Climate change and its influence in nephron mass.

PURPOSE OF REVIEW: The consequences of climate change, including heat and extreme weather events impact kidney function in adults and children. The impacts of climate change on kidney development during gestation and thereby on kidney function later in life have been poorly described. Clinical evidence is summarized to highlight possible associations between climate change and nephron mass. RECENT FINDINGS: Pregnant women are vulnerable to the effects of climate change, being less able to thermoregulate, more sensitive to the effects of dehydration, and more susceptible to infections. Exposure to heat, wildfire smoke, drought, floods and climate-related infections are associated with low birth weight, preterm birth and preeclampsia. These factors are associated with reduced nephron numbers, kidney dysfunction and higher blood pressures in offspring in later life. Exposure to air pollution is associated with higher blood pressures in children and has variable effects on estimated glomerular filtration rate. SUMMARY: Climate change has important impacts on pregnant women and their unborn children. Being born too small or too soon is associated with life-time risk of kidney disease. Climate change may therefore have a dual effect of impacting fetal kidney development and contributing to cumulative postnatal kidney injury. The impact on population kidney health of future generations may be significant.

Addressing Health Inequities and Disparities in Children With Kidney Disease in Disadvantaged Areas: the Latin American and Caribbean Experience.

Purpose of Review: Compared with high-income countries, healthcare disparities and inequities are more evident in low, lower-middle, and upper-middle-income countries with poorer housing and nutrition conditions. At least 20% of Latin America and the Caribbean are low and lower-middle-income countries. Despite the majority of the other countries being upper-middle income, the United Nations Children's Fund had classified all the regions as "less developed," with limited access to health care for the most vulnerable, the children. Latin America and the Caribbean regions represent an extensive territory with communication limitations and an unstable socio-political and economic environment. After considering the vast population affected by poverty worldwide and the long-term impact of kidney disease starting in childhood, it is crucial to better understand and analyze the multifactorial limiting conditions in accessing specialized care such as pediatric nephrology in disadvantaged areas. Recent Findings: Constraints in accessing basic healthcare in rural areas make it impossible to receive specialized pediatric nephrology care including dialysis and transplantation. Disturbingly, incidence and prevalence figures of acute kidney injury, chronic and end-stage kidney disease in some Latin American and the Caribbean countries are unknown, and these conditions still represent a death sentence for underprivileged populations. However, the monumental efforts of the dedicated healthcare providers and stakeholders that pioneered the actions in the past 50 years have shown remarkable progress in developing pediatric nephology services across the continent. Summary: In this review, we compile some of the latest evidence about the care of children and adolescents with kidney conditions in Latin America and the Caribbean, along with the experiences from the field in the care of these patients facing adverse conditions. We also highlight recommendations to address inequities and disparities.

Histopathological Changes of Long-Term Peritoneal Dialysis Using Physiological Solutions: A Case Report and Review of the Literature.

BACKGROUND: Long-term peritoneal dialysis (PD), especially with nonphysiological solutions, is afflicted with the severe complication of encapsulating peritoneal sclerosis (EPS). Physiologic PD solutions have been introduced to reduce pH trauma. Data on peritoneal biopsies in pediatrics with long-term PD using physiological solutions are scant. CASE REPORT: We report an adolescent who had been on 10-h continuous hourly cycles using mostly 2.27% Physioneal™ for 5 years. There were two episodes of peritonitis in October 2017 (Klebsiella oxytoca) and May 2018 (Klebsiella pneumoniae), which were treated promptly. This adolescent, who lost two kidney transplants from recurrent focal and segmental glomerulosclerosis, underwent a peritoneal membrane biopsy at the time of a third PD catheter placement, 16 months after the second renal transplant. Laparoscopically, the peritoneum appeared grossly normal, but fibrosis and abundant hemosiderin deposition were noted on histology. The thickness of the peritoneum was 200-900 (mean 680) µm; normal for age of 14 years is 297 [IQR 229, 384] µm. The peritoneum biopsy did not show specific EPS findings, as the mesothelial cells were intact, and there was a lack of fibrin exudation, neo-membrane, fibroblast proliferation, infiltration, or calcification. CONCLUSIONS: While the biopsy was reassuring with respect to the absence of EPS, significant histopathological changes suggest that avoiding pH trauma may not ameliorate the effects of glucose exposure in long-term PD.

Longitudinal Changes in Cardiac Structure and Function in Pediatric Kidney Transplant Recipients.

BACKGROUND: Cardiovascular disease results in increased morbidity and mortality in pediatric kidney transplant recipients. Longitudinal changes in cardiac structure and function and the association with blood pressure control over time in pediatric kidney transplant recipients are unknown. METHODS: To determine the influence of blood pressure control on cardiac changes following pediatric kidney transplant, we conducted a retrospective cohort study of children who received their first kidney transplant at the Hospital for Sick Children from 2004 to 2015. Children were followed until transfer to adult care or censoring in July 2018. Cardiac structure and function parameters were collected from clinical echocardiograms and assessed using standardized scores. Blood pressure control was determined by systolic blood pressure Z scores (above or below the 90th percentile) in combination with antihypertensive medications. A segmented mixed-effects model assessed Z scores of interventricular septum thickness, left ventricular end-diastolic dimension, and left ventricular posterior wall dimension. RESULTS: Of 142 children included, 58% were men, mean age at transplant was 11 (±4.5) years, and average follow-up time was 4 (±3) years. All cardiac structural Z scores improved during follow-up. Interventricular septum thickness normalized at 4.0 years post-transplant. Left ventricular end-diastolic dimension normalized at 1.5 years post-transplant. Left ventricular posterior wall dimension normalized at 6.3 years post-transplant. Left ventricular mass index showed sustained improvement up to 12 years post-transplant. Individuals with uncontrolled blood pressure had increased left ventricular mass (ß=2.97 [95% CI, 0.77-5.16]). CONCLUSIONS: Cardiac structural abnormalities improve following kidney transplantation and normalize within 7 years, especially with controlled blood pressure. Strict blood pressure control is critical after pediatric kidney transplantation.

Mesoamerican Endemic Nephropathy (MeN): A Disease Reported in Adults That May Start Since Childhood?

Mesoamerican endemic nephropathy (MeN) is a type of chronic kidney disease (CKD) of uncertain etiology that occurs along the Pacific coast of the southern part of Mexico and Central America. During the past 20 years MeN has become a leading cause of death in the region, clamming close to 50,000 lives, with 40% of these deaths occurring in young people. The cause remains unknown, but most researchers believe in a multifactorial etiology that includes social determinants of poverty. Existing evidence suggests that subclinical kidney injury begins early in life and leads to a higher than expected prevalence of CKD among children in Central America. Access to health services in the region, specifically kidney replacement therapy, remains limited. We proposed a strategy to address the perceived needs and urge coordinated efforts of governments, academic organizations, and international bodies to develop a comprehensive plan of action to mitigate this situation among the vulnerable and economically disadvantaged population.

An Interdisciplinary Approach to Optimize the Care of Transitioning Adolescents and Young Adults with CKD.

Adolescents and young adults (AYAs) with CKD or end-stage kidney disease (ESKD) have unique medical, dental, psychosocial, neurocognitive, and academic needs and require close interdisciplinary collaboration to optimize their care. The etiology of CKD in AYAs is diverse compared to older adults. With their continuously improved survival, AYAs must start preparation for health-care transition (HCT) from pediatric- to adult-focused health care in the pediatric setting and it must continue at the adult-focused setting, given that their brain maturation and self-management skill acquisition occur until their mid-20s. While the growth and physical maturation of most visible body parts occur before 18 years of age, the prefrontal cortex of the brain, where reasoning, impulse control, and other higher executive functions reside, matures around 25 years of age. The HCT process must be monitored using patient- and caregiver-measuring tools to guide interventions. The HCT process becomes more complex when patients and/or caregivers have a language barrier, different cultural beliefs, or lower literacy levels. In this article, we discuss the unique comorbidities of pediatric-onset CKD/ESKD, provide information for a planned HCT preparation, and suggest interdisciplinary coordination as well as cultural and literacy-appropriate activities to achieve optimal patient outcomes.

Chronic Kidney Disease in Children Aged 6-15 Years and Associated Risk Factors in Apizaco, Tlaxcala, Mexico, a Pilot Study.

INTRODUCTION: Tlaxcala, a small state in central Mexico, has the highest prevalence of chronic kidney disease (CKD) deaths in population aged 5-14 in Mexico, most of them with unknown etiology. OBJECTIVE: To determine the prevalence of CKD in apparently healthy pediatric population in Apizaco, Tlaxcala. METHODS: A cross-sectional pilot study was carried out in children deemed as healthy; subjects with previous diagnosis of CKD were excluded. Informed consent was obtained in all cases. A physical examination was performed, a questionnaire was applied. Blood and urine samples were obtained for serum creatinine, urinalysis, and microalbumin/creatinine ratio. A second and third evaluation was performed after 6 and 18 months in those found with urinary anomalies/CKD to confirm the diagnosis. RESULTS: One hundred and nine subjects completed physical examination, which are the biological samples. Median age was 12 years. CKD stage 2 was confirmed in 5 subjects in the sixth month confirmation visit (4.6%). One patient accepted renal biopsy and Alport Syndrome was found. In a robust multivariate analysis, the risk factors related to reduction in the glomerular filtration rate were males -5.15 mL/min/1.73 m2 (p = 0.002), older participants as by -1.58 mL/min/1.73 m2 per year (p < 0.0001), and among participants living close to a river -3.76 mL/min/1.73 m2 (p = 0.033). DISCUSSION/CONCLUSION: The prevalence of CKD in the population studied in Apizaco Tlaxcala was confirmed in 4.6 cases per 100 inhabitants between 6 and 15 years. Males, older age, and living close to a river were the risk predictive factors. More studies are needed to determine the causes of the high CKD prevalence in this population.

A Cross-Sectional Study of Growth and Metabolic Bone Disease in a Pediatric Global Cohort Undergoing Chronic Hemodialysis.

OBJECTIVE: We sought to assess worldwide differences among pediatric patients undergoing hemodialysis. Because practices differ widely regarding nutritional resources, treatment practice, and access to renal replacement therapy, investigators from the Pediatric Investigation and Close Collaboration to examine Ongoing Life Outcomes, the pediatric subset of the MONitoring Dialysis Outcomes Cohort (PICCOLO MONDO) performed this cross-sectional study. We hypothesized that growth would be better in developed countries, possibly at the expense of bone mineral disease. STUDY DESIGN: In this cross-sectional study, we analyzed growth by height z score and recommended age-specific bone mineral metabolism markers from 225 patients <18 years of age maintained on hemodialysis, between the years of 2000 to 2012 from 21 countries in different regions. RESULTS: The patients' median age was 16 (IQR 14-17) years, and 45% were females. A height z score less than the third percentile was noted in 34% of the cohort, whereas >66% of patients reported normal heights, with patients from North America having the greatest proportion (>80%). More than 70% of the entire cohort had greater than the age-recommended levels of phosphorus, particularly in the Asia-Pacific and North America, where we also observed the greatest body mass index z score (0.99 ± 1.6) and parathyroid hormone levels (557.1 [268.4-740.5]). Below-recommended parathyroid hormone levels were noted in 26% and elevated levels in 61% of the entire sample, particularly in the Asia Pacific region. Lower-than-recommended calcium levels were noted in 36% of the entire cohort, particularly in Latin America. CONCLUSIONS: We found regional differences in growth- and age-adjusted bone mineral metabolism markers. Children from North America had the best growth, received the most dialysis, but also had the worst phosphate control and body mass index z scores.

Does Vitamin D Affect Chronic Renal Allograft Function in Pediatric Transplant Patients?

BACKGROUND Correction of hypovitaminosis D is simple, but it is unclear whether it is associated with an accelerated decline of renal allograft function in pediatric renal transplantation patients. This retrospective single center cohort study aimed at analyzing the effect of vitamin D and covariates on the slope of 1/creatinine after the first year. MATERIAL AND METHODS After ethics committee approval, 37 (14 male) pediatric renal transplant recipients on mycophenolate mofetil, who were followed between 2006 and 2014, were included in this study. We analyzed the slope of 1/creatinine, length of follow-up, average vitamin D levels, calcium, phosphate, alkaline phosphatase levels, intact parathyroid hormone (PTH) levels, and therapeutic drug monitoring parameters. RESULTS Median slope of 1/creatinine was -2.587e-006 L/µmol. We divided the 37 patients into two groups based on slope: 18 patients with a poorer slope and 19 patients with a good slope, with the median slope of 1/creatinine being significantly different between the two groups. Creatinine and cystatin C at one-year post-transplantation did not differ between the two groups. Average vitamin D levels were 71.4±31.01 pmol/L and identical in each group (averages 71.67 and 69.23 pmol/L, respectively). Only the mycophenolic acid coefficient of variation (MPA CV), which may promote formation of donor-specific antibodies, and PTH levels were significantly associated with 1/creatinine slope. CONCLUSIONS Our data suggest that the impact of mild and moderate decreased levels of vitamin D can have a mild impact on the progression of allograft dysfunction in transplant recipients. However, given the medication burden and adherence challenges in adolescents, correction of mildly decreased vitamin D levels may not be necessary.

Female Adolescents with Chronic or End-Stage Kidney Disease and Strategies for their Care.

The prevalence of chronic or end-stage kidney disease in pediatric girls is lower than in boys, however, girls have unique morbidities that can have great effect on their quality of life. For female adolescents, creatinine excretion peaks at approximately 14 years of age and is significantly less than males, owing to lower muscle mass. Females have higher nitric oxide activity, and estrogens may contribute to lower blood pressure. Females excrete less growth hormone during the prepubertal and pubertal years. Females between the ages of 8 and 10 years show increased levels of parathyroid hormone and vitamin D, however, female adolescents with chronic kidney disease have less estrogen and loss of the luteinizing hormone pulsatile pattern. These biological, hormonal, and physical changes affect the psychosocial aspects of female adolescents with chronic kidney disease/end-stage kidney disease, and they must learn to manage their health to achieve good outcomes. Patients and their parents must learn disease management through a customized health care transition preparation in both the pediatric- and adult-focused settings. Clinical strategies are suggested for the care of these special patients.

Deviations from the expected relationship between serum FGF23 and other markers in children with CKD: a cross-sectional study.

BACKGROUND: High levels of fibroblast growth factor-23 (FGF23) are associated with mortality. In chronic kidney disease (CKD), FGF23 levels rise as renal function declines. We analyzed the contribution of laboratory values to the variance of FGF23 levels in relationship to a curve of expected FGF23 levels for a given GFR. METHODS: Following approval by the research ethics boards, we measured FGF23, CysC eGFR, creatinine, urea, albumin, calcium, phosphate, vitamin D metabolites, PTH, alkaline phosphatase, CRP, and venous gases in 141 pediatric CKD patients (45, 37, 32, 13 and 14 CKD stages I, II, III, IV, and V, respectively). Data were expressed as median (25th, 75th percentile). RESULTS: FGF23 correlated significantly with CysC, CysC eGFR, PTH, 1.25 (OH)2 vitamin D, phosphate, and pH. The correlation of the latter three remained significant in the multivariate analysis. We calculated a formula for the expected FGF23 value for a given level of eGFR which reads Y = 1295 * e-0.07247*X + 38.35. Deviation by more than 20% from the curve also depended on phosphate, 1.25 (OH)2 vitamin D and pH. CONCLUSIONS: Our data emphasize the importance of phosphate and 1.25 (OH)2 vitamin D levels. The impact of acidosis on FGF23 warrants further studies.

The compelling case for therapeutic drug monitoring of mycophenolate mofetil therapy.

We have reviewed current evidence on the therapeutic drug monitoring (TDM) of mycophenolic acid (MPA) in relationship to drug efficacy and safety. The relationship between actual MPA exposure and mycophenolate mofetil (MMF) dose has been shown to be weak in children and adolescents. The TDM of MPA exposure should ideally be performed using full pharmacokinetic profiles or limited sampling strategies. Recent evidence has provided some rationale for using the post-dose trough level as a single measure. In terms of short-term efficacy, there is strong evidence that a MPA area under the time-concentration curve of >30 mg × h/L reduces acute rejection episodes early after renal transplantation, and there is evolving evidence that aiming for the same exposure over the long term may be a viable strategy to reduce the formation of donor-specific antibodies. Strong evidence also supports the existence of important drug interactions and age/developmental dependent differences in drug metabolism that may necessitate the need for TDM of MMF therapy. Based on these findings and given the substantial inter- and intra-patient variability of MPA exposure, it would appear that MMF therapy should be subject to TDM to avoid over- and under-dosing. This may be a viable strategy to reduce treatment-emergent adverse events and to increase the effective pediatric transplant survival rates.

Can the new CKD-EPI BTP-B2M formula be applied in children?

Although measuring creatinine to determine kidney function is currently the clinical standard, new markers such as beta-trace protein (BTP) and beta-2-microglobulin (B2M) are being investigated in an effort to measure glomerular filtration rate more accurately. In their recent publication, Inker et al. (Am J Kidney Dis 2015; 67:40-48) explored the use of these two relatively new markers in combination with some commonly available clinical characteristics in a large cohort of adults with chronic kidney disease. Their research led them to develop three formulae using BTP, B2M, and a combination of the two. The combined formula is particularly attractive as it removes all gender bias, which applies to both serum creatinine and cystatin C. Using data from a cohort of 127 pediatric patients from our center, we sought to determine whether these formulae would be equally as effective in children as in adults. Unfortunately, we found that the formulae cannot be applied to the pediatric population.

Assessment of glomerular filtration rate in the neonate: is creatinine the best tool?

PURPOSE OF REVIEW: This article answers the question of whether creatinine is the best biomarker for monitoring neonatal glomerular filtration rate (GFR) in view of recent advances in measuring neonatal renal function. RECENT FINDINGS: We rely largely on serum creatinine for the estimation of GFR in the newborn, even though creatinine is freely exchanged through the placenta. During the first few days of life, the serum creatinine reflects maternal renal function or the maternal creatinine. Back filtration of creatinine in preterm newborns is also a serious limitation. This review summarizes current knowledge on the prenatal and postnatal handling of creatinine as well as that of other, more novel biomarkers of GFR, such as cystatin C (CysC) and ß-trace protein (BTP). Only small amounts of CysC cross the placenta, whereas BTP does not cross the placenta at all. However, BTP measurements are not widely available. Recent studies on renal volumetry are also discussed. SUMMARY: Currently, CysC may be the most suitable marker of neonatal renal function, but its availability is still limited, it is more costly, and the best method of reporting acute kidney injury and neonatal estimated GFR remains to be established.

Developmental changes of MPA exposure in children.

BACKGROUND: Developmental changes (ontogeny) of drug disposition of Mycophenolate mofetil (MMF) have been understudied. METHODS: The charts of 37 pediatric renal transplant recipients (median age 7.3 years, median follow-up 7.8 (IQR 6.6, 14.3 years) who had regular mycophenolic acid (MPA) trough level monitoring in combination with tacrolimus (n = 31) or sirolimus (n = 6) therapy were analyzed retrospectively for their dose-normalized MPA exposure, steroid dose, albumin, hematocrit, and cystatin C estimated glomerular filtration rate (eGFR). Using appropriate univariate and multivariate methods, we determined whether MPA exposure was age dependent when controlling for the confounders. RESULTS: Dose-normalized MPA trough levels could be calculated in 2,128 (median 45/patient) instances. Spearman rank correlation analysis revealed that age correlated with dose-normalized MPA trough level for both body weight and body surface area, as well as serum albumin, hematocrit, steroid dose, and eGFR. In the multivariate analysis, serum albumin and steroid dose were not significant, and hematocrit only being significant when the youngest group of patients < 6 years of age was compared. eGFR was the most important confounder, but age dependency remained significant when controlling for all confounders. CONCLUSIONS: Small children are at a significantly greater risk for low MPA trough levels than adolescents, highlighting the need for pharmacokinetic monitoring of MPA.

Minimum mycophenolic acid levels are associated with donor-specific antibody formation.

Although de novo DSA are associated with inferior graft survival, there are no effective strategies to prevent their formation. Underexposure to MPA (prodrug: MMF) also contributes to rejection rates early after transplantation, but the effect of this phenomenon on the formation of DSA long-term post-transplantation is unknown. Data are expressed as mean (standard deviation). All available data from 32 renal transplant recipients (age at transplantation 7.5 [4.5] yr) on tacrolimus and MPA immunosuppression with an average follow-up of 9.4 (s.d. 4.6) yr were analyzed. DSA were measured using the Luminex assay (>500 MFI was considered DSA-positive). Tacrolimus and MPA levels were measured with the Abbot Tacro II and EMIT assay, respectively. Among 1964 MPA and 3462 tacrolimus trough levels, the average MPA trough level was 3.2 (1.5) mg/L and the average tacrolimus level was 6.7 (2.8) ng/mL. At last follow-up, only 5/32 patients had undetectable DSA, with 5/32 having no class I antibodies and 6/32 having no class II antibodies. DSA formation was associated with a lower minimum MPA trough level (0.27 [0.23] vs. 0.47 [0.18] mg) and cystatin C eGFR (48 [21] vs. 70 [23] mL/min/1.73 m(2)) for class I DSA formers. The average eGFR of patients without class I DSA was 70 (23) mL/min/1.73 m(2), whereas the average eGFR of patients with class I DSA was 48 (21) mL/min/1.73 m(2) (p = 0.0071). MPA trough levels <1.3 mg/L long-term post-transplantation are associated with the formation of DSA. The association between the formation of DSA and minimum MPA exposure may support a strategy for preventing the formation of DSA.