Joanna A.E. van Wijk

Pediatric acute kidney injury in the ICU: an independent evaluation of pRIFLE criteria

ObjectiveThe present study was undertaken to evaluate the practicability of the proposed pediatric RIFLE (pRIFLE) criteria in a patient population at risk for acute kidney injury (AKI) and to analyze the prevalence and association of AKI as defined by pRIFLE with mortality.DesignRetrospective, descriptive cohort study.SettingSingle-center, 9-bed PICU facility.PatientsChildren with respiratory failure requiring mechanical ventilation for more than 4 days admitted between January 2002 and December 2006.InterventionsNone.Measurements and resultsData of 103 patients were studied. Median age was 4.5 years (range 1 month–17 years). Six patients received renal replacement therapy. Seventeen patients (17%) died. Sixty patients (58%) developed AKI by pRIFLE. Mean time to attainment of the first RIFLE stratum was 1.9 ± 1.6 days. By pRIFLE, 34 of the 60 patients fulfilled the maximum AKI criteria on the first day after admission based on the estimated creatinine clearance criterion. Patients with AKI according to the pRIFLE scoring system had five times higher mortality than patients without AKI (25 vs. 5%, P < 0.05).ConclusionsWe observed a high incidence of significant AKI in a PICU population at risk, which was associated with high mortality. Pediatric RIFLE criteria may guide in the early identification of patients at risk for AKI and in the initiation of therapy.

ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3

Nephronophthisis is an autosomal recessive cystic kidney disease that leads to renal failure in childhood or adolescence. Most NPHP gene products form molecular networks. Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3. We show that ANKS6 localizes to the proximal cilium and confirm its role in renal development through knockdown experiments in zebrafish and Xenopus laevis. We also identify six families with ANKS6 mutations affected by nephronophthisis, including severe cardiovascular abnormalities, liver fibrosis and situs inversus. The oxygen sensor HIF1AN hydroxylates ANKS6 and INVS and alters the composition of the ANKS6-INVS-NPHP3 module. Knockdown of Hif1an in Xenopus results in a phenotype that resembles loss of other NPHP proteins. Network analyses uncovered additional putative NPHP proteins and placed ANKS6 at the center of this NPHP module, explaining the overlapping disease manifestation caused by mutation in ANKS6, NEK8, INVS or NPHP3.

Atypical hemolytic uremic syndrome in children: complement mutations and clinical characteristics

BackgroundMutations in complement factor H (CFH), factor I (CFI), factor B (CFB), thrombomodulin (THBD), C3 and membrane cofactor protein (MCP), and autoantibodies against factor H (αFH) with or without a homozygous deletion in CFH-related protein 1 and 3 (∆CFHR1/3) predispose development of atypical hemolytic uremic syndrome (aHUS).MethodsDifferent mutations in genes encoding complement proteins in 45 pediatric aHUS patients were retrospectively linked with clinical features, treatment, and outcome.ResultsIn 47% of the study participants, potentially pathogenic genetic anomalies were found (5xCFH, 4xMCP, and 4xC3, 3xCFI, 2xCFB, 6xαFH, of which five had ∆CFHR1/3); four patients carried combined genetic defects or a mutation, together with αFH. In the majority (87%), disease onset was preceeded by a triggering event; in 25% of cases diarrhea was the presenting symptom. More than 50% had normal serum C3 levels at presentation. Relapses were seen in half of the patients, and there was renal graft failure in all except one case following transplant.ConclusionsPerforming adequate DNA analysis is essential for treatment and positive outcome in children with aHUS. The impact of intensive initial therapy and renal replacement therapy, as well as the high risk of recurrence of aHUS in renal transplant, warrants further understanding of the pathogenesis, which will lead to better treatment options.

Unilateral multicystic dysplastic kidney: a meta-analysis of observational studies on the incidence, associated urinary tract malformations and the contralateral kidney

BACKGROUND Many papers are published on cohorts with unilateral multicystic dysplastic kidney (MCDK) patients, but show variable results as to the incidence of associated urinary tract abnormalities. The objective of this study was to describe the status of the urinary tract, including contralateral hypertrophy and malformations, in patients with unilateral MCDK based on a meta-analysis of the literature, taking into account the timing of diagnosis (pre- versus postnatal) as a possible source of bias. METHODS A systematic review of the scientific literature in English was conducted using PubMed and Embase. A meta-analysis was performed with the studies that were identified using our reproducible search. RESULTS Based on analysis of the data in 19 populations, the overall incidence of unilateral MCDK is 1 in 4300 with an increasing trend over the years. A total of 67 cohorts with over 3500 patients with unilateral MCDK were included in the meta-analysis. Fifty-nine percent of patients were male and the MCDKs were significantly more often found on the left side (53.1%). Associated anomalies in the solitary functioning kidney were found in 1 in 3 patients, mainly vesicoureteric reflux (VUR, in 19.7%). In patients with VUR, 40% have severe contralateral VUR, defined as grade III-V. Contralateral hypertrophy, present in 77% of patients after a follow-up of at least 10 years, showed a trend to be less pronounced in patients with VUR. Timing of the diagnosis of MCDK did not essentially influence the results. CONCLUSIONS These aggregate results provide insight into the incidence, demographic data and associated anomalies in patients with unilateral MCDK. One in three patients with unilateral MCDK show anomalies in the contralateral, solitary functioning kidney. However, studies into the long-term consequences of these anomalies are scarce.

Glomerular number and function are influenced by spontaneous and induced low birth weight in rats

A link exists between low birth weight and diseases in adulthood, such as hypertension, cardiovascular disease, and insulin resistance. Intrauterine growth restriction (IUGR) has been used to explain this association and has been shown to lead to a nephron endowment in humans. A reduction in glomerular number has been described in animal models with induced low birth weight as well but not in animals with spontaneous low birth weight. It therefore is debatable whether the models are suitable. The effect on glomerular number and size was studied in rats with naturally occurring IUGR and experimental IUGR, induced by bilateral uterine artery ligation. Design-based stereologic methods were used. Urinary protein excretion was determined as a measure of renal damage. Results showed a decrease of approximately 20% in glomerular number in both groups of IUGR (control 35,400, naturally occurring IUGR 30,900, and experimental IUGR 28,000 glomeruli per kidney). Mean glomerular volume was increased in both IUGR groups, which was associated with an increased proteinuria. It is concluded that IUGR leads to a nephron endowment with a compensatory glomerular enlargement. This compensation is associated with more proteinuria in the long run. Uterine artery ligation in the pregnant rat is a suitable model to study the effects of IUGR on the kidney.

Unilateral renal agenesis: a systematic review on associated anomalies and renal injury

BACKGROUND Unilateral renal agenesis (URA) is associated with other congenital anomalies of the kidney and urinary tract (CAKUT) and extra-renal anomalies. However, the reported prevalences of these anomalies are highly variable. We estimated the prevalence of associated CAKUT and extra-renal anomalies in patients with URA. Furthermore, we determined the prevalence of renal injury in URA patients. METHODS We conducted a systematic review of English and non-English articles using PubMed and Embase.com. Included studies reported at least one of the following items: incidence of URA, gender, side of URA, prenatal diagnosis, performance of micturating cystourethrogram, associated CAKUT, urinary tract infection or extra-renal anomalies. Studies that described a mean/median glomerular filtration rate (GFR) and proportions of patients with hypertension, micro-albuminuria or a decreased GFR were also included. RESULTS Analyses were based on 43 included studies (total number of patients: 2684, 63% male). The general incidence of URA was 1 in ∼2000. Associated CAKUT were identified in 32% of patients, of which vesicoureteral reflux was most frequently identified (24% of patients). Extra-renal anomalies were found in 31% of patients. Hypertension could be identified in 16% of patients, whereas 21% of patients had micro-albuminuria. Ten per cent of patients had a GFR<60 mL/min/1.73 m2;. CONCLUSIONS These aggregate results provide insight in the prevalence of associated anomalies and renal injury in patients with URA. Our systematic review implicates that URA is not a harmless malformation by definition. Therefore, we emphasize the need for clinical follow-up in URA patients starting at birth.

Hypertension and microalbuminuria in children with congenital solitary kidneys.

Aim:  According to the hyperfiltration hypothesis, a low nephron endowment will lead to hyperfiltration in the remaining glomeruli and is associated with systemic hypertension, proteinuria and glomerulosclerosis. Being born with one functioning kidney instead of two, for instance because of unilateral renal agenesis or multicystic dysplastic kidney, is a cause of congenital renal mass reduction.

Renal injury in children with a solitary functioning kidney—the KIMONO study

BACKGROUND Children with a solitary functioning kidney (SFK) have an increased risk of developing hypertension, albuminuria and chronic kidney disease in later life. This renal injury is hypothesized to be caused by glomerular hyperfiltration that follows renal mass reduction in animal studies. Furthermore, children with an SFK show a high incidence of congenital anomalies of the kidney and urinary tract (CAKUT), which could further compromise renal function. METHODS A retrospective study of renal injury markers was performed in 206 children, divided into groups based on the origin of SFK [primary (congenital) SFK (n = 116) and secondary SFK (n = 90)]. Data on ipsilateral CAKUT were stratified separately. For blood pressure, albuminuria and glomerular filtration rate, longitudinal models were additionally developed using generalized estimated equation analysis. RESULTS Renal injury, defined as the presence of hypertension and/or albuminuria and/or the use of renoprotective medication, was present in 32% of all children with an SFK at a mean age of 9.5 (SD 5.6) years. Children with ipsilateral CAKUT had higher proportions of renal injury (48.3 versus 24.6%, P < 0.05). Furthermore, longitudinal models showed a decrease in glomerular filtration rate in both groups from the beginning of puberty onwards. CONCLUSIONS This large cohort study demonstrates that renal injury is present in children with an SFK at a young age, whereas our longitudinal models show an increased risk for chronic kidney disease in adulthood. Renal injury is even more pronounced in the presence of ipsilateral CAKUT. Therefore, we underline that clinical follow-up of all children with an SFK is needed.

Effect of Corticosteroid Therapy on Low-Molecular–Weight Protein Markers of Kidney Function

Serum cystatin C, β2-microglobulin, and β-trace protein are endogenous markers of glomerular filtration rate (GFR). Cystatin C, in particular, is a promising alternative to creatinine for the detection of incipient renal failure. However, corticosteroids affect the extrarenal metabolism of cystatin C, which limits the use of cystatin C as a marker of GFR in a variety of clinical settings. Low-molecular–weight (LMW) β-trace protein might be a useful alternative in this respect. The present study set out to compare the effect of corticosteroid therapy on the serum concentrations of cystatin C, β2-microglobulin, and β-trace protein. We studied a group of 108 children being treated or followed for malignancy (n = 41) or renal disease (n = 67). In the former group 14 patients (34%) were treated with glucocorticoids, in the latter 18 (27%). We compared single-injection inulin clearance studies in 76 patients not receiving steroids with 32 in patients receiving corticosteroid treatment (median dose 33.0 mg prednisone-equivalent per m2 body surface area per day, range 1.2–70.4). Mean (SD) age was 9.7 (5.8) years, mean (SD) GFR 92.8 (34.6) mL · min−1 · (1.73 m2)−1. Patients included in the …

Clinical Implications of the Solitary Functioning Kidney

Congenital anomalies of the kidney and urinary tract are the major cause of ESRD in childhood. Children with a solitary functioning kidney form an important subgroup of congenital anomalies of the kidney and urinary tract patients, and a significant fraction of these children is at risk for progression to CKD. However, challenges remain in distinguishing patients with a high risk for disease progression from those patients without a high risk of disease progression. Although it is hypothesized that glomerular hyperfiltration in the lowered number of nephrons underlies the impaired renal prognosis in the solitary functioning kidney, the high proportion of ipsilateral congenital anomalies of the kidney and urinary tract in these patients may further influence clinical outcome. Pathogenic genetic and environmental factors in renal development have increasingly been identified and may play a crucial role in establishing a correct diagnosis and prognosis for these patients. With fetal ultrasound now enabling prenatal identification of individuals with a solitary functioning kidney, an early evaluation of risk factors for renal injury would allow for differentiation between patients with and without an increased risk for CKD. This review describes the underlying causes and consequences of the solitary functioning kidney from childhood together with its clinical implications. Finally, guidelines for follow-up of solitary functioning kidney patients are recommended.