Clinical practice recommendations for kidney involvement in tuberous sclerosis complex: a consensus statement by the ERKNet Working Group for Autosomal Dominant Structural Kidney Disorders and the ERA Genes & Kidney Working Group.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the presence of proliferative lesions throughout the body. Management of TSC is challenging because patients have a multifaceted systemic illness with prominent neurological and developmental impact as well as potentially severe kidney, heart and lung phenotypes; however, every organ system can be involved. Adequate care for patients with TSC requires a coordinated effort involving a multidisciplinary team of clinicians and support staff. This clinical practice recommendation was developed by nephrologists, urologists, paediatric radiologists, interventional radiologists, geneticists, pathologists, and patient and family group representatives, with a focus on TSC-associated kidney manifestations. Careful monitoring of kidney function and assessment of kidney structural lesions by imaging enable early interventions that can preserve kidney function through targeted approaches. Here, we summarize the current evidence and present recommendations for the multidisciplinary management of kidney involvement in TSC.

Low agreement between various eGFR formulae in pediatric and young adult ADPKD patients.

BACKGROUND: Young autosomal dominant polycystic kidney disease (ADPKD) patients are becoming the new target population for the development of new treatment options. Determination of a reliable equation for estimated glomerular filtration rate (eGFR) from early stages is needed with the promising potential interventional therapies. METHODS: Prospective and longitudinal study on a cohort of 68 genotyped ADPKD patients (age range 0-23 years) with long-term follow-up. Commonly used equations for eGFR were compared for their relative performance. RESULTS: The revised Schwartz formula (CKiD) showed a highly significant decline in eGFR with aging (- 3.31 mL/min/1.73 m2/year, P < 0.0001). The recently updated equation by the Schwartz group (CKiDU25) showed a smaller (- 0.90 mL/min/1.73 m2/year) but significant (P = 0.001) decline in eGFR with aging and also showed a significant sex difference (P < 0.0001), not observed by the other equations. In contrast, the full age spectrum (FAS) equations (FAS-SCr, FAS-CysC, and the combined) showed no age and sex dependency. The prevalence of hyperfiltration is highly dependent on the formula used, and the highest prevalence was observed with the CKiD Equation (35%). CONCLUSIONS: The most widely used methods to calculate eGFR in ADPKD children (CKiD and CKiDU25 equations) were associated with unexpected age or sex differences. The FAS equations were age- and sex-independent in our cohort. Hence, the switch from the CKiD to CKD-EPI equation at the transition from pediatric to adult care causes implausible jumps in eGFR, which could be misinterpreted. Having reliable methods to calculate eGFR is indispensable for clinical follow-up and clinical trials. A higher resolution version of the Graphical abstract is available as Supplementary information.

Risk Severity Model for Pediatric Autosomal Dominant Polycystic Kidney Disease Using 3D Ultrasound Volumetry.

BACKGROUND: Height-adjusted total kidney volume (htTKV) measured by imaging defined as Mayo Imaging Class (MIC) is a validated prognostic measure for autosomal dominant polycystic kidney disease (ADPKD) in adults to predict and stratify disease progression. However, no stratification tool is currently available in pediatric ADPKD. Because magnetic resonance imaging and computed tomography in children are difficult, we propose a novel 3D ultrasound-based pediatric Leuven Imaging Classification to complement the MIC. METHODS: A prospective study cohort of 74 patients with genotyped ADPKD (37 female) was followed longitudinally with ultrasound, including 3D ultrasound, and they underwent in total 247 3D ultrasound assessments, with patients' median age (interquartile range [IQR]) at diagnosis of 3 (IQR, 0-9) years and at first 3D ultrasound evaluation of 10 (5-14) years. First, data matching was done to the published MIC classification, followed by subsequent optimization of parameters and model type. RESULTS: PKD1 was confirmed in 70 patients (95%), PKD2 in three (4%), and glucosidase IIα unit only once (1%). Over these 247 evaluations, the median height was 143 (IQR, 122-166) cm and total kidney volume was 236 (IQR, 144-344) ml, leading to an htTKV of 161 (IQR, 117-208) ml/m. Applying the adult Mayo classification in children younger than 15 years strongly underestimated ADPKD severity, even with correction for height. We therefore optimized the model with our pediatric data and eventually validated it with data of young patients from Mayo Clinic and the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease used to establish the MIC. CONCLUSIONS: We proposed a five-level Leuven Imaging Classification ADPKD pediatric model as a novel classification tool on the basis of patients' age and 3D ultrasound-htTKV for reliable discrimination of childhood ADPKD severity.

Persistent Markers of Kidney Injury in Children Who Developed Acute Kidney Injury After Pediatric Cardiac Surgery: A Prospective Cohort Study.

Background Acute kidney injury (AKI) after pediatric cardiac surgery is common. Longer-term outcomes and the incidence of chronic kidney disease after AKI are not well-known. Methods and Results All eligible children (aged <16 years) who had developed AKI following cardiac surgery at our tertiary referral hospital were prospectively invited for a formal kidney assessment ≈5 years after AKI, including measurements of estimated glomerular filtration rate, proteinuria, α1-microglobulin, blood pressure, and kidney ultrasound. Longer-term follow-up data on kidney function were collected at the latest available visit. Among 571 patients who underwent surgery, AKI occurred in 113 (19.7%) over a 4-year period. Fifteen of these (13.3%) died at a median of 31 days (interquartile range [IQR], 9-57) after surgery. A total of 66 patients participated in the kidney assessment at a median of 4.8 years (IQR, 3.9-5.7) after the index AKI episode. Thirty-nine patients (59.1%) had at least 1 marker of kidney injury, including estimated glomerular filtration rate <90 mL/min per 1.73 m2 in 9 (13.6%), proteinuria in 27 (40.9%), α1-microglobinuria in 5 (7.6%), hypertension in 13 (19.7%), and abnormalities on kidney ultrasound in 9 (13.6%). Stages 1 to 5 chronic kidney disease were present in 18 (27.3%) patients. Patients with CKD were more likely to have an associated syndrome (55.6% versus 20.8%, P=0.015). At 13.1 years (IQR, 11.2-14.0) follow-up, estimated glomerular filtration rate <90 mL/min per 1.73 m² was present in 18 of 49 patients (36.7%), suggesting an average estimated glomerular filtration rate decline rate of -1.81 mL/min per 1.73 m² per year. Conclusions Children who developed AKI after pediatric cardiac surgery showed persistent markers of kidney injury. As chronic kidney disease is a risk factor for cardiovascular comorbidity, long-term kidney follow-up in this population is warranted.

MRI Characteristics of Pediatric Renal Tumors: A SIOP-RTSG Radiology Panel Delphi Study.

BACKGROUND: The SIOP-Renal Tumor Study Group (RTSG) does not advocate invasive procedures to determine histology before the start of therapy. This may induce misdiagnosis-based treatment initiation, but only for a relatively small percentage of approximately 10% of non-Wilms tumors (non-WTs). MRI could be useful for reducing misdiagnosis, but there is no global consensus on differentiating characteristics. PURPOSE: To identify MRI characteristics that may be used for discrimination of newly diagnosed pediatric renal tumors. STUDY TYPE: Consensus process using a Delphi method. POPULATION: Not applicable. FIELD STRENGTH/SEQUENCE: Abdominal MRI including T1- and T2-weighted imaging, contrast-enhanced MRI, and diffusion-weighted imaging at 1.5 or 3 T. ASSESSMENT: Twenty-three radiologists from the SIOP-RTSG radiology panel with ≥5 years of experience in MRI of pediatric renal tumors and/or who had assessed ≥50 MRI scans of pediatric renal tumors in the past 5 years identified potentially discriminatory characteristics in the first questionnaire. These characteristics were scored in the subsequent second round, consisting of 5-point Likert scales, ranking- and multiple choice questions. STATISTICAL TESTS: The cut-off value for consensus and agreement among the majority was ≥75% and ≥60%, respectively, with a median of ≥4 on the Likert scale. RESULTS: Consensus on specific characteristics mainly concerned the discrimination between WTs and non-WTs, and WTs and nephrogenic rest(s) (NR)/nephroblastomatosis. The presence of bilateral lesions (75.0%) and NR/nephroblastomatosis (65.0%) were MRI characteristics indicated as specific for the diagnosis of a WT, and 91.3% of the participants agreed that MRI is useful to distinguish NR/nephroblastomatosis from WT. Furthermore, all participants agreed that age influenced their prediction in the discrimination of pediatric renal tumors. DATA CONCLUSION: Although the discrimination of pediatric renal tumors based on MRI remains challenging, this study identified some specific characteristics for tumor subtypes, based on the shared opinion of experts. These results may guide future validation studies and innovative efforts. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 3.

Enhanced MCP-1 Release in Early Autosomal Dominant Polycystic Kidney Disease.

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) causes kidney failure typically in adulthood, but the disease starts in utero. Copeptin, epidermal growth factor (EGF), and monocyte chemoattractant protein-1 (MCP-1) are associated with severity and hold prognostic value in adults but remain unstudied in the early disease stage. Kidneys from adults with ADPKD exhibit macrophage infiltration, and a prominent role of MCP-1 secretion by tubular epithelial cells is suggested from rodent models. METHODS: In a cross-sectional study, plasma copeptin, urinary EGF, and urinary MCP-1 were evaluated in a pediatric ADPKD cohort and compared with age-, sex-, and body mass index (BMI)-matched healthy controls. MCP-1 was studied in mouse collecting duct cells, human proximal tubular cells, and fetal kidney tissue. RESULTS: Fifty-three genotyped ADPKD patients and 53 controls were included. The mean (SD) age was 10.4 (5.9) versus 10.5 (6.1) years (P = 0.543), and the estimated glomerular filtration rate (eGFR) was 122.7 (39.8) versus 114.5 (23.1) ml/min per 1.73 m2 (P = 0.177) in patients versus controls, respectively. Plasma copeptin and EGF secretion were comparable between groups. The median (interquartile range) urinary MCP-1 (pg/mg creatinine) was significantly higher in ADPKD patients (185.4 [213.8]) compared with controls (154.7 [98.0], P = 0.010). Human proximal tubular cells with a heterozygous PKD1 mutation and mouse collecting duct cells with a PKD1 knockout exhibited increased MCP-1 secretion. Human fetal ADPKD kidneys displayed prominent MCP-1 immunoreactivity and M2 macrophage infiltration. CONCLUSION: An increase in tubular MCP-1 secretion is an early event in ADPKD. MCP-1 is an early disease severity marker and a potential treatment target.

Cervical Spondylodiscitis in an Infant with Torticollis.

Teaching point: Narrowing of the intervertebral space and destruction of the adjacent vertebral end plates on conventional radiography or CT should raise suspicion for spondylodiscitis in symptomatic infants.

A Patient with neonatal cholestasis.

The patient, a boy born in 1991, showed pronounced polyostotic fibrous dysplasia due to McCune-Albright syndrome, as well as Gilbert syndrome and Charcot-Marie-Tooth neuropathy caused by a DNM2 mutation. In addition, the patient, his sister, mother and maternal grandfather had intermittently increased plasma arginine and lysine levels, most probably due to heterozygosity for a novel pathogenic SLC7A2 variant.

Juvenile Fibroadenoma in a Four-Month-Old Male Infant.

Teaching point: As juvenile fibroadenoma is radiologically indistinguishable from a (malignant) phyllodes tumor, a core biopsy is decisive for both treatment and follow-up.

An Atypical Case of Poland Syndrome with Bilateral Features and Dextroposition of the Heart: In the work-up of Poland syndrome, different imaging modalities are necessary to depict the full extent of the anomalies.

Poland syndrome is defined by the unilateral aplasia or hypoplasia of the sternocostal head of the major pectoral muscle and is associated with variable ipsilateral thoracic and upper limb anomalies. Most frequently, the abnormalities are unilateral and on the right side. We present an atypical case of Poland syndrome in a baby girl with bilateral chest abnormalities, mainly on the left side, and secondary dextroposition of the heart. As required in almost all cases of Poland syndrome, different imaging modalities were used to evaluate the extent of our patient's anomalies.

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.

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.

3DUS as an alternative to MRI for measuring renal volume in children with autosomal dominant polycystic kidney disease.

BACKGROUND: Total kidney volume, measured by magnetic resonance imaging (MRI), is a validated disease progression marker in adults with autosomal dominant polycystic kidney disease (ADPKD). However, in childhood, MRI is burdensome, explaining the need for alternatives. METHODS: Kidney volume (KV) was evaluated in 30 children with ADPKD, using three-dimensional ultrasound (3DUS), applying the ellipsoid method and manual contouring (KV3DUS-ellipsoid, KV3DUS-contour respectively); manual contouring on MRI (KVMRI), and the ellipsoid method on two-dimensional ultrasound (2DUS, KV2DUS). Correlations and differences were evaluated using Pearson's r and Wilcoxon signed-rank tests, and variability using Bland-Altman plots. RESULTS: All ultrasound volumetry methods showed significantly lower mean (± SD) KV (mL), compared with MRI-KV2DUS: 159 (±101); K3DUS-ellipsoid: 169 (±105); KV3DUS-contour: 185 (±110); KVMRI: 206 (±130); all p < 0.001. All had a strong correlation with KVMRI: 2DUS: r = 0.96; 3DUS-ellipsoid: r = 0.89 and 3DUS-contour: r = 0.94. Both before and after correction factor application, Bland-Altman plots showed lower variability and absolute error for KV3DUS-contour vs KV2DUS and KV3DUS-ellipsoid. CONCLUSIONS: Compared with MRI, ultrasound volumetry was prone to underestimation. However, KV3DUS-contour represents a valuable alternative for MRI in early ADPKD. Although more time-consuming, KV3DUS-contour is recommended over KV2DUS for estimation and follow-up of KV in ADPKD children, given its smaller error.

Is Autosomal Dominant Polycystic Kidney Disease Becoming a Pediatric Disorder?

Autosomal dominant polycystic kidney disease (ADPKD) affects 1 in 400 to 1,000 live births, making it the most common monogenic cause of renal failure. Although no definite cure is available yet, it is important to affect disease progression by influencing modifiable factors such as hypertension and proteinuria. Besides this symptomatic management, the only drug currently recommended in Europe for selected adult patients with rapid disease progression, is the vasopressin receptor antagonist tolvaptan. However, the question remains whether these preventive interventions should be initiated before extensive renal damage has occurred. As renal cyst formation and expansion begins early in life, frequently in utero, ADPKD should no longer be considered an adult-onset disease. Moreover, the presence of hypertension and proteinuria in affected children has been reported to correlate well with disease severity. Until now, it is controversial whether children at-risk for ADPKD should be tested for the presence of the disease, and if so, how this should be done. Herein, we review the spectrum of pediatric ADPKD and discuss the pro and contra of testing at-risk children and the challenges and unmet needs in pediatric ADPKD care.

An Unusual Presentation of Congenital Esophageal Stenosis Due to Tracheobronchial Remnants in a Newborn Prenatally Diagnosed with Duodenal Atresia.

Congenital esophageal stenosis due to tracheobronchial remnants is defined as an intrinsic stenosis of the esophagus caused by congenital architectural abnormalities of the esophageal wall. Although CES is present at birth, it remains asymptomatic till at the age of 4-10 months, when solid food is introduced. Here we present a case diagnosed in the neonatal period after urgent cesarean for an associated duodenal atresia complicated with perforation. There is a mutual association between duodenal atresia and congenital esophageal stenosis. When duodenal atresia is diagnosed, think of possible associated esophageal abnormalities, especially when duodenal atresia is complicated by gastric perforation prenatally.

Multidetector CT of right-sided congenital diaphragmatic hernia associated with hepatopulmonary fusion in a newborn.

We present a neonate with a complex congenital cardiopathy and a right-sided diaphragmatic hernia complicated with hepatopulmonary fusion. Radiography, abdominal US and multidetector CT (MDCT) demonstrated right-sided lung hypoplasia and liver herniation. In addition, MDCT angiography showed abnormal pulmonary vascular anatomy. At surgery, a right-sided diaphragmatic hernia with a partially herniated liver and hepatopulmonary fusion was confirmed. There was no aberrant systemic vascular supply towards the lower lobe, as seen in extralobar sequestration. MDCT angiography of the chest and upper abdomen with optimal enhancement and reconstruction of the pulmonary and hepatic vasculature can demonstrate associated anomalies in cases of suspected primary or secondary right lung hypoplasia.

A rare presentation of renal Wegener granulomatosis in a child.

We present a rare case of Wegener granulomatosis of the kidney in childhood. The diagnosis was suggested on imaging due to a combination of clinical symptoms, the lack of improvement with antibiotic therapy, and the absence of signs of inflammation on renal imaging. It was confirmed by histological examination following biopsy. The features and appearance of renal Wegener granulomatosis are described, and the differential diagnosis for a childhood renal mass is discussed.