J. Bryan Carmody

Recognition and Reporting of AKI in Very Low Birth Weight Infants

BACKGROUND AND OBJECTIVES AKI is associated with both increased short-term morbidity and mortality and greater long-term risk for CKD. This study determined the prevalence of AKI among very low birth weight infants using a modern study definition, evaluated the frequency of AKI diagnosis reporting in the discharge summary, and determined whether infants were referred to a pediatric nephrologist for AKI follow-up. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Records of very low birth weight infants admitted to a level IV neonatal intensive care unit from 2008 to 2011 were reviewed. AKI was classified using the Kidney Disease: Improving Global Outcomes definition modified to include only serum creatinine. RESULTS AKI occurred in 39.8% of 455 infants; 75 (16.5%) infants experienced multiple episodes of AKI, and 8 (2%) infants were discharged with an abnormal last creatinine. Updated clinical risk index for babies score >10 (odds ratio, 12.9; 95% confidence interval, 7.8 to 21.4) and gestational age <28 weeks (odds ratio, 10.6; 95% confidence interval, 6.8 to 16.7) were strongly associated with AKI in univariate analyses. AKI was associated with increased mortality (odds ratio, 4.0; 95% confidence interval, 1.4 to 11.5) and length of stay (11.7 hospital days; 95% confidence interval, 5.1 to 18.4), even after accounting for gestational age, birth weight, and updated clinical risk index for babies score. AKI was recorded in the discharge summary for only 13.5% of AKI survivors. No infants were referred to a nephrologist for AKI follow-up. CONCLUSIONS AKI occurred in 40% of very low birth weight infants and was concentrated in the most premature and severely ill infants. One in six infants experienced multiple episodes of AKI, and a small number of infants was discharged with an elevated serum creatinine. Reporting a history of AKI in the discharge summary occurred infrequently, and referral to a nephrologist for AKI follow-up did not occur, highlighting areas for quality improvement.

Nephron number and its determinants in early life: a primer

Although there is wide variation, humans possess on average 900,000 nephrons per kidney. So far as is known, nephrons cannot regenerate; therefore, an individual’s nephron endowment has profound implications in determining his or her long-term risk of developing chronic kidney disease. Most of the variability in human nephron number is determined early in life. Nephrogenesis is a complex and carefully orchestrated process that occurs during a narrow time window until 36 weeks gestation in humans, and disruption of any part of this sequence may lead to reduced nephron number. In utero, genetic abnormalities, toxic insults, and nutritional deficiencies can each alter final nephron number. Infants born prematurely must continue nephrogenesis in an ex utero environment where there may be multiple threats to successful nephrogenesis. Once the nephron endowment is determined, postnatal factors (such as acute kidney injury or chronic illnesses) can only decrease nephron number. Current techniques for estimating nephron number require an invasive procedure or complete destruction of the tissue, making noninvasive means for counting nephron surgently needed. A better understanding of nephron number and its determinants, particularly during growth and maturation, could allow the development of therapies to support, prolong, or resume nephrogenesis.

Early-life course socioeconomic factors and chronic kidney disease.

Kidney failure or ESRD affects approximately 650,000 Americans, whereas the number with earlier stages of CKD is much higher. Although CKD and ESRD are usually associated with adulthood, it is likely that the initial stages of CKD begin early in life. Many of these pathways are associated with low birth weight and disadvantaged socioeconomic status (SES) in childhood, translating childhood risk into later-life CKD and kidney failure. Social factors are thought to be fundamental causes of disease. Although the relationship between adult SES and CKD has been well established, the role of early childhood SES for CKD risk remains obscure. This review provides a rationale for examining the association between early-life SES and CKD. By collecting data on early-life SES and CKD, the interaction with other periods in the life course could also be studied, allowing for examination of whether SES trajectories (eg, poverty followed by affluence) or cumulative burden (eg, poverty at multiple time points) are more relevant to lifetime CKD risk.

Pre-operative renal volume predicts peak creatinine after congenital heart surgery in neonates

OBJECTIVE Acute kidney injury is common in neonates following surgery for congenital heart disease. We conducted a retrospective analysis to determine whether neonates with smaller pre-operative renal volume were more likely to develop post-operative acute kidney injury. DESIGN/SETTING We conducted a retrospective review of 72 neonates who underwent congenital heart surgery for any lesion other than patent ductus arteriosus at our institution from January 2007 to December 2011. Renal volume was calculated by ultrasound using the prolate ellipsoid formula. The presence and severity of post-operative acute kidney injury was determined both by measuring the peak serum creatinine in the first 7 days post-operatively and by using the Acute Kidney Injury Network scoring system. RESULTS Using a linear change point model, a threshold renal volume of 17 cm³ was identified. Below this threshold, there was an inverse linear relationship between renal volume and peak post-operative creatinine for all patients (p = 0.036) and the subgroup with a single morphologic right ventricle (p = 0.046). There was a non-significant trend towards more acute kidney injury using Acute Kidney Injury Network criteria in all neonates with renal volume ≤17 cm³ (p = 0.11) and in the subgroup with a single morphologic right ventricle (p = 0.17). CONCLUSIONS Pre-operative renal volume ≤17 cm³ is associated with a higher peak post-operative creatinine and potentially greater risk for post-operative acute kidney injury for neonates undergoing congenital heart surgery. Neonates with a single right ventricle may be at higher risk.

Association Between Early Caffeine Citrate Administration and Risk of Acute Kidney Injury in Preterm Neonates: Results From the AWAKEN Study

Importance Acute kidney injury (AKI) occurs commonly in preterm neonates and is associated with increased morbidity and mortality. Objectives To examine the association between caffeine citrate administration and AKI in preterm neonates in the first 7 days after birth and to test the hypothesis that caffeine administration would be associated with reduced incidence and severity of AKI. Design, Setting, and Participants This study was a secondary analysis of the Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) study, a retrospective observational cohort that enrolled neonates born from January 1 to March 31, 2014. The dates of analysis were October 2016 to December 2017. The setting was an international, multicenter cohort study of neonates admitted to 24 participating level III or IV neonatal intensive care units. Participants met the original inclusion and exclusion criteria of the AWAKEN study. Additional exclusion criteria for this study included participants greater than or equal to 33 weeks’ gestation at birth, admission after age 7 days, use of theophylline in the neonatal intensive care unit, or lack of data to define AKI. There were 675 preterm neonates available for analysis. Exposure Administration of caffeine in the first 7 days after birth. Main Outcomes and Measures The primary outcome was the incidence of AKI (based on the modified neonatal Kidney Disease: Improving Global Outcomes [KDIGO] definition) in the first 7 days after birth. The hypothesis that caffeine administration would be associated with reduced AKI incidence was formulated before data analysis. Results The study cohort (n = 675) was 55.4% (n = 374) male, with a mean (SD) gestational age of 28.9 (2.8) weeks and a mean (SD) birth weight of 1285 (477) g. Acute kidney injury occurred in 122 neonates (18.1%) in the first 7 days after birth. Acute kidney injury occurred less frequently among neonates who received caffeine than among those who did not (50 of 447 [11.2%] vs 72 of 228 [31.6%], P < .01). After multivariable adjustment, administration of caffeine remained associated with reduced odds of developing AKI (adjusted odds ratio, 0.20; 95% CI, 0.11-0.34), indicating that for every 4.3 neonates exposed to caffeine one case of AKI was prevented. Among neonates with early AKI, those receiving caffeine were less likely to develop stage 2 or 3 AKI (adjusted odds ratio, 0.20; 95% CI, 0.12-0.34). Conclusions and Relevance Caffeine administration in preterm neonates is associated with reduced incidence and severity of AKI. Further studies should focus on the timing and dosage of caffeine to optimize the prevention of AKI.

How to use… serum creatinine, cystatin C and GFR

Glomerular filtration rate (GFR) is the best overall measure of kidney function. The GFR is relatively low at birth but increases through infancy and early childhood to reach adult levels of approximately 120 mL/min/1.73 m2 by age 2. While GFR can be measured most accurately by the urinary clearance of an exogenous ideal filtration marker such as inulin, it is more clinically useful to estimate GFR using a single serum measurement of an endogenous biomarker such as creatinine or cystatin C. When in steady state, there is an inverse relationship between creatinine/cystatin C and GFR, allowing GFR to be estimated from either using simple equations. Because of the non-linear relationship between creatinine/cystatin C and GFR, relatively small initial increases in these markers represent significant decreases in GFR. While cystatin C is produced by all nucleated cells, creatinine is a waste product of muscle metabolism and is therefore influenced by diet and muscle mass/body habitus. Decreased GFR is used to diagnose and stage chronic kidney disease (CKD) using the Kidney Disease: Improving Global Outcomes system. A diagnosis of CKD requires GFR <60 mL/min/1.73 m2 for more than 3 months; higher GFR also represents CKD if evidence of kidney damage (such as albuminuria or abnormal imaging) is present. Changes in serum creatinine and urine output are used to diagnose acute kidney injury. It is possible to calculate a kinetic GFR when the creatinine is changing rapidly, though more complex calculations are required.

Metabolic risk factors in nondiabetic adolescents with glomerular hyperfiltration.

Background. In adults, glomerular hyperfiltration is associated with abnormalities related to metabolic syndrome (MetS). We investigated if glomerular hyperfiltration was associated with metabolic abnormalities in US adolescents without diabetes. Methods. We analyzed data from the National Health and Nutrition Examination Survey, a nationally representative sample of US adolescents ages 12–17 years. Estimated glomerular filtration rate (eGFR) was determined using the bedside Schwartz equation; adolescents with hyperfiltration (eGFR >120 mL/min/1.73 m2) were compared to those with normal eGFR (90–120 mL/min/1.73 m2). We calculated mean levels of factors related to MetS, insulin resistance and diabetes risk, adjusting for age, race/ethnicity, sex, socioeconomic status, and BMI z‐score. Results. Overall, 11.8% of US adolescents had hyperfiltration [95% confidence interval (CI) 10.6–13.0]. Hyperfiltration prevalence varied by race (20.2% in Hispanics versus 9.8% non‐Hispanic whites and 7.4% non‐Hispanic blacks; P< 0.001). Compared to those with normal eGFR, adolescents with hyperfiltration had higher adjusted mean levels of triglyceride (83 versus 77 mg/dL; P = 0.05), fasting insulin (15.1 versus 12.9; P< 0.001) and homeostatic model assessment of insulin resistance (3.52 versus 3.01; P = 0.001). These differences persisted after adjusting for BMI z‐score. Adolescents with hyperfiltration had increased odds for hypertriglyceridemia [odds ratio 1.58 (95% CI 1.11–2.23)]. These relationships varied by racial/ethnic group. Conclusions. Glomerular hyperfiltration is associated with hypertriglyceridemia and increased insulin resistance independent of BMI z‐score in a nationally representative sample of US adolescents. Hispanic adolescents are more likely to have hyperfiltration than other racial/ethnic groups. These findings could have significance in evaluations of renal function and MetS in adolescents to identify related risks and target interventions.

Dietary sodium, dietary potassium, and systolic blood pressure in US adolescents

Both high sodium and low potassium diets are associated with hypertension, but whether these risk factors are distinct or overlapping has not been thoroughly investigated. The authors evaluated the relationship between dietary sodium, potassium, and high systolic blood pressure among 4716 adolescents aged 12 to 14 years who participated in the National Health and Nutrition Examination Survey from 1999 to 2012. There was no association with blood pressure across most values of sodium or potassium intake. However, participants who reported sodium intake ≥7500 mg/d, potassium <700 mg/d, or sodium‐potassium ratio ≥2.5 had increased odds for high systolic blood pressure (≥95th percentile for age, sex, and height). Although the high sodium and low potassium groups did not overlap, 49.2% of these adolescents also had a sodium‐potassium ratio ≥2.5. In young adolescents, both excessive sodium and limited potassium are associated with high systolic blood pressure, but the balance between sodium and potassium intake may be more useful in explaining blood pressure in this population.

Birthweight and serum uric acid in American adolescents

Elevated serum uric acid is associated with hypertension and chronic kidney disease. We evaluated the relationship between birthweight and uric acid in a nationally representative sample of 5390 US adolescents aged 12–15 in the National Health and Nutrition Examination Survey from 1999 to 2012. There was an inverse association between birthweight and uric acid after adjustment for sex, age, race, obesity, and dietary sodium intake. Each 1 kg increase in birthweight was associated with decreased uric acid by 0.11 mg/dL (95% CI: −0.16 to −0.06; model R2 = 0.32). This relationship was stronger in adolescents with elevated blood pressure (β = –0.25; 95% CI: −0.44 to −0.06; R2 = 0.50) but persisted in adolescents with normal blood pressure (β = –0.10; 95% CI: −0.15 to −0.05; R2 = 0.31). In conclusion, lower birthweight is associated with higher uric acid in US adolescents. These findings may support the hypothesis that reduced nephron number is associated with elevated uric acid.