Pediatric CKD Research Articles

The FGF23\u2013Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease\u2014a prospective cohort study

BackgroundChronic kidney disease-associated mineral bone disorder (CKD-MBD) is common in pediatric kidney disease patients and a risk factor for future cardiovascular disease (CVD). Fibroblast growth factor-23 (FGF23) and Klotho are novel key players in CKD-MBD, and has been suggested to be involved in the development of CVD.MethodsThis prospective cohort study included 74 pediatric patients; 31 with CKD (age range 0.8–18.8 years, glomerular filtration rate (GFR) range 9–68 mL/min/1.73 m2) and 43 transplanted patients (CKD-T; age range 3.3–17.7 years, GFR range 10–99 mL/min/1.73 m2) examined annually for 3 years. We assessed longitudinal patterns and predictors of FGF23 and soluble Klotho, as well as associations to cardiac remodeling and function using echocardiographic pulse wave Doppler (PWD) and color-coded tissue Doppler imaging (cc-TDI).ResultsThe prevalence of high FGF23 levels (≥95th percentile) was 60% in CKD and 42% in CKD-T patients, despite a low prevalence of hyperphosphatemia and normal Klotho levels. Low GFR at baseline was a predictor for high mean log FGF23 during follow-up in CKD and CKD-T patients (β = −0.2, p < 0.001). A high log FGF23 z-score longitudinally was borderline significantly associated with elevated left ventricular mass index (LVMI) in CKD patients (β = 1.8, p = 0.06). In addition, high log FGF23 (β = −0.43, p = 0.01) and low log Klotho (β = 0.44, p = 0.006) over time were associated with a worse left ventricular diastolic function (cc-TDI e′/a′) in CKD-T patients.ConclusionsIn pediatric CKD and CKD-T patients, the FGF23 level increase and Klotho level decrease with progressing renal failure, despite well-controlled phosphate levels. Following adjustments, both high FGF23 and low Klotho levels were strongly associated with a worse left ventricular diastolic function longitudinally. The potential role of FGF23 and Klotho in cardiac morbidity in pediatric CKD requires further investigation.

Treatment of Pediatric Chronic Kidney Disease-Mineral and Bone Disorder.

In this paper, we review the pathogenesis and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD), especially as it relates to pediatric CKD patients. Disordered regulation of bone and mineral metabolism in CKD may result in fractures, skeletal deformities, and poor growth, which is especially relevant for pediatric CKD patients. Moreover, CKD-MBD may result in extra-skeletal calcification and cardiovascular morbidity. Early increases in fibroblast growth factor 23 (FGF23) levels play a key, primary role in CKD-MBD pathogenesis. Therapeutic approaches in pediatric CKD-MBD aim to minimize complications to the growing skeleton and prevent extra-skeletal calcifications, mainly by addressing hyperphosphatemia and secondary hyperparathyroidism. Ongoing clinical trials are focused on assessing the benefit of FGF23 reduction in CKD. CKD-MBD is a systemic disorder that has significant clinical implications. Treatment of CKD-MBD in children requires special consideration in order to maximize growth, optimize skeletal health, and prevent cardiovascular disease.

Genomic Disorders and Neurocognitive Impairment in Pediatric CKD.

Children with CKD are at increased risk for neurocognitive impairment, but whether neurocognitive dysfunction is solely attributable to impaired renal function is unclear. Data from the CKD in Children Study Chronic Kidney Disease in Children (CKiD) Study indicate that a subset of children with CKD have unsuspected genomic disorders that predispose them to organ malformations and neurocognitive impairment. We therefore tested whether the CKiD Study participants with genomic disorders had impaired neurocognitive performance at enrollment. Compared with noncarriers (n=389), children with genomic disorders (n=31) scored significantly poorer on all measures of intelligence, anxiety/depressive symptoms, and executive function (differences of 0.6-0.7 SD; P=1.2×10-3-2.4×10-4). These differences persisted after controlling for known modifiers, including low birth weight, maternal education, seizure disorder, kidney disease duration, and genetically defined ancestry. The deleterious effect of genomic disorders on neurocognitive function was significantly attenuated in offspring of mothers with higher education, indicating the potential for modification by genetic and/or environmental factors. These data indicate that impaired neurocognitive function in some children with CKD may be attributable to genetic lesions that affect both kidney and neurocognitive development. Early identification of genomic disorders may provide opportunity for early diagnosis and personalized interventions to mitigate the effect on neurocognitive function.

CNDP1 genotype and renal survival in pediatric nephropathies.

The risk of developing type II diabetic nephropathy (DN) is lower in patients carrying the CNDP1 Mannheim polymorphism (homozygosity for the five leucine repeat), resulting in decreased activity of the histidine-dipeptide metabolizing enzyme carnosinase. The role of CNDP1 in other nephropathies is still unknown. To evaluate the impact of the CNDP1 Mannheim allele on pediatric chronic kidney disease (CKD), we prospectively followed the long-term clinical outcome of 272 children with non-diabetic kidney disease (glomerulopathies n=32, non-glomerular kidney disease n=240). Renal failure progression was independent of CNDP1 genotype in the total cohort of CKD children. However, in patients with glomerulopathies, only 39% of patients homozygous for the CNDP1 Mannheim polymorphism attained the primary renal endpoint as compared to 77% of patients with any other CNDP1 genotype (p=0.06). Our findings in pediatric CKD patients suggest that the nephroprotective effect of the CNDP1 Mannheim variant is not restricted to patients with diabetic nephropathy.

Vitamin D insufficiency and deficiency in pediatric renal transplant recipients

Vitamin D deficiency is prevalent in the pediatric CKD population. Recognizing that renal transplant recipients have CKD, we assessed the prevalence of vitamin D insufficiency and deficiency in pediatric renal transplant recipients, compared to a healthy pediatric population. We prospectively studied 25(OH)D levels in 29 pediatric renal transplant recipients and 45 control patients over one yr. The overall prevalence of vitamin D insufficiency and deficiency was common in both populations, at 76% (95% CI: 61, 87%) in the pediatric renal transplant recipients and 91% (95% CI: 80, 98%) in the control group. In the paired renal transplant samples, the mean 25(OH)D level was 52.3 ± 17.9 nmol/L in the winter and 65.6 ± 18.8 nmol/L in the summer (95% CI diff.: 3.9, 22.7), in keeping with a significant seasonal difference. The mean dietary intake of vitamin D in the renal transplant recipients, assessed by three-day dietary record, was 5.7 μg/day, with a vitamin D intake below the EAR in the majority. We did not find an association between vitamin D intake and 25(OH)D levels in this study, likely due to the low dietary intake of vitamin D within the transplant population, identifying a potential area for intervention and improvement.

Progression of pediatric CKD of nonglomerular origin in the CKiD cohort.

Congenital anomalies of the kidney and urinary tract and genetic disorders cause most cases of CKD in children. This study evaluated the relationships between baseline proteinuria and BP and longitudinal changes in GFR in children with these nonglomerular causes of CKD. Urine protein-to-creatinine ratio, casual systolic and diastolic BP (normalized for age, sex, and height), and GFR decline were assessed in the prospective CKD in Children cohort study. A total of 522 children, median age 10 years (interquartile range, 7, 14 years) with nonglomerular CKD were followed for a median of 4.4 years. The mean baseline GFR in the cohort was 52 ml/min per 1.73 m(2) (95% confidence interval [95% CI], 50 to 54) and declined 1.3 ml/min per 1.73 m(2) per year on average (95%CI, 1.6 to 1.1). A 2-fold higher baseline urine protein-to-creatinine ratio was associated with an accelerated GFR decline of 0.3 ml/min per 1.73 m(2) per year (95% CI, 0.4 to 0.1). A 1-unit higher baseline systolic BP z-score was associated with an additional GFR decline of 0.4 ml/min per 1.73 m(2) per year (95% CI, 0.7 to 0.1). Among normotensive children, larger GFR declines were associated with larger baseline urine protein-to-creatinine ratios; eGFR declines of 0.8 and 1.8 ml/min per 1.73 m(2) per year were associated with urine protein-to-creatinine ratio <0.5 and ≥0.5 mg/mg, respectively. Among children with elevated BP, average GFR declines were evident but were not larger in children with higher levels of proteinuria. Baseline proteinuria and systolic BP levels are independently associated with CKD progression in children with nonglomerular CKD.

The duration of hepatitis B vaccine immunity in pediatric dialysis patients.

Dialysis patients are at risk for hepatitis B infection, a serious but preventable disease. Long-term hepatitis B protection has not been defined in pediatric patients with chronic kidney disease stage 5 on dialysis (CKD 5D) who were vaccinated as infants or children. Annual hepatitis B antibody surveillance data were collected retrospectively on a cohort of pediatric CKD 5D patients (n = 202) at a single institution and analyzed by survival analysis to assess hepatitis B immunity duration. Median duration of immunity by Kaplan-Meier analysis since primary vaccination was 106.3 [95 % confidence interval (CI) 93.9, 124.4] months. After the initiation of dialysis, the median duration of hepatitis B immunity was 37.1 (95 % CI 24.2, 72.3) months. Multivariate adjusted analysis showed that there was a significant difference in the duration of hepatitis immunity based on the timing of hepatitis B vaccination (p < 0.001). Patients immunized after starting dialysis had a hazard ratio of 6.13 (95 % CI 2.87, 13.08) for hepatitis B immunity loss compared to patients immunized as infants (p < 0.001). After dialysis initiation, protective hepatitis B antibody levels wane rapidly, with a shortened duration of immunity. In our cohort of pediatric patients with CKD 5D, this decline was more pronounced in children who were immunized after starting dialysis than in those who received hepatitis B immunizations during childhood. Both groups of patients should be monitored with serial antibody titers.

Chronic Kidney Disease in Children and Adolescents

1. Susan F. Massengill, MD* 2. Maria Ferris, MD, MPH, PhD† 1. *Director, Pediatric Nephrology, Levine Children’s Hospital, Adjunct Associate Professor of Pediatrics, University of North Carolina School of Medicine, Charlotte, NC. 2. †Director, Pediatric Dialysis and Transplant Programs, UNC Kidney Center, Founder and Director, The UNC Children’s Hospital TRxANSITION Program, University of North Carolina at Chapel Hill, Chapel Hill, NC. * Abbreviations: 1,25(OH)2 D: : 1,25-dihydroxyvitamin D ACE: : angiotensin-converting enzyme CKD: : chronic kidney disease CKiD: : Chronic Kidney Disease in Children CVD: : cardiovascular disease eGFR: : estimated glomerular filtration rate ESKD: : end-stage kidney disease GFR: : glomerular filtration rate HCT: : health care transition MBD: : metabolic bone disease Chronic kidney disease (CKD) is a devastating diagnosis with many co-morbidities, increasing the risk of mortality 30 to 150 times that of the general pediatric population. Recognition of at-risk children can lead to earlier screening and risk reduction. Primary care clinicians are often unaware of the comorbid conditions and long-term consequences of CKD, particularly with respect to cardiovascular disease, nutrition and growth, neurocognitive development, and burden of disease. After completing this article, readers should be able to: 1. Be aware of the life course of CKD and its co-morbidities. 2. Recall the risk factors and complications of pediatric CKD. 3. Discuss measures to prevent or delay the progression of pediatric CKD. 4. Optimize the communication between the primary care clinician and nephrologist in treating children, adolescents, and young adults with CKD. A 13-month-old toddler new to your practice presents for his 1-year health maintenance visit with poor growth and developmental delay. He is just now sitting without support and appears to have occasional leg pain. He is pale, weighs 7.9 kg, and has a normal blood pressure. The results of laboratory studies are remarkable for anemia (hemoglobin, 9 g/dL [90 g/L]), profound acidosis (carbon dioxide, 12 mEq/L [12 mmol/L]), azotemia (urea nitrogen, 117 mg/dL [41.8 mmol/L]; creatinine, 2.44 mg/dL [216 μmol/L]), and profound hypocalcemia (calcium, 5.6 mg/dL [1.40 mmol/L]), prompting further evaluation where hypocalcemia was confirmed. Urinalysis revealed a specific gravity of 1.005 and proteinuria (1+). Renal ultrasonography revealed bilateral renal hypoplasia. Renal replacement therapy was initiated with peritoneal dialysis, and the patient is on the renal transplantation waiting list. A previously healthy, 14-year-old, African American girl presents with a 3-month history of facial …

Medication Treatment Complexity and Adherence in Children with CKD

The complexity of CKD management in children is increased by the number of comorbid conditions. This study assessed the prevalence of comorbidities in pediatric CKD and the frequency with which multiple comorbidities present together by assessing prevalent medication use by CKD stage and diagnosis and their association with clinical or sociodemographic factors. The association between number and frequency of dosing of medications prescribed and self-report of nonadherence was also assessed. In this cross-sectional analysis of the Chronic Kidney Disease in Children study, medication use at study entry grouped by indication was examined by CKD stage, diagnosis, age, race, ethnicity, income, and CKD duration. Multivariate adjusted predictors of medication use and clustering were examined. Nonadherence was assessed by self-report of missed medications in the past 7 days. The 558 eligible participants had a median age of 11 years and median GFR of 44 ml/min per 1.73 m(2); 62% of participants were male and 78% had nonglomerular kidney disease. The number of medications for treatment of CKD comorbidities increased with advanced CKD stage (2.5-fold for stages IV versus II; P<0.001) and glomerular disease (1.4-fold versus nonglomerular; P<0.001). Three distinct medication clusters were identified that corresponded to treatment of glomerular disease, advanced renal tubular dysfunction, and proteinuric complications, respectively. Nonadherence was associated with increased medication dosing frequency (administration >2 times/d; P<0.001) but not the number of medications. Medical therapy for children with CKD is complex and is affected by glomerular diagnosis, CKD stage, and medication frequency. The need for CKD-related medication treatment cannot be easily predicted by CKD staging alone. Poorer adherence was associated with increased medication frequency, but not with the number of medical problems needing treatment. Consolidating medical treatment and reducing medication frequency may improve adherence rates in children with CKD.

Pediatric Kidney Transplantation in the Developing World: Challenges and Solutions

The prevalence of pediatric RRT and transplantation are low in developing countries, 6–12 and <1 to 5 per million child population (pmcp), respectively. This is due to low GDP/capita of <$10 000, government expenditure on health of <2.6–9% of GDP and paucity of facilities. The reported incidence of pediatric CKD and ESRD is <1.0–8 and 3.4–35 pmcp, respectively. RRT and transplantation are offered mostly in private centers in cities where HD costs $20–100/session and transplants $10 000–20 000. High costs and long distance to centers results in treatment refusal in up to 35% of the cases. In this backdrop 75–85% of children with ESRD are disfranchised from RRT and transplantation. Our center initiated an integrated dialysis–transplant program funded by a community-government partnership where RRT and transplantation was provided “free of cost” with life long follow-up and medication. Access to free RRT at doorsteps and transplantation lead to societal acceptance of transplantation as the therapy of choice for ESRD. This enabled us to perform 475 pediatric transplants in 25 years with 1- and 5-year graft survival of 96% and 81%, respectively. Our model shows that pediatric transplantation is possible in developing countries when freely available and accessible to all who need it in the public sector.

Retraction: Summary of KDIGO guideline: behind the scenes, need for guidance, and a framework for moving forward

The 2102 KDIGO Guidelines for CKD evaluation, classification, and management have updated the original 2002 KDOQI Guidelines, using newer data and addressing issues raised over the last decade concerning definitions and assessment. This commentary highlights the key aspects of the CKD guidelines, and describes the rationale for specific wording and the scope of the document. A precis of key concepts in each of the five sections of the guideline is presented. The guideline document is intended for general practioners and nephrologists, and covers both adult and pediatric CKD evaluation, classification, and management. Throughout the guideline, we have attempted to overtly address areas of controversy or non-consensus, international relevance, and impact on practice and public policy.

Summary of KDIGO guideline: behind the scenes, need for guidance, and a framework for moving forward

The 2102 KDIGO Guidelines for CKD evaluation, classification, and management have updated the original 2002 KDOQI Guidelines, using newer data and addressing issues raised over the last decade concerning definitions and assessment. This commentary highlights the key aspects of the CKD guidelines, and describes the rationale for specific wording and the scope of the document. A precis of key concepts in each of the five sections of the guideline is presented. The guideline document is intended for general practioners and nephrologists, and covers both adult and pediatric CKD evaluation, classification, and management. Throughout the guideline, we have attempted to overtly address areas of controversy or non-consensus, international relevance, and impact on practice and public policy.

Searching the optimal PTH target range in children undergoing peritoneal dialysis: New insights from international cohort studies

The treatment of the mineral and bone disorder associated with chronic kidney disease (CKD-MBD) remains a major challenge in pediatric patients. The principal aims of therapeutic measures are not only to prevent the debilitating skeletal complications and to achieve normal growth but also to preserve long-term cardiovascular health. Serum parathyroid hormone (PTH) levels are used as a surrogate parameter of bone turnover. Whereas it is generally accepted that serum calcium and phosphate levels should be kept within the range for age, current pediatric consensus guidelines differ markedly with respect to the optimal PTH target range and operate on a limited evidence base. Recently, the International Pediatric Dialysis Network (IPPN) established a global registry collecting detailed clinical and biochemical information, including data relevant to CKD-MBD in children on chronic peritoneal dialysis (PD). This review highlights the current evidence basis regarding the optimal PTH target range in pediatric CKD patients, and re-assesses the current guidelines in view of the outcome data collected by the IPPN registry. Based on a comprehensive evaluation of CKD-MBD outcome measures in this global patient cohort, a PTH target range of 1.7-3 times the upper limit of normal (i.e. 100-200 pg/ml) appears reasonable in children undergoing chronic PD.

Cardiac magnetic resonance imaging in children with chronic kidney disease and renal transplantation

CV disease is the major cause of death in patients with CKD. Recently, CMR imaging emerges as a complementary method providing advantages in cardiac assessment; however, data on CMR in pediatric CKD are scarce. We performed CMR in 15 children: two with CKD, six on peritoneal dialysis, seven on hemodialysis, and in 18 children 5.1 (0.4-15.4) yr after kidney Tx. Eight children underwent CMR six months before and after Tx. Results are presented as mean z score ± SD. LV EF was higher and in the normal range in Tx patients compared with CKD (-0.3 ± 1 vs. -2.1 ± 1.6, respectively, p < 0.05), whereas RV EF was similar (-0.9 ± 1.4 vs. -0.9 ± 1.8, p = n.s.). End-diastolic and end-systolic LV volume index (0 ± 1.7 vs. 2.1 ± 3.1; 0.2 ± 1.2 vs. 3.1 ± 3.7, both p < 0.05) and LV mass index (1.4 ± 1.5 vs. 3.4 ± 2.9, p < 0.05) were lower in Tx children. All parameters improved in the eight children after Tx. In conclusion, our CMR analysis suggests marked improvement of cardiac function and morphology in children after kidney Tx. CMR might be an appropriate complementary method for measuring detailed cardiac status in children with CKD.

Chapter 11. Diagnosis of pediatric CKD

Chapter 11. Diagnosis of pediatric CKD

KDOQI Clinical Practice Guideline for Nutrition in Children with CKD: 2008 Update

Regular evaluation of nutritional status and provision of adequate nutrition are key components in the overall management of children with CKD. The traditional and predominant focus of nutritional management for children with impaired kidney function is to prevent the development of PEM and meet the patient's vitamin and mineral needs. More recently, overnutrition characterized by obesity and the long-term implications of unbalanced dietary and lifestyle practices are of increasing concern to the pediatric CKD population, and attention to this issue must be incorporated into the nutrition management scheme.

Chronic kidney disease in children: state of the art

composition of the blood or urine, with or without decreased GFR; and (b) GFR <60 ml/min/1.73 m 2 for ≥3 months, with or without the signs of kidney damage listed above [1]. The prevalence of CKD was as high as 11% in the adult population. 4.7% of the adult population from one study had a glomerular filtration rate (GFR) <60 ml/min (stages 3–5) [2]. Similar studies showed a higher prevalence (5.1%) of known stages 3–5 CKD in the general population, based on analysis of single serum creatinine results held on general practitioners computers [3]. The prevalence and epidemiological information on pediatric CKD is currently imprecise and flawed by methodological differences between the various data sources. The long-term survival of children with end-stage renal disease has improved in the last 25 years but the mortality is still very

Is serum NGAL an accurate marker of renal function in pediatric CKD?

Is serum NGAL an accurate marker of renal function in pediatric CKD?

Sevelamer for treating hyperphosphatemia in pediatric CKD patients

Sevelamer for treating hyperphosphatemia in pediatric CKD patients