Hyperkalemia in pediatric chronic kidney disease.

BACKGROUND: While hyperkalemia is well described in adult chronic kidney disease (CKD), large studies evaluating potassium trends and risk factors for hyperkalemia in pediatric CKD are lacking. This study aimed to characterize hyperkalemia prevalence and risk factors in pediatric CKD. METHODS: Cross-sectional analysis of Chronic Kidney Disease in Children (CKiD) study data evaluated median potassium levels and percentage of visits with hyperkalemia (K ≥5.5 mmoL/L) in relation to demographics, CKD stage, etiology, proteinuria, and acid-base status. Multiple logistic regression was used to identify risk factors for hyperkalemia. RESULTS: One thousand and fifty CKiD participants with 5183 visits were included (mean age 13.1 years, 62.7% male, 32.9% self-identifying as African American or Hispanic). A percentage of 76.6% had non-glomerular disease, 18.7% had CKD stage 4/5, 25.8% had low CO2, and 54.2% were receiving ACEi/ARB therapy. Unadjusted analysis identified a median serum potassium level of 4.5 mmol/L (IQR 4.1-5.0, p <0.001) and hyperkalemia in 6.6% of participants with CKD stage 4/5. Hyperkalemia was present in 14.3% of visits with CKD stage 4/5 and glomerular disease. Hyperkalemia was associated with low CO2 (OR 7.72, 95%CI 3.05-19.54), CKD stage 4/5 (OR 9.17, 95%CI 4.02-20.89), and use of ACEi/ARB therapy (OR 2.14, 95%CI 1.36-3.37). Those with non-glomerular disease were less frequently hyperkalemic (OR 0.52, 95%CI 0.34-0.80). Age, sex, and race/ethnicity were not associated with hyperkalemia. CONCLUSIONS: Hyperkalemia was observed more frequently in children with advanced stage CKD, glomerular disease, low CO2, and ACEi/ARB use. These data can help clinicians identify high-risk patients who may benefit from earlier initiation of potassium-lowering therapies. A higher resolution version of the Graphical abstract is available as Supplementary information.

Longitudinal changes in uric acid concentration and their relationship with chronic kidney disease progression in children and adolescents.

BACKGROUND: Elevated serum uric acid concentration is a risk factor for CKD progression. Its change over time and association with CKD etiology and concomitant changes in estimated glomerular filtration rate (eGFR) in children and adolescents are unknown. METHODS: Longitudinal study of 153 children/adolescents with glomerular (G) and 540 with non-glomerular (NG) etiology from the CKD in Children (CKiD) study. Baseline serum uric acid, change in uric acid and eGFR over time, CKD etiology, and comorbidities were monitored. Adjusted linear mixed-effects regression models quantified the relationship between within-person changes in uric acid and concurrent within-person changes in eGFR. RESULTS: Participants with stable uric acid over follow-up had CKD progression which became worse for increased baseline uric acid (average annual percentage changes in eGFR were - 1.4%, - 7.7%, and - 14.7% in those with G CKD with baseline uric acid < 5.5 mg/dL, 5.5 - 7.5 mg/dL, and > 7.5 mg/dL, respectively; these changes were - 1.4%, - 4.1%, and - 8.6% in NG CKD). Each 1 mg/dL increase in uric acid over follow-up was independently associated with significant concomitant eGFR decreases of - 5.7% (95%CI - 8.4 to - 3.0%) (G) and - 5.1% (95%CI - 6.3 to - 4.0%) (NG) for those with baseline uric acid < 5.5 mg/dL and - 4.3% (95%CI - 6.8 to - 1.6%) (G) and - 3.3% (95%CI - 4.1 to - 2.6%) (NG) with baseline uric acid between 5.5 and 7.5 mg/dL. CONCLUSIONS: Higher uric acid levels and increases in uric acid over time are risk factors for more severe progression of CKD in children and adolescents. A higher resolution version of the Graphical abstract is available as Supplementary information.

Low variability of plant protein intake in the CKiD cohort does not demonstrate changes in estimated GFR nor electrolyte balance.

BACKGROUND: Vegetable or plant-based sources of protein may confer health benefits in children with progressive kidney disease. Our aims were to understand the effect of the proportion of vegetable protein intake on changes in estimated GFR and to understand the effect of the proportion of vegetable protein intake on serum levels of bicarbonate, phosphorus, and potassium. METHODS: Children with baseline eGFR between 30 and 90 mL/min/1.73 m2 were recruited from 59 centers across North America as part of the chronic kidney disease in children (CKiD) study. The percentage of dietary vegetable protein (VP%) was gathered from annual Food Frequency Questionnaires. We performed longitudinal linear mixed models to determine the effect of VP% on eGFR and longitudinal logistic mixed models to determine the effect of VP% on electrolyte balance (potassium, phosphorus, bicarbonate). RESULTS: Two thousand visits from 631 subjects. Across all dichotomized groups of children (sex, African American race, Hispanic ethnicity, glomerular etiology of CKD, hypertension, anemia, hyperkalemia, hyperphosphatemia, acidosis, BMI < 95th percentile), the median VP% was 32-35%. The longitudinal mixed model analysis did not show any effect of VP% on eGFR electrolyte (bicarbonate, phosphorus, and potassium) abnormalities (p > 0.1). CONCLUSIONS: A diverse cohort of children with CKD has a narrow and homogeneous intake of vegetable protein. Due to the low variability of plant-based protein in the cohort, there were no associations between the percentage of plant protein intake and changes in eGFR nor electrolyte balance. A higher resolution version of the Graphical abstract is available as Supplementary information.

Executive summary of the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease

The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease for patients not receiving dialysis represents an update to the KDIGO 2012 guideline on this topic. Development of this guideline update followed a rigorous process of evidence review and appraisal. Guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence. The strength of recommendations is based on the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. The scope includes topics covered in the original guideline, such as optimal blood pressure targets, lifestyle interventions, antihypertensive medications, and specific management in kidney transplant recipients and children. Some aspects of general and cardiovascular health, such as lipid and smoking management, are excluded. This guideline also introduces a chapter dedicated to proper blood pressure measurement since all large randomized trials targeting blood pressure with pivotal outcomes used standardized preparation and measurement protocols adhered to by patients and clinicians. Based on previous and new evidence, in particular the Systolic Blood Pressure Intervention Trial (SPRINT) results, we propose a systolic blood pressure target of less than 120 mm Hg using standardized office reading for most people with chronic kidney disease (CKD) not receiving dialysis, the exception being children and kidney transplant recipients. The goal of this guideline is to provide clinicians and patients a useful resource with actionable recommendations supplemented with practice points. The burden of the recommendations on patients and resources, public policy implications, and limitations of the evidence are taken into consideration. Lastly, knowledge gaps and recommendations for future research are provided.

Executive summary of the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.

The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease for patients not receiving dialysis represents an update to the KDIGO 2012 guideline on this topic. Development of this guideline update followed a rigorous process of evidence review and appraisal. Guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence. The strength of recommendations is based on the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. The scope includes topics covered in the original guideline, such as optimal blood pressure targets, lifestyle interventions, antihypertensive medications, and specific management in kidney transplant recipients and children. Some aspects of general and cardiovascular health, such as lipid and smoking management, are excluded. This guideline also introduces a chapter dedicated to proper blood pressure measurement since all large randomized trials targeting blood pressure with pivotal outcomes used standardized preparation and measurement protocols adhered to by patients and clinicians. Based on previous and new evidence, in particular the Systolic Blood Pressure Intervention Trial (SPRINT) results, we propose a systolic blood pressure target of less than 120 mm Hg using standardized office reading for most people with chronic kidney disease (CKD) not receiving dialysis, the exception being children and kidney transplant recipients. The goal of this guideline is to provide clinicians and patients a useful resource with actionable recommendations supplemented with practice points. The burden of the recommendations on patients and resources, public policy implications, and limitations of the evidence are taken into consideration. Lastly, knowledge gaps and recommendations for future research are provided.

Vitamin D insufficiency, hemoglobin, and anemia in children with chronic kidney disease.

BACKGROUND: 25-Hydroxyvitamin D (25OHD) deficiency is common in children with chronic kidney disease (CKD). It has been associated with an increased risk for anemia in both healthy US children and in adults with CKD. This association has not been explored in children with CKD. METHODS: Children aged 1-16 enrolled in the Chronic Kidney Disease in Children (CKiD) study with mild to moderate kidney dysfunction, and with 25OHD measured at baseline (n = 580), were included in the analysis. The cross-sectional associations between 25OHD and hemoglobin (g/dL) and anemia were assessed. Anemia was defined as hemoglobin < 5th percentile for age and sex. RESULTS: Overall 334 (57.59%) children were vitamin D insufficient/deficient and 137 (23.62%) were anemic. Of those who were vitamin D insufficient/deficient, 95 (28.44%) were anemic. In the overall cohort, the odds of being anemic was 1.9 times higher (95% CI, 1.22-3.04, p < 0.01) in vitamin D insufficient/deficient vs sufficient children, when adjusting for covariates (age, sex, race [black, white, or other], body mass index (BMI), iohexol GFR (iGFR), erythropoietin stimulation agent (ESA) use, iron supplementation use, and underlying cause of CKD). Stratified by race, the odds of being anemic was 2.39 times higher (95% CI, 1.41-4.05, p = 0.001) in vitamin D insufficient/deficient vs vitamin D sufficient white children. The association between vitamin D status and anemia was not significant in black children. CONCLUSIONS: The data support our hypothesis that vitamin D insufficiency/deficiency increases the odds of anemia in children with CKD. The effect was strong and significant among white, but not black, children.

Pilot study of the effect of cholecalciferol supplementation on hepcidin in children with chronic kidney disease: Results of the D-fense Trial.

BACKGROUND: Hepcidin is a key mediator of the anemia of chronic kidney disease (CKD). There is emerging evidence that 25-hydroxyvitamin D (25D) regulates hepcidin production. METHODS: A randomized controlled trial of daily vitamin D supplementation for 12 weeks was performed with the aim to test the effects of 4000 versus 400 IU of cholecalciferol on serum hepcidin levels in children with non-dialysis CKD recruited at a tertiary care children's hospital. Hepcidin was quantified using a validated competitive enzyme-linked immunosorbent assay. 25D levels were measured using the chemiluminescence Liaison 25(OH)D assay system. Co-variables included hemoglobin, C-reactive protein, ferritin, and serum calcium and phosphorus for safety monitoring. RESULTS: A total of 34 subjects were randomized to either the intervention or control group, of whom 26.5% were female and 23.5% were African American. The mean age of the study cohort was 10.9 [standard deviation (SD) 5.8] years, the mean baseline glomerular filtration rate was 60 (SD 17.6) ml/min/1.73 m2, and mean baseline 25D level was 29.7 (SD 11.5) ng/ml. At baseline, 50% of subjects were 25D deficient. There were no significant differences in baseline characteristics between the intervention and control groups. Treatment with 4000 IU cholecalciferol was not associated with significant change in hepcidin level at 4 or 12 weeks, and multivariable generalized estimating equation regression demonstrated no significant difference in change in hepcidin over the treatment period in either arm. The median C-reactive protein level decreased significantly at 12 weeks in the intervention group. CONCLUSIONS: These results do not suggest that daily nutritional vitamin D supplementation modifies serum hepcidin levels in children with CKD. Further study will be required to determine whether supplementation may be effective in children with more advanced CKD or those on dialysis.

Assessment of dietary intake of children with chronic kidney disease.

OBJECTIVE: Our aim was to characterize the nutrient intake of children with chronic kidney disease (CKD) relative to recommended intake levels. METHODS: We conducted a cross-sectional study of dietary intake assessed by Food Frequency Questionnaire (FFQ) in The North American Chronic Kidney Disease in Children (CKiD) prospective cohort study. Nutrient intake was analyzed to estimate the daily consumption levels of various nutrients and compared with national guidelines for intake. RESULTS: There were 658 FFQs available for analysis; 69.9 % of respondents were boys, with a median age [Interquartile range (IQR)] of 11 years (8-15). Median daily sodium, potassium, and phosphorus intake was 3089 mg (2294-4243), 2384 mg (1804-3076), and 1206 mg (894-1612) respectively. Sodium and phosphorus consumptions were higher than recommended in all age groups. Caloric intake decreased with dropping glomerular filtration rate (GFR) (p = 0.003). The median daily caloric intakes were 1307 kcal in male children 2-3 years old, 1875 kcal in children 4-8 years old, 1923 kcal in those 9-13 years old, and 2427 kcal in those 14-18 years old. Respective levels for girls were 1467 kcal, 1736 kcal, 1803 kcal, and 2281 kcal. Median protein intake exceeded recommended levels in all age groups, particularly among younger participants. Younger children were more likely than older children to exceed the recommended intakes for phosphorus (p < 0.001) and the age-specific recommended caloric intake (p < 0.001). Macronutrient distribution (carbohydrate:fat:protein) was consistent with recommendation. CONCLUSIONS: Children in the CKiD cohort consumed more sodium, phosphorus, protein, and calories than recommended. The gap between actual consumption and recommendations indicates a need for improved nutritional counseling and monitoring.

Fibroblast Growth Factor 23 and Risk of CKD Progression in Children.

BACKGROUND AND OBJECTIVES: Plasma fibroblast growth factor 23 (FGF23) concentrations increase early in the course of CKD in children. High FGF23 levels associate with progression of CKD in adults. Whether FGF23 predicts CKD progression in children is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We tested the hypothesis that high plasma FGF23 is an independent risk factor for CKD progression in 419 children, aged 1-16 years, enrolled in the Chronic Kidney Disease in Children (CKiD) cohort study. We measured plasma FGF23 concentrations at baseline and determined GFR annually using plasma disappearance of iohexol or the CKiD study estimating equation. We analyzed the association of baseline FGF23 with risk of progression to the composite end point, defined as start of dialysis or kidney transplantation or 50% decline from baseline GFR, adjusted for demographics, baseline GFR, proteinuria, other CKD-specific factors, and other mineral metabolites. RESULTS: At enrollment, median age was 11 years [interquartile range (IQR), 8-15], GFR was 44 ml/min per 1.73 m2 (IQR, 33-57), and FGF23 was 132 RU/ml (IQR, 88-200). During a median follow-up of 5.5 years (IQR, 3.5-6.6), 32.5% of children reached the progression end point. Higher FGF23 concentrations were independently associated with higher risk of the composite outcome (fully adjusted hazard ratio, 2.52 in the highest versus lowest FGF23 tertile; 95% confidence interval, 1.44 to 4.39, P=0.002; fully adjusted hazard ratio, 1.33 per doubling of FGF23; 95% confidence interval, 1.13 to 1.56, P=0.001). The time to progression was 40% shorter for participants in the highest compared with the lowest FGF23 tertile. In contrast, serum phosphorus, vitamin D metabolites, and parathyroid hormone did not consistently associate with progression in adjusted analyses. CONCLUSIONS: High plasma FGF23 is an independent risk factor for CKD progression in children.

Prevalence and correlates of 25-hydroxyvitamin D deficiency in the Chronic Kidney Disease in Children (CKiD) cohort.

BACKGROUND: Vitamin D plays an important role in the mineral and bone disorder seen in chronic kidney disease (CKD). Deficiency of 25-hydroxyvitamin D (25OHD) is highly prevalent in the adult CKD population. METHODS: The prevalence and determinants of 25OHD deficiency (defined as a level <20 ng/ml) were examined longitudinally in 506 children in the CKiD cohort. Predictors of secondary hyperparathyroidism and the determinants of 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were also evaluated. RESULTS: Deficiency of 25OHD was observed in 28 % of the cohort at enrollment. Significant predictors of 25OHD deficiency were older age, non-white race, higher body mass index, assessment during winter, less often than daily milk intake, non-use of nutritional vitamin D supplement and proteinuria. Lower values of glomerular filtration rate (GFR), serum 25OHD, calcium and higher levels of FGF23 were significant determinants of secondary hyperparathyroidism. Lower GFR, low serum 25OHD, nephrotic-range proteinuria, and high FGF23 levels were significant determinants of serum 1,25(OH)2 D levels. CONCLUSIONS: Deficiency of 25OHD is prevalent in children with CKD and is associated with potentially modifiable risk factors such as milk intake, nutritional vitamin D supplement use, and proteinuria. 25OHD deficiency is a risk factor for secondary hyperparathyroidism and decreased serum 1,25(OH)2D in children with CKD.

Disordered FGF23 and mineral metabolism in children with CKD.

BACKGROUND AND OBJECTIVES: In children with CKD, information is limited regarding the prevalence and determinants of fibroblast growth factor 23 excess and 1,25-dihyroxyvitamin D deficiency across the spectrum of predialysis CKD. This study characterized circulating concentrations of fibroblast growth factor 23 and 1,25-dihyroxyvitamin D, and investigated their interrelationships and associations with GFR and secondary hyperparathyroidism in children with CKD who were enrolled in the Chronic Kidney Disease in Children observational cohort study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma fibroblast growth factor 23 concentrations and determinants of mineral metabolism were measured in 464 children ages 1-16 years with predialysis CKD. GFR was measured by plasma disappearance of iohexol in 70% of participants and estimated by the Chronic Kidney Disease in Children estimating equation using serum creatinine and cystatin C concentrations in the remainder of the participants. Participants were grouped according to CKD stage and by 10-ml/min categories of GFR. RESULTS: Median GFR for the cohort was 45 ml/min per 1.73 m(2) (interquartile range=33-57; range=15-109). Plasma fibroblast growth factor 23 concentration was above the normal range in 67% of participants (with higher levels observed among participants with lower GFR) before higher levels of serum parathyroid hormone and phosphorus were observed. Plasma fibroblast growth factor 23 levels were 34% higher in participants with glomerular disease than in participants with nonglomerular disease, despite similar GFR. Serum phosphorus levels, adjusted for age, were significantly lower at GFR of 60-69 ml/min per 1.73 m(2) than higher GFR, but thereafter they became higher in parallel with fibroblast growth factor 23 as GFR declined. Serum 1,25-dihyroxyvitamin D concentrations were lower in those participants with low GFR values, high fibroblast growth factor 23 levels, 25-hydroxyvitamin D deficiency, and proteinuria. Secondary hyperparathyroidism was present in 55% of participants with GFR<50 ml/min per 1.73 m(2). CONCLUSION: In children with predialysis CKD, high plasma fibroblast growth factor 23 is the earliest detectable abnormality in mineral metabolism, and levels are highest in glomerular diseases.

Nutritional vitamin D use in chronic kidney disease: a survey of pediatric nephrologists.

BACKGROUND: Vitamin D deficiency may contribute to risk of cardiovascular disease, diabetes, and infections, in addition to known effects on mineral metabolism. Controversy remains regarding the use of nutritional vitamin D supplementation in chronic kidney disease (CKD), and the supplementation practices of pediatric nephrologists are unknown. METHODS: An electronic survey containing eight vignettes was sent to physician members of the International Pediatric Nephrology Association in 2011 to identify physician and patient characteristics that influence nephrologists to supplement CKD patients with nutritional vitamin D. Vignettes contained patient characteristics including light vs dark skin, CKD stage, cause of renal disease, parathyroid hormone (PTH), and 25(OH) vitamin D levels. Multivariate logistic generalized estimating equation regression was used to identify predictors of supplementation. RESULTS: Of 1,084 eligible physicians, 504 (46%) completed the survey. Supplementation was recommended in 73% of cases overall (ranging from 91% of those with vitamin D levels <10 ng/mL to 35% with levels >30). Greater CKD severity was associated with greater recommendation of supplementation, especially for patients with higher vitamin D levels (test for interaction p < 0.0001). PTH level above target for CKD stage was associated with greater recommendation to supplement in pre-dialysis CKD, but did not have an impact on recommendations in dialysis patients (test for interaction p < 0.0001). Skin color, cause of CKD, and albumin levels were not associated with supplementation recommendation. CONCLUSIONS: Recommending nutritional vitamin D is common worldwide, driven by CKD stage and vitamin D and PTH levels. Future studies are needed to establish the risks and benefits of supplementation.

Anemia in children with chronic kidney disease.

Anemia is a common comorbidity in children with chronic kidney disease (CKD). This condition is associated with multiple adverse clinical consequences and its management is a core component of nephrology care. Increased morbidity and mortality, increased risk of cardiovascular disease and decreased quality of life have been associated with anemia of CKD in children. Although numerous complex factors interact in the development of this anemia, erythropoietin deficiency and iron dysregulation (including iron deficiency and iron-restricted erythropoiesis) are the primary causes. In addition to iron supplementation, erythropoietin-stimulating agents (ESAs) can effectively treat this anemia, but there are important differences in ESA dose requirements between children and adults. Also, hyporesponsiveness to ESA therapy is a common problem in children with CKD. Although escalating ESA doses to target increased hemoglobin values in adults has been associated with adverse outcomes, no studies have demonstrated this association in children. The question of appropriate target hemoglobin levels in children, and the approach by which to achieve these levels, remains under debate. Randomized, controlled studies are needed to evaluate whether normalization of hemoglobin concentrations is beneficial to children, and whether this practice is associated with increased risks.

Hemoglobin differences by race in children with CKD.

BACKGROUND: There are known racial disparities in the prevalence of anemia in adults with chronic kidney disease (CKD), but these differences have not been well described in children. STUDY DESIGN: Cohort study, cross-sectional analysis. SETTING & PARTICIPANTS: The Chronic Kidney Disease in Children (CKiD) Study is a multicenter prospective cohort study of children with mild to moderate CKD. This analysis included 429 children of African American or white race. PREDICTOR: Race. OUTCOMES & MEASUREMENTS: This study examined the association of race with hemoglobin level. Both multiple linear regression and generalized gamma modeling techniques were used to characterize the association between race and hemoglobin level. RESULTS: 79% of the cohort was white, 21% was African American. Neither median hemoglobin level nor frequency of erythropoiesis-stimulating agent use differed by race. In multivariate analysis, lower levels of iohexol-measured glomerular filtration rate, African American race, and glomerular disease (vs nonglomerular disease) as the underlying cause of CKD were independently associated with decreased hemoglobin levels; independent of glomerular filtration rate and CKD diagnosis, African American children had average hemoglobin levels that were 0.6 g/dL (95% CI, -0.9 to -0.2 g/dL) lower than those of white children. Generalized gamma modeling showed that differences in hemoglobin levels observed by race become more pronounced when moving from high to low in the overall hemoglobin level distribution. LIMITATIONS: Cross-sectional analysis cannot establish causality, and data for iron stores were not available for all patients. CONCLUSIONS: African American compared with white children have lower hemoglobin values in CKD independent of the underlying cause of CKD. These racial differences in hemoglobin levels appear to increase at the lower end of the hemoglobin level distribution in this population.