Longitudinal relationship between albuminuria in infancy and childhood.

BACKGROUND: Mildly increased albuminuria is common in the general adult population and is a strong predictor for cardiovascular events, even in otherwise healthy individuals. The underlying pathophysiological process could be endothelial dysfunction. Previously, we reported that increased albuminuria can also be found in 2-year-olds from the general population. We hypothesized that some individuals have constitutionally higher levels of albuminuria, possibly as an expression of early or inborn endothelial dysfunction. The aim of this study is to evaluate longitudinal persistence of albuminuria from infancy into school age. METHODS: In the population-based GECKO (Groningen Expert Center for Kids with Obesity) cohort, urine was collected from 816 children at the age of 2 years as well as 12 years (random urine and first morning void urine, respectively). We evaluated prevalence and persistence of increased albuminuria (UACR ≥ 3 mg/mmol) at the two time points. RESULTS: The prevalence of UACR ≥ 3 mg/mmol at 2 and 12 years of age was 31.9% (95% CI 28.7-35.2) and 3.1% (95% CI 2.0-4.5), respectively. UACR < 3 mg/mmol at both 2 and 12 years of age was present in 540 children (66.2%). Only 9 children (3.5%) of the 260 children with an UACR ≥ 3 mg/mmol at 2 years had an UACR ≥ 3 mg/mmol at 12 years (p < 0.001). CONCLUSION: Albuminuria in 2-year-olds does largely not persist until the age of 12, indicating that albuminuria at 2 years of age is not a marker for constitutional endothelial dysfunction in this cohort. A higher resolution version of the Graphical abstract is available as Supplementary information.

Albuminuria and markers for cardiovascular risk in 12-year-olds from the general Dutch population: a cross-sectional study.

In adults, albuminuria represents a risk factor for cardiovascular disease and is associated with hypertension and obesity. Pediatric data from the general population are inconsistent and largely based on randomly collected urine. A possible association between antenatal programming and albuminuria at school age has still to be investigated. The purpose of this study is to assess albuminuria in first morning void urine samples in a population-based pediatric cohort and to investigate cross-sectionally the association with factors related to cardiovascular risk. Moreover, we investigate the possible association of antenatal factors with albuminuria. A first morning void urine sample was collected in the population-based GECKO (Groningen Expert Center for Kids with Obesity) Drenthe cohort at the age of 12 years. We investigated cross-sectionally associations between albuminuria and body mass index (BMI), waist circumference (WC), blood pressure (BP) and antenatal factors. The prevalence of UACR (urinary albumin-creatinine ratio) ≥ 3 mg/mmol was 3.3% (95%CI 2.3-4.2). In a multivariate linear regression model, UAC was negatively associated with z-BMI (ß-0.08, p = 0.013) and positively with z-systolic BP (ß 0.09, p = 0.006), model significance p = 0.002. UACR was negatively associated with z-BMI (ß - 0.13, p < 0.001) and positively with z-diastolic BP (ß 0.09, p = 0.003), model significance p = 0.001. Albuminuria was not significantly associated with antenatal factors such as gestational age and standardized birth weight. CONCLUSIONS:  Albuminuria in first morning void urine in 12-year-olds has a lower prevalence than previously reported by randomly collected samples. A negative association between albuminuria and BMI is confirmed. A positive association with blood pressure, but no association with antenatal factors was found. WHAT IS KNOWN: • While, in adults, albuminuria is a recognized risk factor for cardiovascular disease and is associated with hypertension and obesity, pediatric data are inconsistent and largely based on randomly collected urine. • A possible association between antenatal programming and albuminuria at school age has still to be investigated. WHAT IS NEW: • In this population study on first morning void urine samples from 12-year-olds of the general population, albuminuria is negatively associated with body mass index, and positively associated with blood pressure, while there is no association with antenatal factors. • The prevalence of albuminuria at 12 years is lower than previously reported in studies based on randomly collected urine samples, probably due to elimination of orthostatic proteinuria.

Early Proteinuria Lowering by Angiotensin-Converting Enzyme Inhibition Predicts Renal Survival in Children with CKD.

Background Although pharmacotherapeutic proteinuria lowering was found to be nephroprotective in adults, the predictive value of early drug-induced proteinuria reduction for long-term renal survival in pediatric CKD is unknown. We analyzed data from the ESCAPE Trial for a potential association between initial antiproteinuric effect of standardized angiotensin-converting enzyme (ACE) inhibition and renal disease progression in children with CKD.Methods In total, 280 eligible children with CKD stages 2-4 (mean age 11.7 years old, median eGFR 46 ml/min per 1.73 m2, 71% congenital renal malformations) received a fixed dose of ramipril (6 mg/m2 per day) and were subsequently randomized to conventional or intensified BP control. We assessed initial proteinuria reduction from baseline to first measurement on ramipril (at 2.5±1.3 months). We used multivariable Cox modeling to estimate the association between initial proteinuria reduction and the risk of reaching a renal end point (50% eGFR decline or ESRD), which occurred in 80 patients during 5 years of observation.Results Ramipril therapy lowered proteinuria by a mean of 43.5% (95% confidence interval, 36.3% to 49.9%). Relative to proteinuria reduction <30%, 30%-60% and >60% reduction resulted in hazard ratios (95% confidence intervals) of 0.70 (0.40 to 1.22) and 0.42 (0.22 to 0.79), respectively. This association was independent of age, sex, CKD diagnosis, baseline eGFR, baseline proteinuria, initial BP, and concomitant BP reduction.Conclusions The early antiproteinuric effect of ACE inhibition is associated with long-term preservation of renal function in children with CKD. Proteinuria lowering should be considered an important target in the management of pediatric CKD.

Prevalence and distribution of (micro)albuminuria in toddlers.

BACKGROUND: Microalbuminuria is common in the general adult population, with a prevalence of ∼7%, and is an independent indicator of renal and cardiovascular risks. Whether albuminuria is acquired during life (as a result of hypertension/diabetes) or is congenital and already present at birth is unknown. We studied the prevalence of microalbuminuria in toddlers and compared the distribution of albuminuria with that of the general adult population. In addition, we looked for possible associations between microalbuminuria and antenatal, postnatal and maternal factors. METHODS: The urinary albumin concentration (UAC) was measured in 1352 children and the urinary albumin:creatinine ratio (UACR) in 1288 children from the Groningen Expert Center for Kids with Obesity (GECKO) Drenthe cohort (age range 20-40 months). Albuminuria distribution was compared with the albuminuria distribution in 40 854 participants of the general adult cohort of the Prevention of Renal and Vascular End stage Disease (PREVEND) study. Associations between albuminuria (expressed as UAC and UACR) and antenatal, postnatal and maternal factors were tested with linear regression analysis. RESULTS: The median UAC in the GECKO study was 2.3 mg/L (5th-95th percentiles: 2.1-25.5) and in the PREVEND study it was 6.0 mg/L (2.3-28.6) (P distribution comparison 0.053). The prevalence of UAC ≥ 20 mg/L was 6.9% in the GECKO study and 7.8% in the PREVEND study (P = 0.195). The prevalence of UACR ≥ 30 mg/g in the GECKO study was 23.4%. UAC and UACR were lower in boys. UAC was not associated with other determinants, but UACR was associated with age and gestational diabetes. CONCLUSIONS: The distribution of UAC and the prevalence of UAC > 20 mg/L in toddlers and in the young general adult population are comparable. These findings suggest that microalbuminuria is a congenital condition that may predispose to a higher cardiovascular risk later in life.

Discontinuation of RAAS Inhibition in Children with Advanced CKD.

BACKGROUND AND OBJECTIVES: Although renin-angiotensin-aldosterone system inhibition (RAASi) is a cornerstone in the treatment of children with CKD, it is sometimes discontinued when kidney function declines. We studied the reasons of RAASi discontinuation and associations between RAASi discontinuation and important risk markers of CKD progression and on eGFR decline in the Cardiovascular Comorbidity in Children with CKD study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this study, 69 children with CKD (67% male, mean age 13.7 years, mean eGFR 27 ml/min per 1.73 m2) who discontinued RAASi during prospective follow-up were included. Initial change in BP, albuminuria, and potassium after discontinuation were assessed (median time 6 months). Rate of eGFR decline (eGFR slope) during a median of 1.9 years before and 1.2 years after discontinuation were estimated using linear mixed effects modeling. RESULTS: Physician-reported reasons for RAASi discontinuation were increase in serum creatinine, hyperkalemia, and symptomatic hypotension. After discontinuation of RAASi, BP and albuminuria increased, whereas potassium decreased. eGFR declined more rapidly after discontinuation of RAASi (-3.9 ml/min per 1.73 m2 per year; 95% confidence interval, -5.1 to -2.6) compared with the slope during RAASi treatment (-1.5 ml/min per 1.73 m2 per year; 95% confidence interval, -2.4 to -0.6; P=0.005). In contrast, no change in eGFR slope was observed in a matched control cohort of patients in whom RAASi was continued. CONCLUSIONS: Discontinuation of RAASi in children with CKD is associated with an acceleration of kidney function decline, even in advanced CKD.