Early clinical course of biopsy-proven IgA vasculitis nephritis.

BACKGROUND: IgA vasculitis (IgAV) is the most common form of systemic vasculitis in childhood and frequently involves the kidney. A minority of patients with IgA vasculitis nephritis (IgAVN), especially those presenting with heavy proteinuria and/or kidney failure at onset, are at risk of chronic end-stage kidney disease. For deciding upon treatment intensity, knowledge of the short-term clinical course of IgAVN is needed to improve treatment algorithms. METHODS: For this retrospective multicenter study, the medical records of 66 children with biopsy-proven IgAVN were reviewed. Age, gender, medical history and therapeutic interventions were recorded. Laboratory data included serum creatinine, albumin, urinary protein excretion (UPE) and glomerular filtration rate (eGFR). Threshold values were determined for each parameter, full remission was defined as no proteinuria and eGFR > 90 ml/min/1.73m2. RESULTS: Median age at onset of IgAVN was 8.9 years. 14.1% of the children presented with nephrotic syndrome, 50% had an eGFR below 90 ml/min/1.73 m2 and 51.5% showed cellular crescents in renal histology. The treatment regimens varied notably. Forty-four patients were treated with immunosuppression; 17 patients with crescents or nephrotic syndrome were treated with corticosteroid (CS) pulse therapy. After 6 months, UPE had decreased from 3.7 to 0.3 g/g creatinine and the proportion of patients with a decreased eGFR had fallen from 50.0% to 35.5%. Thirteen children (26.5%) achieved full remission within 6 months. CONCLUSIONS: In most patients with IgAVN proteinuria decreases slowly and kidney function improves, but full remission is reached only in a minority after 6 months. Persistent heavy proteinuria in the first two months rarely developed into long-term proteinuria. Therefore, decisions for more intense treatment should take into account the course of UPE over time. For a comparison of treatment effects, patient numbers were too small. Prospective, randomized controlled trials are necessary to clarify risk factors and the effect of immunosuppressive therapies.

The wind of change in the management of autosomal dominant polycystic kidney disease in childhood.

Significant progress has been made in understanding the genetic basis of autosomal dominant polycystic kidney disease (ADPKD), quantifying disease manifestations in children, exploring very-early onset ADPKD as well as pharmacological delay of disease progression in adults. At least 20% of children with ADPKD have relevant, yet mainly asymptomatic disease manifestations such as hypertension or proteinuria (in line with findings in adults with ADPKD, where hypertension and cardiovascular damage precede decline in kidney function). We propose an algorithm for work-up and management based on current recommendations that integrates the need to screen regularly for hypertension and proteinuria in offspring of affected parents with different options regarding diagnostic testing, which need to be discussed with the family with regard to ethical and practical aspects. Indications and scope of genetic testing are discussed. Pharmacological management includes renin-angiotensin system blockade as first-line therapy for hypertension and proteinuria. The vasopressin receptor antagonist tolvaptan is licensed for delaying disease progression in adults with ADPKD who are likely to experience kidney failure. A clinical trial in children is currently ongoing; however, valid prediction models to identify children likely to suffer kidney failure are lacking. Non-pharmacological interventions in this population also deserve further study.

Systematic review on outcomes used in clinical research on autosomal recessive polycystic kidney disease-are patient-centered outcomes our blind spot?

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a rare severe hepatorenal disease. Survivors of pulmonary hypoplasia and patients with milder presentations often achieve long-term survival but frequently require kidney and/or liver transplantation. OBJECTIVE: To examine the use of clinical, surrogate and patient-centered outcomes in studies on ARPKD with special attention to core outcomes of the Standardized Outcomes in NephroloGy project for children with chronic kidney disease (SONG-Kids). DATA SOURCES AND STUDY ELIGIBILITY CRITERIA: A systematic MEDLINE literature search identified 367 ARPKD studies published since 1990; however, of these 134 were excluded because they did not report any clinical outcomes (e.g. only histopathological, genetic, protein structure or radiological markers), 19 studies because they only included prenatal patients and 138 because they were case reports with ≤ 3 patients. STUDY APPRAISAL: Seventy-six eligible studies were examined for study type, size, intervention, and reported outcomes by organ system and type, including all SONG-kids tier 1-3 outcomes. PARTICIPANTS: There were 3231 patient-reports of children and adults with ARPKD. RESULTS: The overwhelming majority of studies reported clinical and surrogate outcomes (75/76 (98%) and 73/76 (96%)), but only 11/76 (14%) examined patient-centered outcomes and only 2/76 (3%) used validated instruments to capture them. Of the SONG-Kids core outcomes, kidney function was reported almost universally (70/76 (92%), infection and survival in three quarters (57/76 (75%), 55/76 (72%)) and measures of life participation (including neurological impairment) only rarely and inconsistently (16/76 (21%)). LIMITATIONS: Thirty studies (39%) were of low quality as they were either narrative case reports (n = 14, 18%) and/or patients with ARPKD were an indistinguishable subgroup (n = 18, 24%). Only 28 trials compared interventions, but none were randomized. CONCLUSIONS AND IMPLICATIONS: Studies that reported clinical outcomes in ARPKD usually covered the core outcome domains of kidney function, infections, and survival, but measures of life participation and patient-centered outcomes are distinctly lacking and require more attention in future trials. A higher resolution version of the Graphical abstract is available as Supplementary information.

Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.

BACKGROUND: Recognition of viral nucleic acids is one of the primary triggers for a type I interferon-mediated antiviral immune response. Inborn errors of type I interferon immunity can be associated with increased inflammation and/or increased susceptibility to viral infections as a result of dysbalanced interferon production. NFX1-type zinc finger-containing 1 (ZNFX1) is an interferon-stimulated double-stranded RNA sensor that restricts the replication of RNA viruses in mice. The role of ZNFX1 in the human immune response is not known. OBJECTIVE: We studied 15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocytic lymphohistiocytosis-like disease, early-onset seizures, and renal and lung disease. METHODS: Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, posttranscriptional regulation of interferon-stimulated genes (ISGs) and predisposition to viral infections in primary cells from patients and controls stimulated with synthetic double-stranded nucleic acids. RESULTS: Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients. Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of the mRNA of ISGs and also associated with poorer clearance of viral infections by monocytes. CONCLUSION: ZNFX1 is an important regulator of the response to double-stranded nucleic acids stimuli following viral infections. ZNFX1 deficiency predisposes to severe viral infections and a multisystem inflammatory disease.

Different approaches to long-term treatment of aHUS due to MCP mutations: a multicenter analysis.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening microangiopathy, frequently causing kidney failure. Inhibition of the terminal complement complex with eculizumab is the only licensed treatment but mostly requires long-term administration and risks severe side effects. The underlying genetic cause of aHUS is thought to influence the severity of initial and recurring episodes, with milder courses in patients with mutations in membrane cofactor protein (MCP). METHODS: Twenty pediatric cases of aHUS due to isolated heterozygous MCP mutations were reported from 12 German pediatric nephrology centers to describe initial presentation, timing of relapses, treatment, and kidney outcome. RESULTS: The median age of onset was 4.6 years, with a female to male ratio of 1:3. Without eculizumab maintenance therapy, 50% (9/18) of the patients experienced a first relapse after a median period of 3.8 years. Kaplan-Meier analysis showed a relapse-free survival of 93% at 1 year. Four patients received eculizumab long-term treatment, while 3 patients received short courses. We could not show a benefit from complement blockade therapy on long term kidney function, independent of short-term or long-term treatment. To prevent 1 relapse with eculizumab, the theoretical number-needed-to-treat (NNT) was 15 for the first year and 3 for the first 5 years after initial presentation. CONCLUSION: Our study shows that heterozygous MCP mutations cause aHUS with a risk of first relapse of about 10% per year, resulting in large NNTs for prevention of relapses with eculizumab. More studies are needed to define an optimal treatment schedule for patients with MCP mutations to minimize the risks of the disease and treatment.

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children.

The uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) accumulate in patients with chronic kidney disease (CKD) as a consequence of altered gut microbiota metabolism and a decline in renal excretion. Despite of solid experimental evidence for nephrotoxic effects, the impact of uremic toxins on the progression of CKD has not been investigated in representative patient cohorts. In this analysis, IS and pCS serum concentrations were measured in 604 pediatric participants (mean eGFR of 27 ± 11 ml/min/1.73m2) at enrolment into the prospective Cardiovascular Comorbidity in Children with CKD study. Associations with progression of CKD were analyzed by Kaplan-Meier analyses and Cox proportional hazard models. During a median follow up time of 2.2 years (IQR 4.3-0.8 years), the composite renal survival endpoint, defined as 50% loss of eGFR, or eGFR <10ml/min/1.73m2 or start of renal replacement therapy, was reached by 360 patients (60%). Median survival time was shorter in patients with IS and pCS levels in the highest versus lowest quartile for both IS (1.5 years, 95%CI [1.1,2.0] versus 6.0 years, 95%CI [5.0,8.4]) and pCS (1.8 years, 95%CI [1.5,2.8] versus 4.4 years, 95%CI [3.4,6.0]). Multivariable Cox regression disclosed a significant association of IS, but not pCS, with renal survival, which was independent of other risk factors including baseline eGFR, proteinuria and blood pressure. In this exploratory analysis we provide the first data showing a significant association of IS, but not pCS serum concentrations with the progression of CKD in children, independent of other known risk factors. In the absence of comorbidities, which interfere with serum levels of uremic toxins, such as diabetes, obesity and metabolic syndrome, these results highlight the important role of uremic toxins and accentuate the unmet need of effective elimination strategies to lower the uremic toxin burden and abate progression of CKD.

[Kidney Cysts and Cystic Nephropathies in Children - A Consensus Guideline by 10 German Medical Societies]. / Nierenzysten und zystische Nierenerkrankungen bei Kindern (AWMF S2k-Leitlinie).

This consensus-based guideline was developed by all relevant German pediatric medical societies. Ultrasound is the standard imaging modality for pre- and postnatal kidney cysts and should also exclude extrarenal manifestations in the abdomen and internal genital organs. MRI has selected indications. Suspicion of a cystic kidney disease should prompt consultation of a pediatric nephrologist. Prenatal management must be tailored to very different degrees of disease severity. After renal oligohydramnios, we recommend delivery in a perinatal center. Neonates should not be denied renal replacement therapy solely because of their age. Children with unilateral multicystic dysplastic kidney do not require routine further imaging or nephrectomy, but long-term nephrology follow-up (as do children with uni- or bilateral kidney hypo-/dysplasia with cysts). ARPKD (autosomal recessive polycystic kidney disease), nephronophthisis, Bardet-Biedl syndrome and HNF1B mutations cause relevant extrarenal disease and genetic testing is advisable. Children with tuberous sclerosis complex, tumor predisposition (e. g. von Hippel Lindau syndrome) or high risk of acquired kidney cysts should have regular ultrasounds. Even asymptomatic children of parents with ADPKD (autosomal dominant PKD) should be monitored for hypertension and proteinuria. Presymptomatic diagnostic ultrasound or genetic examination for ADPKD in minors should only be done after thorough counselling. Simple cysts are very rare in children and ADPKD in a parent should be excluded. Complex renal cysts require further investigation.

Impaired Systolic and Diastolic Left Ventricular Function in Children with Chronic Kidney Disease - Results from the 4C Study.

Children with chronic kidney disease suffer from excessive cardiovascular mortality and early alterations of the cardiovascular system. Tissue doppler imaging is a validated echocardiographic tool to assess early systolic and diastolic cardiac dysfunction. We hypothesized that tissue Doppler velocities would reveal reduced cardiac function in children with chronic kidney disease compared to healthy children. A standardized echocardiographic exam was performed in 128 patients of the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) Study aged 6-17 years with an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m2. Tissue Doppler measurements included early (E') and late (A') diastolic and systolic (S') velocity at the mitral and septal annulus of the left ventricle. Measured values were normalized to z-scores using published reference data. Predictors of E'/A', E/E', S' and left ventricular mass index (LVMI) were assessed by multiple linear regression analyses. Tissue Doppler E' was reduced and tissue Doppler A' increased, resulting in a reduced tissue Doppler E'/A' ratio (z-score -0.14, p < 0.0001) indicating reduced diastolic function compared to healthy children. Reduced tissue Doppler E'/A' Z-Scores were independently associated with lower eGFR (p = 0.002) and increased systolic blood pressure (p = 0.02). While E/E' Z-Scores were increased (Z-score 0.57, p < 0.0001), patients treated with pharmacological RAS blockade but not with other antihypertensive treatments had significantly lower E/E' and higher E'/A' Z-Scores. Systolic tissue Doppler velocities were significantly decreased (Z-score -0.24, p = 0.001) and inversely correlated with E/E' Z-Scores (r = -0.41, p < 0.0001). LVMI was not associated with systolic or diastolic tissue Doppler velocities. Concentric left ventricular hypertrophy showed a tendency to lower S' in multivariate analysis (p = 0.13) but no association to diastolic function. Concentric left ventricular geometry was significantly associated with lower midwall fractional shortening. In summary, systolic and diastolic function assessed by tissue Doppler is impaired. eGFR, systolic blood pressure and the type of antihypertensive medications are significant predictors of diastolic function in children with CKD. Left ventricular morphology is largely independent of tissue Doppler velocities. Tissue Doppler velocities provide sensitive information about early left ventricular dysfunction in this population.

International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people.

These recommendations were systematically developed on behalf of the Network for Early Onset Cystic Kidney Disease (NEOCYST) by an international group of experts in autosomal dominant polycystic kidney disease (ADPKD) from paediatric and adult nephrology, human genetics, paediatric radiology and ethics specialties together with patient representatives. They have been endorsed by the International Pediatric Nephrology Association (IPNA) and the European Society of Paediatric Nephrology (ESPN). For asymptomatic minors at risk of ADPKD, ongoing surveillance (repeated screening for treatable disease manifestations without diagnostic testing) or immediate diagnostic screening are equally valid clinical approaches. Ultrasonography is the current radiological method of choice for screening. Sonographic detection of one or more cysts in an at-risk child is highly suggestive of ADPKD, but a negative scan cannot rule out ADPKD in childhood. Genetic testing is recommended for infants with very-early-onset symptomatic disease and for children with a negative family history and progressive disease. Children with a positive family history and either confirmed or unknown disease status should be monitored for hypertension (preferably by ambulatory blood pressure monitoring) and albuminuria. Currently, vasopressin antagonists should not be offered routinely but off-label use can be considered in selected children. No consensus was reached on the use of statins, but mTOR inhibitors and somatostatin analogues are not recommended. Children with ADPKD should be strongly encouraged to achieve the low dietary salt intake that is recommended for all children.

Low levels of urinary epidermal growth factor predict chronic kidney disease progression in children.

Urinary epidermal growth factor (uEGF) has recently been identified as a promising biomarker of chronic kidney disease (CKD) progression in adults with glomerular disease. Low levels of uEGF predict CKD progression and appear to reflect the extent of tubulointerstitial damage. We investigated the relevance of uEGF in pediatric CKD. We performed a post hoc analysis of the Cardiovascular Comorbidity in Children with CKD (4C) study, which prospectively follows children aged 6-17 years with baseline estimated glomerular filtration rate (eGFR) of 10-60 ml/min/1.73 m2. uEGF levels were measured in archived urine collected within 6 months of enrollment. Congenital abnormalities of the kidney and urinary tract were the most common cause of CKD, with glomerular diseases accounting for <10% of cases. Median eGFR at baseline was 28 ml/min/1.73 m2, and 288 of 623 participants (46.3%) reached the composite endpoint of CKD progression (50% eGFR loss, eGFR < 10 ml/min/1.73 m2, or initiation of renal replacement therapy). In a Cox proportional hazards model, higher uEGF/Cr was associated with a decreased risk of CKD progression (HR 0.76; 95% CI 0.69-0.84) independent of age, sex, baseline eGFR, primary kidney disease, proteinuria, and systolic blood pressure. The addition of uEGF/Cr to a model containing these variables resulted in a significant improvement in C-statistics, indicating better prediction of the 1-, 2- and 3-year risk of CKD progression. External validation in a prospective cohort of 222 children with CKD demonstrated comparable results. Thus, uEGF may be a useful biomarker to predict CKD progression in children with CKD.

Imaging of Kidney Cysts and Cystic Kidney Diseases in Children: An International Working Group Consensus Statement.

Kidney cysts can manifest as focal disease (simple and complex kidney cysts), affect a whole kidney (eg, multicystic dysplastic kidney or cystic dysplasia), or manifest as bilateral cystic disease (eg, autosomal recessive polycystic kidney disease [ARPKD] or autosomal dominant polycystic kidney disease [ADPKD]). In children, as opposed to adults, a larger proportion of kidney cysts are due to genetic diseases (eg, HNF1B nephropathy, various ciliopathies, and tuberous sclerosis complex), and fewer patients have simple cysts or acquired cystic kidney disease. The purpose of this consensus statement is to provide clinical guidance on standardization of imaging tests to evaluate kidney cysts in children. A committee of international experts in pediatric nephrology, pediatric radiology, pediatric US, and adult nephrology prepared systematic literature reviews and formulated recommendations at a consensus meeting. The final statement was endorsed by the European Society of Pediatric Radiology, the European Federation of Societies for Ultrasound in Medicine and Biology, the European Society of Pediatric Nephrology, and reviewed by the European Reference Network for Rare Kidney Diseases. Main recommendations are as follows: US is the method of choice when assessing pediatric kidney cysts, with selected indications for MRI and contrast-enhanced US. CT should be avoided whenever possible because of ionizing radiation. Renal US yields essential diagnostic information in many cases. In patients with ARPKD or other ciliopathies, abdominal US is needed for diagnosis and screening of portal hypertension. US is usually sufficient for follow-up kidney imaging, but MRI can be valuable for clinical trials in patients with ADPKD or in older children with tuberous sclerosis complex to evaluate both kidney cysts and angiomyolipomas.

Presentation of pediatric Henoch-Schönlein purpura nephritis changes with age and renal histology depends on biopsy timing.

BACKGROUND: This study correlates the clinical presentation of Henoch-Schönlein purpura nephritis (HSPN) with findings on initial renal biopsy. METHODS: Data from 202 pediatric patients enrolled in the HSPN registry of the German Society of Pediatric Nephrology reported by 26 centers between 2008 and 2014 were analyzed. All biopsy reports were re-evaluated for the presence of cellular crescents or chronic pathological lesions (fibrous crescents, glomerular sclerosis, tubular atrophy >5%, and interstitial fibrosis >5%). RESULTS: Patients with HSPN with cellular glomerular crescents were biopsied earlier after onset of nephritis (median 24 vs 36 days, p = 0.04) than those without, whereas patients with chronic lesions were biopsied later (57 vs 19 days, p < 0.001) and were older (10.3 vs 8.6 years, p = 0.01) than those without. Patients biopsied more than 30 days after the onset of HSPN had significantly more chronic lesions (52 vs 22%, p < 0.001), lower eGFR (88 vs 102 ml/min/1.73m2, p = 0.01), but lower proteinuria (2.3 vs 4.5 g/g, p < 0.0001) than patients biopsied earlier. Children above 10 years of age had lower proteinuria (1.98 vs 4.58 g/g, p < 0.001), lower eGFR (86 vs 101 ml/min/1.73m2, p = 0.002) and were biopsied significantly later after onset of nephritis (44 vs 22 days, p < 0.001) showing more chronic lesions (45 vs 30%, p = 0.03). Proteinuria and renal function at presentation decreased with age. CONCLUSIONS: In summary, we find an age-dependent presentation of HSPN with a more insidious onset of non-nephrotic proteinuria, impaired renal function, longer delay to biopsy, and more chronic histopathological lesions in children above the age of 10 years. Thus, HSPN presents more like Immunoglobulin A (IgA) nephritis in older than in younger children.

Perinatal Diagnosis, Management, and Follow-up of Cystic Renal Diseases: A Clinical Practice Recommendation With Systematic Literature Reviews.

Importance: Prenatal and neonatal cystic kidney diseases are a group of rare disorders manifesting as single, multiple unilateral, or bilateral cysts or with increased echogenicity of the renal cortex without macroscopic cysts. They may be accompanied by grossly enlarged kidneys, renal oligohydramnios, pulmonary hypoplasia, extrarenal abnormalities, and neonatal kidney failure. The prognosis is extremely variable from trivial to very severe or even uniformly fatal, which poses significant challenges to prenatal counseling and management. Objective: To provide a clinical practice recommendation for fetal medicine specialists, obstetricians, neonatologists, pediatric nephrologists, pediatricians, and human geneticists by aggregating current evidence and consensus expert opinion on current management of cystic nephropathies before and after birth. Methods: After 8 systematic literature reviews on clinically relevant questions were prepared (including 90 studies up to mid-2016), recommendations were formulated and formally graded at a consensus meeting that included experts from all relevant specialties. After further discussion, the final version was voted on by all members using the Delphi method. The recommendations were reviewed and endorsed by the working groups on inherited renal disorders of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and European Society for Paediatric Nephrology (ESPN); the German Society of Obstetrics and Gynecology (DGGG), German Society of Perinatal Medicine (DGPM), and German Society of Ultrasound in Medicine (DEGUM); and the alliance of patient organizations, PKD International. Recommendations: The group makes a number of recommendations on prenatal and postnatal imaging by ultrasound and magnetic resonance imaging, genetic testing, prenatal counseling, in utero therapeutic interventions, and postnatal management of prenatal and neonatal cystic kidney diseases, including provision of renal replacement therapy in neonates. In addition to detailed knowledge about possible etiologies and their prognosis, physicians need to be aware of recent improvements and remaining challenges of childhood chronic kidney disease, neonatal renal replacement therapy, and intensive pulmonary care to manage these cases and to empower parents for informed decision making.

Digital pathology imaging as a novel platform for standardization and globalization of quantitative nephropathology.

The introduction of digital pathology to nephrology provides a platform for the development of new methodologies and protocols for visual, morphometric and computer-aided assessment of renal biopsies. Application of digital imaging to pathology made substantial progress over the past decade; it is now in use for education, clinical trials and translational research. Digital pathology evolved as a valuable tool to generate comprehensive structural information in digital form, a key prerequisite for achieving precision pathology for computational biology. The application of this new technology on an international scale is driving novel methods for collaborations, providing unique opportunities but also challenges. Standardization of methods needs to be rigorously evaluated and applied at each step, from specimen processing to scanning, uploading into digital repositories, morphologic, morphometric and computer-aided assessment, data collection and analysis. In this review, we discuss the status and opportunities created by the application of digital imaging to precision nephropathology, and present a vision for the near future.

Magnetic resonance imaging 4-D flow-based analysis of aortic hemodynamics in Turner syndrome.

BACKGROUND: Cardiovascular surveillance is important in Turner syndrome because of the increased risk of aortic dilation and dissection with consecutively increased mortality. OBJECTIVE: To compare 4-D flow MRI for the characterization of aortic 3-D flow patterns, dimensions and vessel wall parameters in pediatric patients with Turner syndrome and age-matched controls. MATERIALS AND METHODS: We performed 4-D flow MRI measuring in vivo 3-D blood flow with coverage of the thoracic aorta in 25 patients with Turner syndrome and in 16 female healthy controls (age mean ± standard deviation were 16 ± 5 years and 17 ± 4 years, respectively). Blood flow was visualized by time-resolved 3-D path lines. Visual grading of aortic flow in terms of helices and vortices was performed by two independent observers. Quantitative analysis included measurement of aortic diameters, quantification of peak systolic wall shear stress, pulsatility index and oscillatory shear index at eight defined sites. RESULTS: Patients with Turner syndrome had significantly larger aortic diameters normalized to BSA, increased vortices in the ascending aorta and elevated helix flow in the ascending and descending aorta compared to controls (all P<0.03). Patients with abnormal helical or vortical flow in the ascending aorta had significantly larger diameters of the ascending aorta (P<0.03). Peak systolic wall shear stress, pulsatility index and oscillatory shear index were significantly lower in Turner patients compared to controls (p=0.02, p=0.002 and p=0.01 respectively). CONCLUSION: Four-dimensional flow MRI provides new insights into the altered aortic hemodynamics and wall shear stress that could have an impact on the development of aortic dissections.

Magnetic resonance tissue phase mapping demonstrates altered left ventricular diastolic function in children with chronic kidney disease.

BACKGROUND: Echocardiographic examinations have revealed functional cardiac abnormalities in children with chronic kidney disease. OBJECTIVE: To assess the feasibility of MRI tissue phase mapping in children and to assess regional left ventricular wall movements in children with chronic kidney disease. MATERIALS AND METHODS: Twenty pediatric patients with chronic kidney disease (before or after renal transplantation) and 12 healthy controls underwent tissue phase mapping (TPM) to quantify regional left ventricular function through myocardial long (Vz) and short-axis (Vr) velocities at all 3 levels of the left ventricle. RESULTS: Patients and controls (age: 8 years-20 years) were matched for age, height, weight, gender and heart rate. Patients had higher systolic blood pressure. No patient had left ventricular hypertrophy on MRI or diastolic dysfunction on echocardiography. Fifteen patients underwent tissue Doppler echocardiography, with normal z-scores for mitral early diastolic (VE), late diastolic (VA) and peak systolic (VS) velocities. Throughout all left ventricular levels, peak diastolic Vz and Vr (cm/s) were reduced in patients: Vzbase -10.6 ± 1.9 vs. -13.4 ± 2.0 (P < 0.0003), Vzmid -7.8 ± 1.6 vs. -11 ± 1.5 (P < 0.0001), Vzapex -3.8 ± 1.6 vs. -5.3 ± 1.6 (P = 0.01), Vrbase -4.2 ± 0.8 vs. -4.9 ± 0.7 (P = 0.01), Vrmid -4.7 ± 0.7 vs. -5.4 ± 0.7 (P = 0.01), Vrapex -4.7 ± 1.4 vs. -5.6 ± 1.1 (P = 0.05). CONCLUSION: Tissue phase mapping is feasible in children and adolescents. Children with chronic kidney disease show significantly reduced peak diastolic long- and short-axis left ventricular wall velocities, reflecting impaired early diastolic filling. Thus, tissue phase mapping detects chronic kidney disease-related functional myocardial changes before overt left ventricular hypertrophy or echocardiographic diastolic dysfunction occurs.

Left ventricular mass and systolic function in children with chronic kidney disease-comparing echocardiography with cardiac magnetic resonance imaging.

BACKGROUND: Increased left ventricular mass (LVM) is an important risk marker of uremic cardiovascular disease. Calculation of LVM by echocardiography (Echo) relies on geometric assumptions and in adults on hemodialysis overestimates LVM compared to cardiac magnetic resonance (CMR). We compare both techniques in children with chronic kidney disease (CKD). METHODS: Concurrent Echo and CMR was performed in 25 children with CKD (14 after kidney transplantation) aged 8-17 years. RESULTS: Compared to normal children, CMR-LVM was increased (standard deviation score (SDS) 0.39 ± 0.8 (p = 0.03)), stroke volume and cardiac output decreased (SDS -1.76 ± 1.1, p = 0.002 and -1.11 ± 2.0, p = 0.001). CMR-LVM index but not Echo-LVMI correlated to future glomerular filtration rate (GFR) decline (r = -0.52, p = 0.01). Mean Echo-LVM was higher than CMR-LVM (117 ± 40 vs. 89 ± 29 g, p < 0.0001), with wide limits of agreement (-6.2 to 62.8 g). The Echo-CMR LVM difference increased with higher Echo-LVMI (r = 0.77, p < 0.0001). Agreement of classifying left ventricular hypertrophy was poor with Cohen's kappa of 0.08. Mean Echo and CMR-ejection fraction differed by 1.42% with wide limits of agreement (-12.6 to 15.4%). CONCLUSIONS: Echo overestimates LVM compared to CMR, especially at higher LVM. Despite this, CMR confirms increased LVM in children with CKD. Only CMR-LVMI but not Echo-LVMI correlated to future GFR decline.

Alternatively spliced isoforms of WT1 control podocyte-specific gene expression.

The Wilms' tumor suppressor WT1 is a key regulator of podocyte function that is mutated in Denys-Drash and Frasier syndromes. Here we have used an integrative approach employing ChIP, exon array, and genetic analyses in mice to address general and isoform-specific functions of WT1 in podocyte differentiation. Analysis of ChIP-Seq data showed that almost half of the podocyte-specific genes are direct targets of WT1. Bioinformatic analysis further identified coactivator FOXC1-binding sites in proximity to WT1-bound regions, thus supporting coordinated action of these transcription factors in regulating podocyte-specific genes. Transcriptional profiling of mice lacking the WT1 alternative splice isoform (+KTS) had a more restrictive set of genes whose expression depends on these alternatively spliced isoforms. One of these genes encodes the membrane-associated guanylate kinase MAGI2, a protein that localizes to the base of the slit diaphragm. Using functional analysis in mice, we further show that MAGI2α is essential for proper localization of nephrin and the assembly of the slit diaphragm complex. Finally, a dramatic reduction of MAGI2 was found in an LPS mouse model of glomerular injury and in genetic cases of human disease. Thus, our study highlights the central role of WT1 in podocyte differentiation, identifies that WT1 has a central role in podocyte differentiation, and identifies MAGI2α as the crucial isoform in slit diaphragm assembly, suggesting a causative role of this gene in the etiology of glomerular disorders.