiovascular disease and mortality. Molecular properties of Cystatin C (CyC), 13 kDa, potentially make it a preferred MM marker over Beta-2-Microglobulin (B2M), 12 kDa. We compared CyC and B2M kinetics to investigate if CyC can be used as preferred MM marker. CyC (mg/L) and B2M (μg/mL) were measured in 21 low-flux HD sessions in seven children. Blood samples were taken at HD start (pre), 1 and 2 hours into HD and at end of HD (post) for all sessions and 60 minutes after the first HD (Eq). PreCyC (9.85 ± 2.15) did not differ (P > 0.05) from postCyC (10.04 ± 2.83). PostB2M (38.87 ± 7.12) was higher (P 0.05), while EqB2M was lower than postB2M (36.48 ± 7.68 vs. 41.09 ± 8.99, P < 0.05). MMs as represented by B2M and CyC are elevated in children on standard HD. Intensified HD modalities would be needed for their removal. B2M is affected by the dialytic process with a rise during HD independent of ultrafiltration and decrease 1 hour after, while CyC remains unchanged. We suggest that CyC be used as preferred marker of MM removal and as a marker of adequacy of intensified HD regimens.

Cystatin C (CyC) concentration has been suggested as a marker of middle-molecule accumulation, hemodialysis (HD) adequacy and for estimating residual renal function (RRF), but it has not been studied in pediatric HD. High CyC is associated with increased cardiovascular disease (CVD). We investigated CyC kinetics and the effect of RRF on CyC in a pediatric HD population. A total of 21 HD sessions and 20 interdialytic periods were analyzed in seven patients, age 5–19 years, of whom four were anuric (A) and three were non-anuric (NA). CyC was measured before (preHD) and after (postHD) three standard HD sessions in 1 week and prior to the first session of the following week. We found no difference (p = 0.67) in CyC concentration between preHD CyC (9.85 ± 2.15 mg/l; A vs. NA, p = 0.37) and postHD CyC (10.04 ± 2.83 mg/l; A vs NA, p = 0.28). The weekly average preHD CyC median concentration was 10.14 mg/l (A vs. NA, p = 0.87) and correlated with age (r = 0.808, p = 0.03) and height measurement (r = 0.799, p = 0.03), but not with RRF, single-pool Kt/V, ultrafiltration, HD duration or blood liters processed. Cystatin C is very elevated in children on HD. It does not rise between HD sessions, is not removed by standard HD and remains at steady state; therefore, elimination is extrarenal. Low RRF does not affect CyC elimination. CyC increases with age and height. If a high CyC concentration can be proven to have a causative role in the development of CVD, routine intensified HD regimens in children may be indicated for its removal.

Objective: To report a case of hyperphosphatemia associated with administration of intravenous clindamycin phosphate in a child with renal dysfunction. Case Summary: We describe the case of a 12-year-old boy who developed hyperphosphatemia while receiving intravenous clindamycin phosphate. The child had a history of asthma but was otherwise healthy. He was transferred to our facility for management of methicillin-resistant Staphylococcus aureus bacteremia, periorbital cellulitis, osteomyelitis, and necrotizing pneumonia. He received intravenous vancomycin and clindamycin 930 mg administered every 8 hours. Concurrently, he developed acute kidney injury. His baseline phosphorus concentration was within the normal range but increased as high as 11.7 mg/dL while he received clindamycin. Despite receiving oral phosphate binder therapy and a low phosphorus diet, he had little reduction in serum phosphorus values. Intravenous clindamycin was suspected as a potential cause for hyperphosphatemia, and a recommendation was made to switch from intravenous to oral clindamycin solution since it contains a different salt formulation. Given the severity of the child's disseminated infection and questions of whether he could absorb the enteral formulation, the decision was made to continue intravenous clindamycin and he was ultimately transferred to a rehabilitation facility for further care on intravenous clindamycin. Discussion: Excess oral or intravenous intake of phosphorus can result in hyperphosphatemia, as the body's plasma phosphate concentration exceeds the kidney's diminished filtration capacity. In this patient, use of the Naranjo probability scale indicated a possible adverse event associated with clindamycin. Phosphate intake from intravenous clindamycin and decreased glomerular filtration rate may have contributed to the child's hyperphosphatemia. Conclusions: While intravenous clindamycin was not the sole cause for this patient's hyperphosphatemia, health care professionals should be aware of the potential for increased phosphate load when administering this drug to a patient with renal dysfunction.

Online clearance (OLC) monitor measures conductivity difference between dialysate entering and leaving the dialyser. Derived ionic dialysance (ID) represents effective urea clearance from which Kt/V is calculated, allowing Kt/V monitoring at every treatment without blood sampling. We tested ID accuracy in children and provide recommendations for its use. Using Fresenius machines 2008 K with built-in OLC monitors, we studied 45 hemodialysis (HD) sessions and 168 calculated Kt/V results in 11 patients. Urea distribution volume (V), needed to calculate Kt/V from ID, was estimated using three methods: Mellits and Cheek (MC), KDOQI recommended total body water nomograms (TBWN) and OLC-derived independent from tested HD sessions. Reference spKt/V from pre- and post-HD BUN (Daugirdas) was compared with Kt/V calculated from ID using three different estimated V's. ID was accurate in calculating Kt/V in children when V derived from OLC was used (P = 0.42), with absolute error 0.14 ± 0.12. If TBWN-derived V was used, Kt/V was consistently underestimated by 0.32 ± 0.22. TBWN-derived V can still be recommended for use with OLC for monitoring trend in Kt/V, if underestimation of spKt/V of average 0.3 is accounted for. MC-derived V results in even greater underestimation of spKt/V and therefore cannot be recommended for use with OLC.

Our differential diagnosis was acute glomerulonephritis due to infections known to cause nephrotic syndrome (NS) in the first year of life, including syphilis, toxoplasmosis, cytomegalovirus (CMV), rubella, hepatitis B, hepatitis C, human immunodeficiency virus (HIV), parvovirus, Epstein-Barr virus (EBV), herpes simplex virus (HSV), hemolytic–uremic syndrome (HUS), autoimmune disease [systemic lupus erythematosus (SLE), vasculitis], malignancy, and primary (genetic) NS with later presentation at 9 months of age (Table 1). Due to severe gross hematuria, NS and decreased renal function on admission, percutaneous renal biopsy was performed on hospital day 1 without complications. Renal ultrasonography with Doppler flow showed no evidence of renal vein thrombosis. Histologic laboratory tests showed complement levels C3 and C4 were within normal limits [120 (85–157) and 27 (15–38) mg/dl respectively], as well as total complement CH50 46 (40–70). All tests for infectious causes were negative, including antibodies to HSV, Rubella, toxoplasmosis, EBV, hepatitis C, HIV, parvovirus; polymerase chain reaction (PCR) for EBV and parvovirus; hepatitis B antigen; rapid plasma reagin test for syphilis; and nasopharyngeal viral culture including adenovirus, influenza A and B, parainfluenza, meta-pneumovirus, and respiratory syncytial virus. Stool culture for Escherichia coli O157 was negative. Serologic tests to look for SLE (antinuclear antibodies, antibodies to double-stranded DNA) and vasculitis (antineutrophil cytoplasmic antibodies) were also negative. A peripheral blood smear was done to evaluate for HUS and malignancy. The smear showed normocytic anemia without red blood cell morphologic abnormalities and no evidence of microangiopathic hemolysis. For possibility of Denys-Drash syndrome (DDS) in an infant with female phenotype, karyotype was tested and showed normal 46 XX female. Genetic testing for gene mutations in PLCE1, LAMB2, WT1, NPHS1, and NPHS2 genes for early-onset NS showed DNA sequence variants in NPHS1 (heterozygous transition G>A, nucleotide position IVS9+8) and WT1 (heterozygous, transition T>C, nucleotide position 844, codon position 282, amino acid change cysteine>arginine), which were of unknown clinical significance and have not been associated with NS (Athena Diagnostics Inc., Worchester, MA, USA). This refers to the article that can be found at http://dx.doi.org/10.1007/ s00467-011-1965-z

For all transplant patients, the transplant physician must balance the risk of rejection caused by under-immunosuppression against the risk of drug toxicity, secondary infections and post-transplant lymphoproliferative disorder with over-immunosuppression. A Food and Drug Administration (FDA)-approved in vitro assay, the Cylex® ImmuKnowTM assay, provides a global assessment of cellular immune function to help monitor the immune status of immunosuppressed patients. This assay uses the plant lectin phytohemagglutinin to stimulate lymphocytes; an ATP assay is then used to measure the degree of activation of CD4+ T cells. However, the normal values for this assay were developed with healthy adult patients. In this study, we determined the normal ranges for the ImmuKnowTM assay in healthy children and compared those values to levels obtained in healthy adults and in stable pediatric renal transplant patients. We found that healthy children 12 yr of age and older showed immune function levels indistinguishable from adults, while healthy children under 12 had significantly lower immune function levels than adults. For adults, the ImmuKnowTM assay zones (in ng/mL ATP) of strong, moderate and low immune function correspond to >525, 225 to 525, and 395, 175–395 and

To define glomerular filtration rate (GFR) decline, hypertension (HTN), and proteinuria in subjects with autosomal recessive polycystic kidney disease (ARPKD) and compare with 2 congenital kidney disease control groups in the Chronic Kidney Disease in Children cohort.GFR decline (iohexol clearance), rates of HTN (ambulatory/casual blood pressures), antihypertensive medication usage, left ventricular hypertrophy, and proteinuria were analyzed in subjects with ARPKD (n = 22) and 2 control groups: aplastic/hypoplastic/dysplastic disorders (n = 44) and obstructive uropathies (n = 44). Differences between study groups were examined with the Wilcoxon rank sum test.Annualized GFR change in subjects with ARPKD was -1.4 mL/min/1.73 m(2) (-6%), with greater decline in subjects age ≥ 10 years (-11.5%). However, overall rates of GFR decline did not differ significantly in subjects with ARPKD vs controls. There were no significant differences in rates of HTN or left ventricular hypertrophy, but subjects with ARPKD had a greater percent on ≥ 3 blood pressure medications (32% vs 0%, P.0001), more angiotensin-converting enzyme inhibitor use (82% vs 27% vs 36%, P.0005), and less proteinuria (urine protein: creatinine = 0.1 vs 0.6, P.005).This study reports rates of GFR decline, HTN, and proteinuria in a small but well-phenotyped ARPKD cohort. The relatively slow rate of GFR decline in subjects with ARPKD and absence of significant proteinuria suggest that these standard clinical measures may have limited utility in assessing therapeutic interventions and highlight the need for other ARPKD kidney disease progression biomarkers.

Online clearance (OLC) monitor measures conductivity difference between dialysate entering and leaving the dialyser. Derived ionic dialysance (ID) represents effective urea clearance from which Kt/V is calculated, allowing Kt/V monitoring at every treatment without blood sampling. We tested ID accuracy in children and provide recommendations for its use. Using Fresenius machines 2008 K with built-in OLC monitors, we studied 45 hemodialysis (HD) sessions and 168 calculated Kt/V results in 11 patients. Urea distribution volume (V), needed to calculate Kt/V from ID, was estimated using three methods: Mellits and Cheek (MC), KDOQI recommended total body water nomograms (TBWN) and OLC-derived independent from tested HD sessions. Reference spKt/V from pre- and post-HD BUN (Daugirdas) was compared with Kt/V calculated from ID using three different estimated V's. ID was accurate in calculating Kt/V in children when V derived from OLC was used (P = 0.42), with absolute error 0.14 ± 0.12. If TBWN-derived V was used, Kt/V was consistently underestimated by 0.32 ± 0.22. TBWN-derived V can still be recommended for use with OLC for monitoring trend in Kt/V, if underestimation of spKt/V of average 0.3 is accounted for. MC-derived V results in even greater underestimation of spKt/V and therefore cannot be recommended for use with OLC.

A 9-month old girl presented to the emergency room with brown urine and generalized edema. She had been born at full term with normal growth and development. Her parents were unrelated and had no other children. She had been in good health until she developed brown urine 4 days prior to presentation and was noted to have edema 1 day prior to being seen in emergency department. Her physical exam was remarkable for moderate generalized edema, mild pallor, and irritability. Vital signs were within normal limits except for elevated blood pressure (115/63 mmHg). Her urine specimen was turbid and brown. Microscopic exam showed red blood cells (RBC) too numerous to count, 2–5 white blood cells (WBC), and 5–10 squamous epithelial cells per high power field. No RBC casts were seen. Urine protein/creatinine ratio was 17. Renal function panel revealed normal electrolytes, elevated serum creatinine at 0.49 mg/dl (estimated glomerular filtration rate Schwartz 63 ml/min/1.73 m), and low serum albumin at 1.9 g/dl. Complete blood count showed mild anemia with hemoglobin 8.9 g/dl, platelet count 273,000/mm, and WBC 13,900/ mm. Renal ultrasound showed bilaterally enlarged kidneys with increased cortical echogenicity. Chest X-ray was within normal limits. The infant was admitted to the hospital.

To assess depression in children with chronic kidney disease and to determine associations with patient characteristics, intellectual and educational levels, and health-related quality of life (HRQoL).Subjects aged 6-17 years from the Chronic Kidney Disease in Children cohort study completed the Children's Depression Inventory (CDI), Wechsler Abbreviated Scales of Intelligence, Wechsler Individual Achievement Test-II-Abbreviated, and the Pediatric Inventory of Quality of Life Core Scales 4.0. Regression analyses determined associations of CDI score and depression status with subject characteristics, intellectual and educational levels, and HRQoL. A joint linear mixed model and Weibull model were used to determine the effects of CDI score on longitudinal changes in glomerular filtration rate and time to renal replacement therapy.A total of 344 subjects completed the CDI. Eighteen (5%) had elevated depressive symptoms, and another 7 (2%) were being treated for depression. In adjusted analyses, maternal education beyond high school was associated with 5% lower CDI scores (estimate, 0.95; 95% CI, 0.92-0.99). Depression status was associated with lower IQ (99 vs 88; P = .053), lower achievement (95 vs 77.5; P.05), and lower HRQoL by parent and child reports (effect estimates, -15.48; 95% CI, -28.71 to -2.24 and -18.39; 95% CI, -27.81 to -8.96, respectively). CDI score was not related to change in glomerular filtration rate.Children with depression had lower psychoeducational skills and worse HRQoL. Identifying and treating depression should be evaluated as a means of improving the academic performance and HRQoL of children with chronic kidney disease.

Objective To identify renal transplant patients at a higher risk for allograft thrombosis and develop a risk stratification protocol for post-operative anticoagulation. Background According to the North American Pediatric Renal Transplant Cooperative Study data, vascular thrombosis is responsible for 12% of renal transplant failures. Congenital and acquired prothrombotic disorders have recently been found to play a major role in defining outcome of the renal transplants. Methods In 2007, we initiated universal screening for acquired and congenital thrombophilic risk factors for all renal transplant patients prior to transplant. They were assigned a risk category (Level I-IV) based on the presence of thrombophilic risk factors and their post-operative anticoagulation plan was pre-determined based on their risk level (Table). Low-dose unfractionated heparin drip was initiated a few hours after the transplant and titrated to achieve a 1.5 fold aPTT level. Anticoagulation was changed to low molecular weight heparin (LMWH) on day 2–4, when the risk of major bleed was over, and the serum creatinine had normalized. Result Nine patients have been screened and 8/9 were found to be at high risk for thrombosis (Level II or III). The prothrombotic risk factors identified were Prothrombin gene mutation (2), MTHFR (8), Lupus anticoagulant (2) and low protein S (2). Five patients have undergone renal transplant, and have been treated with LMWH post-operatively as per plan, with successful outcome. No patient has developed allograft thrombosis. 1/5 patients developed a peri-renal hematoma requiring evacuation, but completed prophylactic LMWH therapy. Conclusion Renal allograft thrombosis is preventable. Universal screening can stratify risk and allow an effective intervention to reduce that risk. Our Institution has developed a unique risk stratification protocol to identify patients at high risk for allograft thrombosis and prevent this complication by post-operative anticoagulation. Risk Categorization and Management Plan Risk Level Thrombophilia Management Level I Evidence of Thrombophilia (other than MTHFR) and previous thrombosis Heparin postoperatively and then LMWH bid for 6 months Level II Evidence of Thrombophilia (other than MTHFR), No history of thrombosis Heparin postoperatively, LMWH bid for 3 months, then qd for 3 months Level III MTHFR with normal homocysteine Heparin postoperatively, then LMWH qd for 3 months Level IV No evidence of thrombophilia No anticoagulation