Molecular genetic evaluation of pediatric renovascular hypertension due to renal artery stenosis and abdominal aortic coarctation in neurofibromatosis type 1.

The etiology of renal artery stenosis (RAS) and abdominal aortic coarctation (AAC) causing the midaortic syndrome (MAS), often resulting in renovascular hypertension (RVH), remains ill-defined. Neurofibromatosis type 1 (NF-1) is frequently observed in children with RVH. Consecutive pediatric patients (N = 102) presenting with RVH secondary to RAS with and without concurrent AAC were prospectively enrolled in a clinical data base, and blood, saliva and operative tissue, when available, were collected. Among the 102 children, 13 were having a concurrent clinical diagnosis of NF-1 (12.5%). Whole exome sequencing was performed for germline variant detection, and RNA-Seq analysis of NF1, MAPK pathway genes and MCP1 levels were undertaken in five NF-1 stenotic renal arteries, as well as control renal and mesenteric arteries from children with no known vasculopathy or NF-1. In 11 unrelated children with sequencing data, 11 NF1 genetic variants were identified, of which 10 had not been reported in gnomAD. Histologic analysis of NF-1 RAS specimens consistently revealed intimal thickening, disruption of the internal elastic lamina and medial thinning. Analysis of transcript expression in arterial lesions documented an approximately 5-fold reduction in NF1 expression, confirming heterozygosity, MAPK pathway activation and increased MCP1 expression. In summary, NF-1-related RVH in children is rare but often severe and progressive and, as such, important to recognize. It is associated with histologic and molecular features consistent with an aggressive adverse vascular remodeling process. Further research is necessary to define the mechanisms underlying these findings.

Histologic and morphologic character of pediatric abdominal aortic developmental coarctation and hypoplasia.

OBJECTIVES: Abdominal aortic coarctation and hypoplasia are uncommon diseases, recognized most often in pediatric-aged individuals. Comprehensive studies regarding the pathologic spectrum of these aortopathies are nonexistent. This investigation was undertaken to better define the histologic and morphologic character of abdominal aortic narrowings affecting children and assess its potential relevance to contemporary clinical practice. METHODS: Aortic specimens obtained during open operations in children being treated for symptomatic, noninflammatory abdominal aortic narrowings at the University of Michigan were subjected to histologic study after hematoxylin and eosin, Movat, Verhoeff Van Gieson, and Masson's trichrome preparations. Microscopic findings were correlated with the anatomic aortic images. In addition, a detailed review was completed of all prior reports in the English literature that included images depicting the histologic character of noninflammatory abdominal aortic narrowings in children. RESULTS: Among a series of 67 pediatric-aged individuals undergoing open surgical interventions for abdominal aortic narrowings, eight children ranging in age from 9 months to 18 years, had adequate aortic tissue available for study. The loci of the specimens paralleled the anatomic sites of segmental coarctations observed in the entire series, with involvement of the suprarenal abdominal aorta (n = 3), intrarenal aorta (n = 2), and infrarenal aorta (n = 1). Diffusely hypoplastic abdominal aortas (n = 2) included one case of a de facto aortic duplication, represented by a channel that paralleled the narrow native aorta and gave origin to celiac artery branches, as well as the superior mesenteric and renal arteries. Concentric or eccentric intimal fibroplasia was observed in every aorta, often with internal elastic fragmentation and duplication (n = 4). Media abnormalities included elastic tissue disorganization (n = 3) and focal medial fibrosis (n = 1). Organizing luminal thrombus occurred in two infants. Coexistent ostial stenoses of the celiac, superior mesenteric, or renal arteries were observed in all but the only child who had an infrarenal aortic coarctation. Neurofibromatosis type 1 affected one child whose histologic findings were indistinguishable from those of the other children. A review of prior published histologic images of abdominal aortic coarctation and hypoplasia affecting children from other centers revealed a total of 14 separate reports, each limited to single case photomicrographs, of which 11 exhibited intimal fibroplasia. CONCLUSIONS: Intimal fibroplasia is a common accompaniment of developmental abdominal aortic coarctation and hypoplasia. It is posited that intimal fibroplasia, which is likely progressive in instances of abnormal shear stresses in these diminutive vessels, may contribute to less salutary outcomes after endovascular and certain open reconstructions of pediatric abdominal aortic narrowings.

Histologic and morphologic character of pediatric renal artery occlusive disease.

OBJECTIVE: The pathologic nature of pediatric renal artery occlusive lesions causing renovascular hypertension has been the subject of numerous anecdotal reports. This study was undertaken to define the character of childhood renal artery stenoses. A better understanding of this disease is particularly germane, given its unknown etiology and the limited success of certain contemporary treatment options. METHODS: Renal artery specimens obtained during open operations in children being treated for renovascular hypertension from 2004 to 2016 were studied. Excluded from study were arteries subjected to earlier open or endovascular operations. Histologic preparations employing hematoxylin-eosin, Movat, Masson trichrome, and Verhoeff-van Gieson stains allowed characterization of the intima, media, and adventitial tissues. External and luminal diameters were measured. Microscopic data were correlated with preoperative arteriographic images. The histologic and morphologic findings were assessed in regard to coexistent nonrenal arterial and aortic lesions as well as known syndromic diseases. RESULTS: Thirty-three stenotic renal arteries from 28 children were subjected to examination. Stenoses involved the proximal-ostial renal arteries (24), central renal arteries (7), and distal segmental renal arteries (2). Ostial stenoses commonly exhibited preocclusive concentric hyperplasia of intimal tissues, frequent internal elastic lamina disruptions, and diminutive and discontinuous media. Central and distal renal stenoses most often exhibited lesser intimal cellular hyperplasia and more noticeable fibrodysplasia of the media and adventitia. The mean external and luminal diameters of the renal arteries having ostial stenoses were smaller than the expected renal artery size for a given age. Abdominal aortic coarctation or hypoplastic aortas occurred in 14 children. Neurofibromatosis type 1 affected four children with ostial renal artery disease and one child with midrenal artery disease, but there were no distinguishing features unique to their stenoses. CONCLUSIONS: Pediatric renal artery stenotic disease affects exceedingly small arteries. Ostial lesions frequently exhibit extensive luminal encroachments characterized by cellular hyperplasia of intimal tissues and scant medial smooth muscle. Central and distal renal arterial stenoses were characterized most often by extensive fibrodysplasia of the media and adventitia. The early success and durability of catheter-based angioplasty may be compromised by the cellular abnormalities of pediatric renal artery occlusive disease observed in this investigation.

A Novel Recurrent COL5A1 Genetic Variant Is Associated With a Dysplasia-Associated Arterial Disease Exhibiting Dissections and Fibromuscular Dysplasia.

OBJECTIVE: While rare variants in the COL5A1 gene have been associated with classical Ehlers-Danlos syndrome and rarely with arterial dissections, recurrent variants in COL5A1 underlying a systemic arteriopathy have not been described. Monogenic forms of multifocal fibromuscular dysplasia (mFMD) have not been previously defined. Approach and Results: We studied 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. Arterial medial fibroplasia and smooth muscle cell disorganization were confirmed histologically. The COL5A1 c.1540G>A variant is predicted to be pathogenic in silico and absent in gnomAD. The c.1540G>A variant is on a shared 160.1 kb haplotype with 0.4% frequency in Europeans. Furthermore, exome sequencing data from a cohort of 264 individuals with mFMD were examined for COL5A1 variants. In this mFMD cohort, COL5A1 c.1540G>A and 6 additional relatively rare COL5A1 variants predicted to be deleterious in silico were identified and were associated with arterial dissections (P=0.005). CONCLUSIONS: COL5A1 c.1540G>A is the first recurring variant recognized to be associated with arterial dissections and mFMD. This variant presents with a phenotype reminiscent of vascular Ehlers-Danlos syndrome. A shared haplotype among probands supports the existence of a common founder. Relatively rare COL5A1 genetic variants predicted to be deleterious by in silico analysis were identified in ≈2.7% of mFMD cases, and as they were enriched in patients with arterial dissections, may act as disease modifiers. Molecular testing for COL5A1 should be considered in patients with a phenotype overlapping with vascular Ehlers-Danlos syndrome and mFMD.

Industry Compensation to Physician Vascular Specialist Authors of Highly-referenced Aortic Aneurysm Studies.

BACKGROUND: Industry payments to physicians may influence their attitudes toward medical devices and products. Disclosure of industry compensation by authors of scientific manuscripts usually occurs at the authors' discretion and is seldom audited as part of the peer review process. The purpose of this analysis was to characterize industry compensation among highly cited research articles related to aortic aneurysm. METHODS: A Web of Science search for English language articles published from 2013-2017 using the search term "aortic aneurysm" identified publications for this study. The top 99 most-cited publications were abstracted by author. Physician authors with reported industry compensation from 2013-2016 were identified using the ProPublica Dollars for Docs search tool (linked to Centers for Medicare and Medicaid Services Open Payments data), based on provider name, medical specialty, and geographic location. Statistical analysis included descriptive statistics and categorical tests. RESULTS: The 99 articles had 1,264 unique authors, of whom 105 physicians (8.3%) received industry compensation during the study period. Fourteen of the 105 authors self-reported having received industry compensation. The remaining 91 authors (86.7%) did not disclose their industry-reported compensation. Industry payments during the study period totaled $6,082,574 paid through 13,489 transactions from 169 different manufacturers. In-kind items and services were the most common form of payment (65.3%). The median transaction amount was $58.32. [$138.34]. Food and beverage accounted for the largest number of transactions (N=9653), followed by travel and lodging (N=2365), consulting (N=513), and promotional speaking (N=436). Consulting accounted for the most total dollars over the study period ($1,970,606), followed by travel and lodging ($1,122,276), promotional speaking ($972,894), food and beverage ($568,251), royalty or license ($504,631), honoraria ($452,167), and education ($428,489). Royalty and license payments had the highest median transaction amount ($15,418. [$29,049]), and was the only category with a median transaction amount greater than $5,000. In contrast, several categories had median transaction amounts under $50, including food and beverage ($32. [$77]), gifts ($34. [$86]), and entertainment ($30. [$69]). No significant difference in payment amounts by medical specialty was identified (P=0.071). CONCLUSIONS: Only 8.3% of physician authors of highly cited aortic aneurysm studies received industry compensation, but 86.7% of those physician authors receiving payments did not disclose industry compensation within the manuscripts. Potential bias associated with industry compensation may be underestimated and conservatively biased based on author self-reporting.

Industry compensation and self-reported financial conflicts of interest among authors of highly cited peripheral artery disease studies.

OBJECTIVE: Industry compensation to authors may influence the interpretation of study results. Scientific journals often require author disclosure of a relevant financial conflict of interest (FCOI) but seldom quantify compensation and leave reporting up to the author's discretion. Professional and public concerns related to potential bias introduced into medical research by FCOI have arisen, especially when physician compensation from manufacturers is not disclosed. Little is known, however, about the prevalence of industry compensation to authors of related publications, payment amounts, or how this information compares with self-reported FCOI. The objective of this study was to compare industry compensation and disclosed FCOI among highly referenced publications related to treatment of peripheral artery disease, a disease that affects approximately 8.5 million Americans and is often treated with medications and devices. METHODS: "Peripheral artery disease" was used as a Web of Science search term to identify publications from 2013 to 2016, excluding review articles, conference proceedings, book chapters, abstract publications, and non-English language publications. The top 99 most cited publications were abstracted for self-reported FCOI by author. Industry compensation to authors was queried using a ProPublica Dollars for Docs custom data set based on Centers for Medicare and Medicaid Services Open Payments data. Providers practicing in the United States in any of the following specialties were included: cardiology, cardiothoracic surgery, vascular and interventional radiology, or vascular surgery. Payment transactions were matched to physician authors on the basis of provider name, specialty, and geographic location. Statistical analysis included descriptive statistics and categorical tests. Descriptive statistics are reported as frequency (percentage) or median (interquartile range). RESULTS: Among 1008 vascular specialist authors identified, 218 (22%) self-reported FCOI. Fifty-six physician authors had compensation reported to the Centers for Medicare and Medicaid Services by industry during the study period. Among those identified as recipients of industry compensation, 28 (50%) self-reported FCOI. Industry payments to the 56 authors totaled $11,139,987, with a median total payment of $18,827 (interquartile range, $152,084) per author. Food and beverage was the most frequently identified nature of payment (n = 8981 [74%]), promotional speaking involved the largest total amount of payments ($3,256,431), and royalty or license was the highest median payment ($51,431 [$72,215]). Physicians reporting FCOI received a total of $9,435,340 during the study period vs $1,706,647 for those who did not report any FCOI. Median total payments were higher among authors reporting FCOI vs not ($81,224 [$324,171] vs $9494 [$43,448]; P < .001). CONCLUSIONS: Nondisclosed author compensation from industry is relatively uncommon among highly cited peripheral artery disease research studies but may be associated with substantial payments. These results suggest that self-reported FCOI does not provide a comprehensive overview of industry compensation. Reporting all payments rather than only those deemed relevant by the author might provide a more complete and transparent report of potential FCOI, allowing independent assessment of relevance in interpreting study findings.

Surgical management of pediatric renin-mediated hypertension secondary to renal artery occlusive disease and abdominal aortic coarctation.

BACKGROUND: Renovascular hypertension (RVH) associated with renal artery and abdominal aortic narrowings is the third most common cause of pediatric hypertension. Untreated children may experience major cardiopulmonary complications, stroke, renal failure, and death. The impetus of this study was to describe the increasingly complex surgical practice for such patients with an emphasis on anatomic phenotype and contemporary outcomes after surgical management as a means of identifying those factors responsible for persistent or recurrent hypertension necessitating reoperation. METHODS: A retrospective analysis was performed of consecutive pediatric patients with RVH undergoing open surgical procedures at the University of Michigan from 1991 to 2017. Anatomic phenotype and patient risk factors were analyzed to predict outcomes of blood pressure control and the need for secondary operations using ordered and binomial logistic multinomial regression models, respectively. RESULTS: There were 169 children (76 girls, 93 boys) who underwent primary index operations at a median age of 8.3 years; 31 children (18%) had neurofibromatosis type 1, 76 (45%) had abdominal aortic coarctations, and 28 (17%) had a single functioning kidney. Before treatment at the University of Michigan, 51 children experienced failed previous open operations (15) or endovascular interventions (36) for RVH at other institutions. Primary surgical interventions (342) included main renal artery (136) and segmental renal artery (10) aortic reimplantation, renal artery bypass (55), segmental renal artery embolization (10), renal artery patch angioplasty (8), resection with reanastomosis (4), and partial or total nephrectomy (25). Non-renal artery procedures included patch aortoplasty (32), aortoaortic bypass (32), and splanchnic arterial revascularization (30). Nine patients required reoperation in the early postoperative period. During a mean follow-up of 49 months, secondary interventions were required in 35 children (21%), including both open surgical (37) and endovascular (14) interventions. Remedial intervention to preserve primary renal artery patency or a nephrectomy if such was impossible was required in 22 children (13%). The remaining secondary procedures were performed to treat previously untreated disease that became clinically evident during follow-up. Age at operation and abdominal aortic coarctation were independent predictors for reoperation. The overall experience revealed hypertension to be cured in 74 children (44%), improved in 78 (46%), and unchanged in 17 (10%). Children undergoing remedial operations were less likely (33%) to be cured of hypertension. There was no perioperative death or renal insufficiency requiring dialysis after either primary or secondary interventions. CONCLUSIONS: Contemporary surgical treatment of pediatric RVH provides a sustainable overall benefit to 90% of children. Interventions in the very young (<3 years) and concurrent abdominal aortic coarctation increase the likelihood of reoperation. Patients undergoing remedial surgery after earlier operative failures are less likely to be cured of hypertension. Judicious postoperative surveillance is imperative in children surgically treated for RVH.

Computational analysis of renal artery flow characteristics by modeling aortoplasty and aortic bypass interventions for abdominal aortic coarctation.

OBJECTIVE: Suprarenal abdominal aortic coarctation (SAAC) alters flow and pressure patterns to the kidneys and is often associated with severe angiotensin-mediated hypertension refractory to drug therapy. SAAC is most often treated by a thoracoabdominal bypass (TAB) or patch aortoplasty (PA). It is currently unclear what effect these interventions have on renal flow and pressure waveforms. This study, using retrospective data from a patient with SAAC subjected to a TAB, undertook computational modeling to analyze aortorenal blood flow preoperatively as well as postoperatively after a variety of TAB and PA interventions. METHODS: Patient-specific anatomic models were constructed from preoperative computed tomography angiograms of a 9-year-old child with an isolated SAAC. Fluid-structure interaction (FSI) simulations of hemodynamics were performed to analyze preoperative renal flow and pressure waveforms. A parametric study was then performed to examine the hemodynamic impact of different bypass diameters and patch oversizing. RESULTS: Preoperative FSI results documented diastole-dominated renal perfusion with considerable high-frequency disturbances in blood flow and pressure. The postoperative TAB right and left kidney volumes increased by 58% and 79%, respectively, reflecting the increased renal artery blood flows calculated by the FSI analysis. Postoperative increases in systolic flow accompanied decreases in high-frequency disturbances, aortic pressure, and collateral flow after all surgical interventions. In general, lesser degrees of high-frequency disturbances followed PA interventions. High-frequency disturbances were eliminated with the 0% PA in contrast to the 30% and 50% PA oversizing and TAB interventions, in which these flow disturbances remained. CONCLUSIONS: Both TAB and PA dramatically improved renal artery flow and pressure waveforms, although disturbed renal waveforms remained in many of the surgical scenarios. Importantly, only the 0% PA oversizing scenario eliminated all high-frequency disturbances, resulting in nearly normal aortorenal blood flow. The study also establishes the relevance of patient-specific computational modeling in planning interventions for the midaortic syndrome.

The Association of Intracranial Aneurysms in Women with Renal Artery Aneurysms.

BACKGROUND: Renal artery aneurysms (RAAs) may reflect a systemic dysplastic arteriopathy, independent of a recognized connective tissue disease. It is hypothesized that RAAs are associated with an increased risk of intracranial aneurysms (IcAs). The objective of this study was to better define the association of IcAs in women with RAAs. METHODS: Women aged 20 to 60 years who presented with RAAs at the University of Michigan from 2001 to 2016 were included in the study. Their clinical status and radiologic images were retrospectively reviewed, with particular attention directed to the prevalence of IcAs. Phenotypic characteristics predictive of associated cerebrovascular lesions were assessed using various statistical analyses, including binomial logistic regression. RESULTS: Among 83 women with RAAs, the average age at the time of RAA detection was 45.3 ± 9.9 years (range, 20-60 years). Hypertension affected 56 (67.5%) patients and poorly controlled hypertension prompted imaging for suspected renal arterial disease in 12 (14.5%) patients. Multifocal fibromuscular dysplasia occurred in 12 (14.8%) of patients, and unifocal stenosis affected 7 (8.4%) patients. Imaging of the intracranial vasculature (n = 31) documented 12 aneurysms in 9 women, with the cavernous internal carotid artery being the most commonly affected artery. Among the study's patients, 20 (24.1%) had an "at-risk disorder for IcA formation," although the frequency of relevant "at-risk disorders" in those with and without IcAs was not statistically different (P = 0.21). Rupture risk defined by PHASES score was less than 1% for 10 IcAs, but 2 IcAs carried a 2.4% and 7.2% rupture risk, respectively, over a 5-year time period. Surgical management was pursued in 6 (50%) of the study's IcAs. CONCLUSIONS: Coexisting RAAs and IcAs may reflect a systemic arteriopathy. IcAs appear to occur with greater frequency in women with RAAs than the general population. This observation warrants prospective investigation as to the clinical appropriateness and relevance of cerebrovascular imaging in women with RAAs. Furthermore, this study's findings prompt further investigation of the underlying pathogenesis of what appears to be a broader and more complex arterial disease than previously recognized.

Arterial reconstructions for chronic lower extremity ischemia in preadolescent and adolescent children.

OBJECTIVE: Chronic lower extremity ischemia in pediatric patients is uncommon. The intent of this study was to better define the arterial reconstructive options and their long-term durability in preadolescent and adolescent children having clinically relevant arterial occlusions affecting the lower extremity. METHODS: The medical records of 33 consecutive pediatric patients who underwent lower extremity revascularization for chronic ischemia at the University of Michigan from 1974 to 2016 were reviewed. Patients were categorized by age, clinical manifestation, surgical intervention undertaken, and outcomes. RESULTS: Operative treatments involved 26 preadolescent children (mean age, 6.1 years; range, 3-9 years) and 7 adolescent children (mean age, 13.9 years; range, 10-17 years). Occlusions were due to earlier injury related to catheter (14), cannula (2), or both catheter and cannula (14); penetrating trauma (2); and vasculitis (1). Preoperative manifestations included symptomatic extremity ischemia (25), growth retardation manifested by documented limb length discrepancies (21), and scoliosis (5). Primary arterial reconstructions were delayed after the precipitating vascular event an average of 5.3 and 11.2 years in the preadolescent and adolescent children, respectively. Primary procedures involved revascularizations of 36 extremities (in preadolescents and adolescents) including autologous vein (26/5), polyethylene terephthalate (Dacron; 1/0), and expanded polytetrafluoroethylene (0/3) bypasses and vein patch angioplasty (0/1). Vein grafts traversing the abdominal cavity (15) were wrapped with a synthetic mesh. Excluding one early graft occlusion, there were no major early postoperative complications after the primary procedures. Secondary operations followed 31% of the primary operations, being performed an average of 8.8 and 6.7 years later (in 8 preadolescent and 3 adolescent children, respectively) for late graft occlusions (6), graft stenoses (3), aneurysmal vein grafts (2), and anastomotic pseudoaneurysm (1). The unassisted primary graft patency rate was 69%, and the assisted secondary graft patency rate was 94%. Symptomatic ischemia resolved in all but two children. Mean postoperative ankle-brachial indices improved to 1.08 from 0.76 preoperatively. Among children having postoperative documentation of limb lengths, the limb length discrepancies became less (11), were unchanged (1), or progressed (3). Follow-up averaged 8.0 years. There was no operative mortality in this experience. CONCLUSIONS: Primary lower extremity arterial reconstructions in children with chronic lower extremity ischemia can be successfully undertaken with excellent results. Nevertheless, the potential for late primary graft failures, evident in nearly a third of this experience, mandates careful long-term follow-up and may necessitate secondary interventions to maintain satisfactory outcomes.

Arterial reconstructions for pediatric splanchnic artery occlusive disease.

OBJECTIVE: Pediatric splanchnic arterial occlusive disease is uncommon and a rare cause of clinically relevant intestinal ischemia. This study was undertaken to better define the clinical manifestations and appropriate treatment of celiac artery (CA) and superior mesenteric artery (SMA) occlusive disease in children. METHODS: Clinical courses of 30 consecutive children undergoing operations for splanchnic arterial occlusive disease at the University of Michigan from 1992 to 2017 were retrospectively analyzed. RESULTS: Vascular reconstructions were performed for splanchnic arterial disease in 18 boys and 12 girls, 1.5 to 16 years of age (mean, 7.5 ± 4.1 years). Isolated splanchnic arterial disease was uncommon (2 children), being more often associated with abdominal aortic coarctations (19 children) or ostial renal artery stenoses (25 children). Primary splanchnic arterial reconstructions (30) included aortic reimplantation of SMAs (15) or celiacomesenteric arteries (2), aortoceliac and aortomesenteric bypasses (7), reimplantation of the CA as a patch over the stenotic SMA orifice (3), and patch angioplasty of the CA (2) or SMA (1). There was no perioperative mortality. Two groups (I and II) were identified for study. Group I children (14) experienced symptomatic intestinal ischemia, manifested by various combinations of chronic postprandial abdominal discomfort (14), ischemia-related intestinal bleeding (2), or failure to thrive (4). Four children in group I became symptomatic after known CA and SMA occlusive disease was left untreated at the time they underwent earlier interventions for renovascular hypertension. Seven secondary redo interventions were undertaken for recurrent symptoms in six group I children. Only one major periprocedural complication occurred: segmental colon infarction. The assisted patency rate of reconstructed arteries in group I children was 93%, and intestinal ischemic symptoms resolved in every child. Group I follow-up from the most recent splanchnic arterial reconstruction averaged 4.3 years. Group II children (16) without manifestations of intestinal ischemia underwent prophylactic splanchnic arterial reconstructions in concert with combined aortic and renal artery procedures (11), isolated abdominal aortic reconstructions (3), or renal artery reconstructions alone (2). Group II children experienced no major perioperative morbidity and remained asymptomatic postoperatively, and none required secondary splanchnic artery interventions. Group II follow-up averaged 7.4 years. CONCLUSIONS: Pediatric splanchnic artery occlusive lesions are often associated with developmental aortic and renal artery occlusive disease. Carefully conducted therapeutic and prophylactic reconstructive procedures are appropriate in children having splanchnic arterial occlusive disease.

Pancreaticoduodenal and Gastroduodenal Artery Aneurysms Associated with Celiac Artery Occlusive Disease.

BACKGROUND: The purpose of this study is to better define the clinical relevance of aneurysms affecting collateral vessels in patients with celiac artery (CA) occlusive disease. METHODS: True pancreaticoduodenal artery (PDA) and gastroduodenal artery (GDA) aneurysms associated with CA stenoses or occlusions reported from 1970 to 2010 in the English literature and similar cases treated at the University of Michigan were reviewed. Clinical presentations and differing treatment modalities were documented and analyzed. RESULTS: One hundred twenty-five patients having CA occlusive disease exhibited true arterial aneurysms affecting the PDA (105 patients), GDA (10 patients), or both PDA and GDA and their branches (10 patients). Aneurysm size averaged 2.1 cm. Included were 110 patients culled from the literature and 15 treated by the authors. The mean age of patients in this series was 59 years and there was no gender predilection. Aneurysms were asymptomatic in 26%. Abdominal pain affected 54% of the patients, including all who experienced rupture. Rupture occurred in 48 patients of whom 15 were hemodynamically unstable, including 6 who died. Surgical interventions included endovascular embolization (39), aneurysmectomy alone (25), and aneurysmectomy with arterial reconstruction (20). Salutary outcomes occurred in 91% of the cases. Open surgical procedures have remained constant, but were equaled by endovascular interventions in 1996, with the latter having increased 3-fold in the past 15 years. CONCLUSIONS: PDA and GDA aneurysms associated with CA occlusive disease carry a high risk of nonfatal rupture, warranting early treatment. Endovascular and open interventions may be successfully undertaken with minimal risks in treating these uncommon aneurysms.

Surgical treatment of abdominal aortic aneurysms in infancy and early childhood.

OBJECTIVE: Pediatric abdominal aortic aneurysms (AAAs) are rare. The intent of this report was to review the presentation and surgical management of AAAs in infancy and early childhood. METHODS: The clinical courses of young children undergoing AAA surgery were subjected to a retrospective review and analysis. RESULTS: Eleven children, nine boys and two girls, ranging in age from 2 weeks to 6 years, underwent surgical treatment of AAA at the University of Michigan from 2002 to 2014. Aneurysms were supraceliac (2), suprarenal (2), pararenal (2), or infrarenal (5). Associated iliac aneurysms (3) affected two children. Concomitant stenoses affected the renal (14), superior mesenteric (4), and celiac (3) arteries. AAAs were attributed to developmental defects (7), including three arising immediately beyond aortic narrowings; infection after umbilical artery catheterization (2); tuberous sclerosis (1); and trauma (1). Primary operative interventions included aneurysmectomy with a thoracoabdominal bypass (4), open aneurysmorrhaphy (2), closed aneurysmorrhaphy (2), and aneurysmectomy with an infrarenal aortoaortic bypass (1) or an aortoiliac bypass (2). Perioperative death occurred in one child who had preoperative heart and renal failure. Aortic graft occlusion affected two children at 1 month and 3 years postoperatively. The remaining children incurred no aortic reconstruction-related morbidity. Follow-up among the 10 survivors averaged 4.9 years. CONCLUSIONS: Successful surgical treatment of AAAs in infants and young children requires careful execution of a diverse group of surgical techniques based on the etiology, the child's size and growth potential, and the aneurysm's location and coexisting branch involvement.

Pediatric nonaortic arterial aneurysms.

OBJECTIVE: Pediatric arterial aneurysms are extremely uncommon. Indications for intervention remain poorly defined and treatments vary. The impetus for this study was to better define the contemporary surgical management of pediatric nonaortic arterial aneurysms. METHODS: A retrospective analysis was conducted of 41 children with 61 aneurysms who underwent surgical treatment from 1983 to 2015 at the University of Michigan. Arteries affected included: renal (n = 26), femoral (n = 7), iliac (n = 7), superior mesenteric (n = 4), brachial (n = 3), carotid (n = 3), popliteal (n = 3), axillary (n = 2), celiac (n = 2), ulnar (n = 2), common hepatic (n = 1), and temporal (n = 1). Intracranial aneurysms and aortic aneurysms treated during the same time period were not included in this study. Primary outcomes analyzed were postoperative complications, mortality, and freedom from reintervention. RESULTS: The study included 27 boys and 14 girls, with a median age of 9.8 years (range, 2 months-18 years) and a weight of 31.0 kg (range, 3.8-71 kg). Multiple aneurysms existed in 14 children. Obvious factors that contributed to aneurysmal formation included: proximal juxta-aneurysmal stenoses (n = 14), trauma (n = 12), Kawasaki disease (n = 4), Ehlers-Danlos type IV syndrome (n = 1), and infection (n = 1). Preoperative diagnoses were established using arteriography (n = 23), magnetic resonance angiography (n = 6), computed tomographic arteriography (n = 5), or ultrasonography (n = 7), and confirmed during surgery. Indications for surgery included risk of expansion and rupture, potential thrombosis or embolization of aneurysmal thrombus, local soft tissue and nerve compression, and secondary hypertension in the case of renal artery aneurysms. Primary surgical techniques included: aneurysm resection with reanastomsis, reimplantation, or angioplastic closure (n = 16), interposition (n = 10) or bypass grafts (n = 2), ligation (n = 9), plication (n = 8), endovascular occlusion (n = 3), and nephrectomy (n = 4) in cases of unreconstructable renal aneurysmal disease. Later secondary operations were required to treat stenoses at the site of the original aneurysm repairs (n = 2) and new aneurysmal development (n = 1). Postoperative follow-up averaged 47 months (range, 1-349 months). No major perioperative morbidity and no mortality was encountered in this experience. CONCLUSIONS: Pediatric arterial aneurysms represent a complex disease that affects multiple vascular territories. Results of the current series suggest that individualized surgical treatment, ranging from simple ligations to major arterial reconstructions, was durable and can be undertaken with minimal risk.

Remedial operations for failed endovascular therapy of 32 renal artery stenoses in 24 children.

BACKGROUND: Percutaneous transluminal angioplasty (PTA) for the treatment of pediatric renovascular hypertension (RVH) in contemporary practice is accompanied with ill-defined complications. This study examines the mode of pediatric renal PTA failures and the results of their surgical management. METHODS: Twenty-four children underwent remedial operations at the University of Michigan from 1996 to 2014 for failures of renal PTA. Their clinical courses were retrospectively reviewed and results analyzed. RESULTS: Renal PTA of 32 arteries, including 13 with stenting, was performed for severe RVH in 12 boys and 12 girls, having a mean age of 9.3 years. Developmental ostial stenoses affected 22 children. PTA failures included: 27 restenoses and five thromboses. Remedial operations included: 13 renal artery-aortic reimplantations, one segmental renal artery-main renal artery reimplantation, ten aortorenal bypasses, one arterioplasty, one iliorenal bypass, and six nephrectomies for unreconstructable arteries; the latter all in children younger than 10 years. Follow-up averaged 2.1 years. Postoperatively, hypertension was cured, improved, or unchanged in 25, 54, and 21 %, respectively. There was no perioperative renal failure or mortality. CONCLUSIONS: Renal PTA for the treatment of pediatric RVH due to ostial disease may be complicated by failures requiring complex remedial operations or nephrectomy, the latter usually affecting younger children.

Infantile Renovascular Hypertension with Failure to Thrive.

Severe hypertension in infancy is a rare cause of failure to thrive. The successful surgical management of this disease in an infant having refractory renovascular hypertension and growth failure is reported.

Renal artery aneurysms.

Renal artery aneurysms are rare in the general population, although the true incidence and natural history remain elusive. Controversy over criteria for repair persists across decades. Indications for repair presently include aneurysm size >2 cm, female gender within childbearing age, symptoms like pain and hematuria, medically refractory hypertension including that associated with functionally important renal artery stenosis, thromboembolism, dissection, and rupture. Conventional surgical reconstruction options are variable and continue to offer technically sound and durable results. Endovascular therapies with novel devices also offer technical success with few major adverse events, and are increasingly employed as indications for intervention broaden. This review summarizes the accumulated evidence on true renal artery aneurysms with a particular focus on contemporary treatment criteria, natural history, options for repair and outcomes following such.

The contemporary management of renal artery aneurysms.

BACKGROUND: Renal artery aneurysms (RAAs) are rare, with little known about their natural history and growth rate or their optimal management. The specific objectives of this study were to (1) define the clinical features of RAAs, including the precise growth rate and risk of rupture, (2) examine the current management and outcomes of RAA treatment using existing guidelines, and (3) examine the appropriateness of current criteria for repair of asymptomatic RAAs. METHODS: A standardized, multi-institutional approach was used to evaluate patients with RAAs at institutions from all regions of the United States. Patient demographics, aneurysm characteristics, aneurysm imaging, conservative and operative management, postoperative complications, and follow-up data were collected. RESULTS: A total of 865 RAAs in 760 patients were identified at 16 institutions. Of these, 75% were asymptomatic; symptomatic patients had difficult-to-control hypertension (10%), flank pain (6%), hematuria (4%), and abdominal pain (2%). The RAAs had a mean maximum diameter of 1.5 ± 0.1 cm. Most were unilateral (96%), on the right side (61%), saccular (87%), and calcified (56%). Elective repair was performed in 213 patients with 241 RAAs, usually for symptoms or size >2 cm; the remaining 547 patients with 624 RAAs were observed. Major operative complications occurred in 10%, including multisystem organ failure, myocardial infarction, and renal failure requiring dialysis. RAA repair for difficult-to-control hypertension cured 32% of patients and improved it in 26%. Three patients had ruptured RAA; all were transferred from other hospitals and underwent emergency repair, with no deaths. Conservatively treated patients were monitored for a mean of 49 months, with no acute complications. Aneurysm growth rate was 0.086 cm/y, with no difference between calcified and noncalcified aneurysms. CONCLUSIONS: This large, contemporary, multi-institutional study demonstrated that asymptomatic RAAs rarely rupture (even when >2 cm), growth rate is 0.086 ± 0.08 cm/y, and calcification does not protect against enlargement. RAA open repair is associated with significant minor morbidity, but rarely a major morbidity or mortality. Aneurysm repair cured or improved hypertension in >50% of patients whose RAA was identified during the workup for difficult-to-control hypertension.