Anke Raaijmakers

Criteria for HNF1B analysis in patients with congenital abnormalities of kidney and urinary tract

BACKGROUND Congenital anomalies of kidneys and urinary tract (CAKUT) are the most predominant developmental disorders comprising ∼20-30% of all anomalies identified in the prenatal period. Mutations in hepatocyte nuclear factor 1-beta (HNF-1β) involved in the development of kidneys, liver, pancreas and urogenital tract are currently the most frequent monogenetic cause of CAKUT found in 10-30% of patients depending on screening policy and study design. We aimed to validate criteria for analysis of HNF1B in a prospective cohort of paediatric and adult CAKUT patients. METHODS We included CAKUT patients diagnosed in our paediatric and adult nephrology departments from January 2010 until April 2013 based on predefined screening criteria. Subjects presenting with at least one major renal criterion or one minor renal criterion combined with one or more extra-renal criteria in the personal history or a familial history of renal or extra-renal manifestations were considered eligible. RESULTS We prospectively screened 205 patients and detected HNF1B mutations in 10% [n = 20, 12 children, median age 4.2 (range 0-13.1) years and 8 adults, median age 34.8 (range 16.6-62) years]. We observed that bilateral renal anomaly, renal cysts from unknown origin, a combination of two major renal anomalies and hypomagnesaemia were predictive for finding HNF1B mutations (P < 0.001; P < 0.001; P = 0.004; P = 0.008, respectively). CONCLUSIONS We demonstrated that HNF1B mutations are responsible for ∼10% of CAKUT cases, both in children and in adults. Based on our results we propose adapted criteria for HNF1B analysis to reduce the screening costs without missing affected patients. These criteria should be reaffirmed in a larger validation cohort.

Design and feasibility of “PREMATurity as predictor of children's Cardiovascular–renal Health” (PREMATCH): A pilot study

Abstract The microvasculature and macrovasculature undergo extensive, organ-specific perinatal maturation. Multiple studies show associations between low birth weight and subsequent cardiovascular dysfunction in adulthood, suggesting that extreme preterm birth interferes with this maturation process. Therefore, we designed PREMATCH (PREMATurity as predictor of Cardiovascular–renal Health) to phenotype the microcirculation and macrocirculation during childhood in former preterm infants. A well-characterized cohort of former extreme preterm birth survivors and gender- and age-matched controls (aged 8–13 years) will be investigated for microvascular and macrovascular structure and function. In addition to cognitive performance and anthropometrics, we will investigate (i) the microvascular structure and function by endothelial function (photoplethysmography), sublingual capillary glycocalyx function (sidestream dark field imaging) and retinal structure (diameters of arterioles and venules); and (ii) the macrovascular phenotype by cardiac and renal ultrasound, repeated blood pressure measurements and arterial pulse-wave recordings. The PREMATCH study is unique in its design, and ongoing recruitment demonstrates excellent feasibility. The expectation is that the results of this study will identify risk factors during childhood for subsequent cardiovascular–renal disease in the adult life of former preterm infants, while further analysis on mediators in neonatal life of this cardiovascular–renal outcome may provide new information on perinatal risk factors. Trial registration: ClinicalTrials.gov identifier: NCT02147457.

Calculating the Social Rhythm Metric (SRM) and Examining Its Use in Interpersonal Social Rhythm Therapy (IPSRT) in a Healthy Population Study

In psychiatry, the social zeitgeber theory argues that social life provides important social cues that entrain circadian rhythms. Disturbance of these social cues might lead do dis-entrainment of circadian rhythms and evoke somatic symptoms that increase the risk of mood disorders. In preventing and treating patients with bipolar disorders, the Interpersonal and Social Rhythm Therapy (IPSRT) relies on the Social Rhythm Metric (SRM) to (re)establish patients’ social cues and an re-entrain circadian rhythms. Since the SRM quantifies social rhythms that are derived from a patient’s interaction with a social environment, this contribution (a) calculates the SRM of the social environment of a representative healthy population study (n = 1249), (b) evaluates the robustness of the SRM as a quantifier of social rhythms by matching the scores of the pilot study, revealing the near absence of variance across population characteristics and investigation months—circadian rhythms need to be entrained for every month and for everyone—and (c) examines its use in IPSRT by relating high SRM-scores to lower psychological distress (p = 0.004) and low SRM-scores to higher social and emotional dysfunction (p = 0.018).

Catch-up growth in the first two years of life in Extremely Low Birth Weight (ELBW) infants is associated with lower body fat in young adolescence

Aim To investigate growth patterns and anthropometrics in former extremely low birth weight (ELBW, <1000 g) children and link these outcomes to neurocognition and body composition in childhood. Methods ELBW children were examined at birth (n = 140), at 9 and 24 months (n≥96) and at approximately 11 years within the framework of the PREMATCH (PREMATurity as predictor children’s of Cardiovascular and renal Health) case–control (n = 93–87) study. Regional growth charts were used to convert anthropometrics into Z–scores. Catch–up growth in the first two years of life was qualified as present if ΔZ–score >0.67 SDS. At 11 years, anthropometrics, neurocognitive performance, body composition, grip strength and puberty scores were assessed. Results ELBW neonates displayed extra–uterine growth restriction with mean Z–scores for height, weight and head circumference of –0.77, –0.93 and –0.46 at birth, –1.61, –1.67 and –0.72 at 9 months, –1.22, –1.61 and –0.84 at 24 months, and –0.42, –0.49 and –1.09 at 11 years. ELBW children performed consistently worse on neurocognitive testing with an average intelligence quotient equivalent at 11 years of 92.5 (SD 13.1). Catch–up growth was not associated with neurocognitive performance. Compared to controls, ELBW cases had lower grip strength (13.6 vs. 15.9 kg) and percentage lean body weight (75.1 vs. 80.5%), but higher body fat (24.6 vs. 19.2%) and advanced puberty scores at 11 years (all P≤0.025). Catch–up growth for weight and height in the first two years of life in cases was associated with a lower percentage body fat compared to cases without catch–up growth (16.8% catch-up growth for weight vs. 25.7%, P<0.001; 20.9% catch-up for height vs. 25.8%, P = 0.049). Conclusions In young adolescence, former ELBW children still have difficulties to reach their target height. Compared to normal birth weight controls, ELBW adolescents show lower neurocognitive performance and grip strength and a higher percentage body fat, a potential risk factor for adverse health outcomes in adulthood. Our key finding is that catch–up growth in ELBW children in the first two years of life is associated with a lower percentage body fat and is therefore likely to be beneficial.

Urine of Preterm Neonates as a Novel Source of Kidney Progenitor Cells

In humans, nephrogenesis is completed prenatally, with nephrons formed until 34 weeks of gestational age. We hypothesized that urine of preterm neonates born before the completion of nephrogenesis is a noninvasive source of highly potent stem/progenitor cells. To test this hypothesis, we collected freshly voided urine at day 1 after birth from neonates born at 31-36 weeks of gestational age and characterized isolated cells using a single-cell RT-PCR strategy for gene expression analysis and flow cytometry and immunofluorescence for protein expression analysis. Neonatal stem/progenitor cells expressed markers of nephron progenitors but also, stromal progenitors, with many single cells coexpressing these markers. Furthermore, these cells presented mesenchymal stem cell features and protected cocultured tubule cells from cisplatin-induced apoptosis. Podocytes differentiated from the neonatal stem/progenitor cells showed upregulation of podocyte-specific genes and proteins, albumin endocytosis, and calcium influx via podocyte-specific transient receptor potential cation channel, subfamily C, member 6. Differentiated proximal tubule cells showed upregulation of specific genes and significantly elevated p-glycoprotein activity. We conclude that urine of preterm neonates is a novel noninvasive source of kidney progenitors that are capable of differentiation into mature kidney cells and have high potential for regenerative kidney repair.

Retinal microvascular diameter, a hypertension-related trait, in ECG-gated vs. non-gated images analyzed by IVAN and SIVA

The diameters of the retinal microvasculature reflect intermediate target organ damage and predict adverse health outcomes. In view of the pulsatility of the cerebral blood flow and refinement of software used for off-line analysis, we assessed the repeatability of retinal microvascular diameters in ECG-gated vs. non-gated images using nonmydriatic retinal photographs (Canon Cr-DGi visualization system) postprocessed by IVAN (Vasculomatic ala Nicola, version 1.1) or SIVA (Singapore I Vessel Assessment, version 3.6). Using these algorithms, we determined the central retinal arteriolar (CRAE) and venular (CRVE) equivalents and their ratio (arteriole-to-venule ratio (AVR)). The estimates of CRAE (mean, 158.5 μm), CRVE (222.5 μm) and AVR (0.71) in 10 volunteers were unaffected (P⩾0.059) by ECG gating. We assessed intragrader repeatability by the Bland and Altman approach in 30 participants with non-gated images and 30 with ECG-gated photographs. Repeatability, which was expressed as the percentage of near maximal variability (4-s.d. range), did not improve with ECG gating. Using SIVA, CRAE and CRVE were systematically larger (P⩽0.031), and the AVR estimates were similar (P⩾0.15) compared with IVAN. The differences (IVAN−SIVA) averaged −5.4 μm for CRAE, −3.9 μm for CRVE and −0.012 for AVR in the non-gated images and −3.3 μm, −6.9 μm and 0.006, respectively, in the ECG-gated photographs. In conclusion, ECG gating does not affect estimates of the retinal microvascular diameters or improve intragrader repeatability. SIVA yields slightly but significantly larger estimates of the retinal arteriolar and venular diameters. Combining historical readings analyzed by IVAN with more recent readings by SIVA is possible only for AVR and is not recommended for either CRAE or CRVE.

Does Extremely Low Birth Weight Predispose to Low-Renin Hypertension?

Low birth weight and prematurity are risk factors for hypertension in adulthood. Few studies in preterm or full-term born children reported on plasma renin activity (PRA). We tested the hypothesis that renin might modulate the incidence of hypertension associated with prematurity. We enrolled 93 prematurely born children with birth weight <1000 g and 87 healthy controls born at term, who were all examined at ≈11 years. Renal length and glomerular filtration rate derived from serum cystatin C were 0.28 cm (95% confidence interval, 0.09–0.47) and 11.5 mL/min per 1.73 m2 (6.4–16.6) lower in cases, whereas their systolic/diastolic blood pressure (BP) was 7.5 mm Hg (4.8–10.3)/4.0 mm Hg (2.1–5.8) higher (P<0.001 for all). The odds of having systolic prehypertension or systolic hypertension associated with extreme low birth weight were 6.43 (2.52–16.4; P<0.001) and 10.9 (2.46–48.4; P=0.002). Twenty-four hours of urinary sodium excretion was similar in cases and controls (102.1 versus 106.8 mmol; P=0.47). Sodium load per nephron was estimated as sodium excretion divided by kidney length (mmol/cm). PRA was 0.54 ng/mL per hour (0.23–0.85; P=0.001) lower in cases. PRA, systolic BP, and sodium load were available in 43 cases and 56 controls. PRA decreased with systolic BP (slope −0.022 ng/mL per hour/−mm Hg; P=0.048), but was unrelated to sodium load (slope +0.13 mmol/cm−mm Hg; P=0.54). The slope of PRA on systolic BP was similar (P=0.17) in cases and controls. In conclusion, extremely low birth weight predisposes young adolescents to low-renin hypertension, but does not affect the inverse association between PRA and BP. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT02147457.

Neonatal creatinemia trends as biomarker of subsequent cognitive outcome in extremely low birth weight neonates

BACKGROUND AND AIMS Serum creatinine is traditionally used as a marker of renal function in neonates and relates to gestational age and disease severity in extremely low birth weight (ELBW) infants. Creatinine is commonly used as a biomarker for early morbidity, but we aim to compare postnatal creatinemia trends as a biomarker for subsequent cognitive outcome. We hypothesize that impaired microcirculation not only in the kidney, but also in general (i.e. brain development) can explain this possible link. STUDY DESIGN AND OUTCOME MEASURES A cohort of ELBW infants was analyzed by Bayley Scales of Infant Development (BSID-II) at the corrected age of 2years old. Besides other perinatal indicators, neonatal creatinemia trends of survivors (n=140) and BSID scores (n=96) are compared and analyzed using optimal matching analysis. Hierarchical clustering analysis is applied to identify createnimia trends. RESULTS Four different creatinemia trends were identified (persistently high, normal, low, high but normalizing). A low creatinemia trend is significantly associated with the lowest percentages of postnatal corticosteroids, NSAIDS and intraventricular hemorrhage (p=0.005, p=0.013 and p=0.041 respectively) compared to a normal or persistently high creatinemia trend and associated with the best cognitive outcome (+13 points compared to the mean creatinemia trend and +23 points compared to a persistently high creatinemia trend). CONCLUSIONS Creatinemia trends after birth are not only useful to predict renal function, but are also associated with cognitive outcome in extremely low birth weight infants. Neonates who have low creatinemia trends after birth, have the highest BSID scores at the age of two years old.

Catch-up growth in former preterm neonates: No time to waste

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Association between cognition and the retinal microvasculature in 11-year old children born preterm or at term

Background Retinal microvessels can be visualized non-invasively and mirror the status of the cerebral microvasculature. Aims To investigate whether in young children born prematurely or at term cognitive performance is related to retinal microvascular traits. Study design, subjects In 93 prematurely born infants (birth weight < 1000 g) and 87 controls born at term, we measured head circumference (HC) and determined intelligence quotient (IQ) by combining matrix reasoning and spatial span (Wechsler Non-Verbal test, Dutch version) and post-processed retinal photographs using Singapore I Vessel Assessment software (version 3.6). Outcome measures, results Compared with controls, cases had smaller HC (51.7 vs 53.4 cm; p < 0.001), lower IQ (93.9 vs 109.2; p < 0.001), smaller retinal arteriolar (CRAE; 162.7 vs 174.0 μm; p < 0.001) and venular (CRVE; 234.9 vs 242.8 μm; p = 0.003) diameters and CRAE/CRVE ratio (0.69 vs 0.72; p = 0.001). A 1-SD decrease in CRAE was associated with smaller HC (−0.53 cm; p < 0.001) and lower total IQ (−3.74; p < 0.001), matrix reasoning (−1.77; p = 0.004) and spatial span (−2.03; p = 0.002). These associations persisted after adjustment for sex and age and risk factors for cognitive impairment, including blood pressure, body mass index and parental educational attainment. Conclusions HC, total IQ, matrix reasoning and spatial span decrease with smaller retinal arteriolar diameter. Our findings suggest that maldevelopment of the cerebral microcirculation, as mirrored by the retinal microvasculature, has lasting effects on the growth of the brain and cognitive performance of prematurely born children.