Deborah Stein

Multidisciplinary consensus on the classification of prenatal and postnatal urinary tract dilation (UTD classification system)

OBJECTIVE Urinary tract (UT) dilation is sonographically identified in 1-2% of fetuses and reflects a spectrum of possible uropathies. There is significant variability in the clinical management of individuals with prenatal UT dilation that stems from a paucity of evidence-based information correlating the severity of prenatal UT dilation to postnatal urological pathologies. The lack of correlation between prenatal and postnatal US findings and final urologic diagnosis has been problematic, in large measure because of a lack of consensus and uniformity in defining and classifying UT dilation. Consequently, there is a need for a unified classification system with an accepted standard terminology for the diagnosis and management of prenatal and postnatal UT dilation. METHODS A consensus meeting was convened on March 14-15, 2014, in Linthicum, Maryland, USA to propose: 1) a unified description of UT dilation that could be applied both prenatally and postnatally; and 2) a standardized scheme for the perinatal evaluation of these patients based on sonographic criteria (i.e. the classification system). The participating societies included American College of Radiology, the American Institute of Ultrasound in Medicine, the American Society of Pediatric Nephrology, the Society for Fetal Urology, the Society for Maternal-Fetal Medicine, the Society for Pediatric Urology, the Society for Pediatric Radiology and the Society of Radiologists in Ultrasounds. RESULTS The recommendations proposed in this consensus statement are based on a detailed analysis of the current literature and expert opinion representing common clinical practice. The proposed UTD Classification System (and hence the severity of the UT dilation) is based on six categories in US findings: 1) anterior-posterior renal pelvic diameter (APRPD); 2) calyceal dilation; 3) renal parenchymal thickness; 4) renal parenchymal appearance; 5) bladder abnormalities; and 6) ureteral abnormalities. The classification system is stratified based on gestational age and whether the UT dilation is detected prenatally or postnatally. The panel also proposed a follow-up scheme based on the UTD classification. CONCLUSION The proposed grading classification system will require extensive evaluation to assess its utility in predicting clinical outcomes. Currently, the grading system is correlated with the risk of postnatal uropathies. Future research will help to further refine the classification system to one that correlates with other clinical outcomes such as the need for surgical intervention or renal function.

Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity

Chronically increased echogenicity on renal ultrasound is a sensitive early finding of chronic kidney disease that can be detected before manifestation of other symptoms. Increased echogenicity, however, is not specific for a certain etiology of chronic kidney disease. Here, we performed whole exome sequencing in 79 consanguineous or familial cases of suspected nephronophthisis in order to determine the underlying molecular disease cause. In 50 cases, there was a causative mutation in a known monogenic disease gene. In 32 of these cases whole exome sequencing confirmed the diagnosis of a nephronophthisis-related ciliopathy. In 8 cases it revealed the diagnosis of a renal tubulopathy. The remaining 10 cases were identified as Alport syndrome (4), autosomal-recessive polycystic kidney disease (2), congenital anomalies of the kidney and urinary tract (3), and APECED syndrome (1). In 5 families, in whom mutations in known monogenic genes were excluded, we applied homozygosity mapping for variant filtering, and identified 5 novel candidate genes (RBM48, FAM186B, PIAS1, INCENP, and RCOR1) for renal ciliopathies. Thus, whole exome sequencing allows the detection of the causative mutation in 2/3 of affected individuals, thereby presenting the etiologic diagnosis and allows identification of novel candidate genes.

Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis

BACKGROUND AND OBJECTIVES Nephrolithiasis is a prevalent condition that affects 10%-15% of adults in their lifetime. It is associated with high morbidity due to colicky pain, the necessity for surgical intervention, and sometimes progression to CKD. In recent years, multiple monogenic causes of nephrolithiasis and nephrocalcinosis have been identified. However, the prevalence of each monogenic gene in a pediatric renal stone cohort has not yet been extensively studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS To determine the percentage of cases that can be explained molecularly by mutations in one of 30 known nephrolithiasis/nephrocalcinosis genes, we conducted a high-throughput exon sequencing analysis in an international cohort of 143 individuals <18 years of age, with nephrolithiasis (n=123) or isolated nephrocalcinosis (n=20). Over 7 months, all eligible individuals at three renal stone clinics in the United States and Europe were approached for study participation. RESULTS We detected likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 16.8% (24 of 143) of affected individuals; 12 of the 27 detected mutations were not previously described as disease causing (44.4%). We observed that in our cohort all individuals with infantile manifestation of nephrolithiasis or nephrocalcinosis had causative mutations in recessive rather than dominant monogenic genes. In individuals who manifested later in life, causative mutations in dominant genes were more frequent. CONCLUSIONS We present the first exclusively pediatric cohort examined for monogenic causes of nephrolithiasis/nephrocalcinosis, and suggest that important therapeutic and preventative measures may result from mutational analysis in individuals with early manifestation of nephrolithiasis or nephrocalcinosis.

Mutations in SLC26A1 Cause Nephrolithiasis

Nephrolithiasis, a condition in which urinary supersaturation leads to stone formation in the urinary system, affects about 5%-10% of individuals worldwide at some point in their lifetime and results in significant medical costs and morbidity. To date, mutations in more than 30 genes have been described as being associated with nephrolithiasis, and these mutations explain about 15% of kidney stone cases, suggesting that additional nephrolithiasis-associated genes remain to be discovered. To identify additional genes whose mutations are linked to nephrolithiasis, we performed targeted next-generation sequencing of 18 hypothesized candidate genes in 348 unrelated individuals with kidney stones. We detected biallelic mutations in SLC26A1 (solute carrier family 26 member 1) in two unrelated individuals with calcium oxalate kidney stones. We show by immunofluorescence, immunoblotting, and glycosylation analysis that the variant protein mimicking p.Thr185Met has defects in protein folding or trafficking. In addition, by measuring anion exchange activity of SLC26A1, we demonstrate that all the identified mutations in SLC26A1 result in decreased transporter activity. Our data identify SLC26A1 mutations as causing a recessive Mendelian form of nephrolithiasis.

Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome

BACKGROUND AND OBJECTIVES Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. RESULTS In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. CONCLUSIONS Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.

Time to aortic occlusion: It’s all about access

INTRODUCTION Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a less invasive method of proximal aortic occlusion compared with resuscitative thoracotomy with aortic cross-clamping (RTACC). This study compared time to aortic occlusion with REBOA and RTACC, both including and excluding time required for common femoral artery (CFA) cannulation. METHODS This was a retrospective, single-institution review of REBOA or RTACC performed between February 2013 and January 2016. Time of skin incision to aortic cross-clamp for RTACC, time required for CFA cannulation by percutaneous and open methods, and time from guide-wire insertion to balloon inflation at Zone 1 for REBOA, were obtained from videographic recordings. RESULTS Eighteen RTACC and 21 REBOAs were performed. Median (Q1, Q3) time from skin incision to aortic cross-clamping was 317 seconds (227, 551 seconds). Median (Q1, Q3) time from start of arterial access to Zone 1 balloon occlusion was 474 seconds (431, 572 seconds) (vs. RTACC, p = 0.01). All REBOA procedures were performed with the same device. The median time to complete CFA cannulation was 247 seconds (range, 164–343 seconds), with no difference between percutaneous or open procedures (p = 0.07). The median (Q1, Q3) time to aortic occlusion in REBOA once arterial access had been established was 245 seconds (179, 295.5 seconds), which was significantly shorter than RTACC (p = 0.003). CONCLUSIONS Once CFA access is achieved, time to aortic occlusion is faster with REBOA. Time to aortic occlusion is less than the time required to cannulate the CFA either by percutaneous or open approaches, emphasizing the importance of accurate and expedient CFA access. Resuscitative endovascular balloon occlusion of the aorta may represent a feasible alternative to thoracotomy for aortic occlusion. Time to aortic occlusion will likely decrease with the advent of newer REBOA technology. The rate-limiting portion of REBOA continues to be obtaining CFA access. LEVEL OF EVIDENCE Therapeutic, level V.

The ABC's of Pancreatic Trauma: Airway, Breathing, and Computerized Tomography Scan?

OBJECTIVES Missed pancreatic injury carries significant morbidity. Computerized tomography (CT) imaging is useful, but may lack sensitivity to identify pancreatic injury. New-generation CT scanners should improve sensitivity, but this has not been studied. A previous study published in 2002 evaluating the sensitivity for identifying pancreatic injury with single-slice CT scanners yielded a 68% correlation between operative and CT findings. We aim to study the accuracy of modern CT for diagnosis and grading of pancreatic injury. METHODS All trauma admissions from 2008 and 2012 were retrospectively reviewed. Patients with a pancreatic injury, either on CT or intraoperatively, were included (n = 96). Sensitivity and specificity were calculated using Students t test. RESULTS 48 patients had injuries noted on CT and in the operating room. In this group, 68.8% had CT findings discordant with operative findings. Of these, 78.8% had no injury noted on CT, of which 26.9% required surgical intervention. Seven patients with injury on CT had none identified in the operating room. Based on these results, the sensitivity for CT imaging to identify an injury is 36.4% with a positive predictive value of 68.2%. CONCLUSIONS Our results indicate that despite advances in CT technology, the sensitivity and specificity for identifying pancreatic injury remains low. Although CT scans remain critical in trauma evaluation, awareness of this diagnostic gap is important. Further analysis is required to determine any impact on patient outcomes.

Tissue expander-stimulated lengthening of arteries for the treatment of midaortic syndrome in children

Background: Midaortic syndrome (MAS) is a rare condition characterized by stenosis of the abdominal aorta. Patients with disease refractory to medical management will usually require either endovascular therapy or surgery with use of prosthetic graft material for bypass or patch angioplasty. We report our early experience with a novel approach using a tissue expander (TE) to lengthen the normal native arteries in children with MAS, allowing primary aortic repair without the need for prosthetic graft material. Methods: We conducted a retrospective review of patients with MAS undergoing the TE‐stimulated lengthening of arteries (TESLA) procedure at our institution from 2010 to 2014. Data are presented as mean (range). Results: Five patients aged 4.8 years (3–8 years) underwent the TESLA procedure. Stages of this procedure include the following: stage I, insertion of retroaortic TE; stage II, serial TE injections; and stage III, final repair with excision of aortic stenosis and primary end‐to‐end aortic anastomosis. Stage II was completed in 4 months (1–9 months) with 12 (7–20) TE injections. Goal lengthening was achieved in all patients. Stage III could not be completed in one patient because of extreme aortic inflammation, which precluded safe excision of the aortic stenosis and required use of a prosthetic bypass graft. The other four patients completed stage III with two (one to three) additional vessels also requiring reconstruction (renal or mesenteric arteries). At 3.2 years (1–6 years) of follow‐up, all patients are doing well. Conclusions: The TESLA procedure allows surgical correction of MAS without the need for prosthetic grafts in young children who are still growing.

Evaluation and treatment of hypertensive crises in children.

Hypertensive crises in children are medical emergencies that must be identified, evaluated, and treated promptly and appropriately to prevent end-organ injury and even death. Treatment in the acute setting typically includes continuous intravenous antihypertensive medications with monitoring in the intensive care unit setting. Medications commonly used to treat severe hypertension have been poorly studied in children. Dosing guidelines are available, although few pediatric-specific trials have been conducted to facilitate evidence-based therapy. Regardless of what medication is used, blood pressure should be lowered gradually to allow for accommodation of autoregulatory mechanisms and to prevent cerebral ischemia. Determining the underlying cause of the blood pressure elevation may be helpful in guiding therapy.