Red blood cell-derived arginase release in hemolytic uremic syndrome.

BACKGROUND: Hemolysis is a cardinal feature of hemolytic uremic syndrome (HUS) and during hemolysis excess arginase 1 is released from red blood cells. Increased arginase activity leads to reduced L-arginine, as it is converted to urea and L-ornithine, and thereby reduced nitric oxide bioavailability, with secondary vascular injury. The objective of this study was to investigate arginase release in HUS patients and laboratory models and correlate arginase levels to hemolysis and kidney injury. METHODS: Two separate cohorts of patients (n = 47 in total) with HUS associated with Shiga toxin-producing enterohemorrhagic E. coli (EHEC) and pediatric controls (n = 35) were investigated. Two mouse models were used, in which mice were either challenged intragastrically with E. coli O157:H7 or injected intraperitoneally with Shiga toxin 2. An in vitro model of thrombotic microangiopathy was developed in which Shiga toxin 2- and E. coli O157 lipopolysaccharide-stimulated human blood cells combined with ADAMTS13-deficient plasma were perfused over glomerular endothelial cells. Two group statistical comparisons were performed using the Mann-Whitney test, multiple groups were compared using the Kruskal-Wallis test followed by Dunn's procedure, the Wilcoxon signed rank test was used for paired data, or linear regression for continuous variables. RESULTS: HUS patients had excessively high plasma arginase 1 levels and activity (conversion of L-arginine to urea and L-ornithine) during the acute phase, compared to remission and controls. Arginase 1 levels correlated with lactate dehydrogenase activity, indicating hemolysis, as well as the need for dialysis treatment. Patients also exhibited high levels of plasma alpha-1-microglobulin, a heme scavenger. Both mouse models exhibited significantly elevated plasma arginase 1 levels and activity. Plasma arginase 1 levels correlated with lactate dehydrogenase activity, alpha-1-microglobulin and urea levels, the latter indicative of kidney dysfunction. In the in vitro model of thrombotic microangiopathy, bioactive arginase 1 was released and levels correlated to the degree of hemolysis. CONCLUSIONS: Elevated red blood cell-derived arginase was demonstrated in HUS patients and in relevant in vivo and in vitro models. The excessively high arginase levels correlated to the degree of hemolysis and kidney dysfunction. Thus, arginase inhibition should be investigated in HUS.

New insights into the pathogenesis of Streptococcus pneumoniae-associated hemolytic uremic syndrome.

The purpose of this review is to describe Streptococcus pneumoniae-associated hemolytic uremic syndrome (P-HUS) with emphasis on new insights into the pathophysiology and management over the past 10 years. Even though awareness of this clinico-pathological entity has increased, it likely remains under-recognized. Recent observations indicate that although neuraminidase activity and exposure of the T-antigen are necessary for development of P-HUS, they are not sufficient; activation of the alternate pathway of complement may also contribute. It is unclear, however, whether or not eculizumab and/or plasmapheresis are of value.

Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans.

Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A.

Acquired Multiple Cysts of the Kidney in Neuroblastoma Survivors.

Cystic kidney disease includes a wide range of hereditary, developmental, and acquired conditions of the kidneys. Some of the inherited causes of cystic kidney disease include autosomal dominant polycystic kidney diseases (caused by mutations in PKD1 or PKD2), autosomal recessive polycystic kidney disease, tuberous sclerosis complex, von Hippel-Lindau disease, oral-facial-digital syndrome type I, and Hadju-Cheney syndrome. Acquired cystic kidney disease has been reported in patients receiving long-term hemodialysis or peritoneal dialysis and in children after liver transplantation. Acute kidney injury can occur in patients with neuroblastoma, usually as a result of thrombotic microangiopathy associated with bone marrow transplantation. End-stage renal disease is described in long-term survivors. However, in this case report, we provide what is to our knowledge the first description of multiple kidney cysts in long-term survivors of stage IV neuroblastoma. None of the 7 patients we describe with neuroblastoma and multiple kidney cysts had a family history of autosomal dominant polycystic kidney disease. Also, all lacked stigmata of tuberous sclerosis complex, von Hippel-Lindau disease, or Hadju-Cheney syndrome. Two patients progressed to end-stage renal disease; in addition, one of them developed an oncocytoid renal cell carcinoma.

Imaging features of tuberous sclerosis complex with autosomal-dominant polycystic kidney disease: a contiguous gene syndrome.

BACKGROUND: Genes for tuberous sclerosis complex (TSC) type 2 and autosomal-dominant polycystic kidney disease (ADPKD) type 1 are both encoded over a short segment of chromosome 16. When deletions involve both genes, an entity known as the TSC2/ADPKD1 contiguous gene syndrome, variable phenotypes of TSC and ADPKD are exhibited. This syndrome has not been reviewed in the radiology literature. Unlike renal cysts in TSC, cystic disease in TSC2/ADPKD1 contiguous gene syndrome results in hypertension and renal failure. A radiologist might demonstrate polycystic kidney disease before the patient develops other stigmata of TSC. Conversely, in patients with known TSC, enlarged and polycystic kidneys should signal the possibility of the TSC2/ADPKD1 contiguous gene syndrome and not simply TSC. Distinguishing these diagnoses has implications in prognosis, treatment and genetic counseling. OBJECTIVE: To describe the clinical and imaging findings of tuberous sclerosis complex and polycystic kidney disease in seven pediatric patients. MATERIALS AND METHODS: We retrospectively reviewed renal and brain imaging of children and young adults with genetically proven or high clinical suspicion for TSC2/ADPKD1 contiguous gene syndrome. RESULTS: We included seven pediatric patients from two referral institutions. Ages ranged from birth to 21 years over the course of imaging. The mean follow-up period was 9 years 8 months (4 years 6 months to 20 years 6 months). No child progressed to end-stage renal disease during this period. Three patients were initially imaged for stigmata of TSC, three for abdominal distension and one for elevated serum creatinine concentration. All patients developed enlarged, polycystic kidneys. The latest available imaging studies demonstrated that in 12 of the 14 kidneys 50% or more of the parenchyma was ultimately replaced by >15 cysts, resulting in significant cortical thinning. The largest cysts in each kidney ranged from 2.4 cm to 9.3 cm. Echogenic lesions were present in 13 of the 14 kidneys, in keeping with angiomyolipomas (ranging from 0.4 cm to 7.8 cm). Compared to the latest imaging studies, the initial studies only demonstrated 64% of kidneys to be borderline or enlarged; the majority had 10 or more cysts and 0-5 echogenic foci in each kidney, measuring 0.8 cm maximally, which were possible angiomyolipomas. Increased cortical echogenicity was observed in eight kidneys, and decreased corticomedullary differentiation was demonstrated in six kidneys. Cortical thinning varied with size and number of cysts. CONCLUSION: The sonographic renal findings in TSC2/ADPKD1 contiguous gene syndrome progress over time and demonstrate a specific pattern of renal disease different from typical tuberous sclerosis complex. There are multiple cysts at presentation and there is progressive enlargement of the kidneys and of the renal cysts. Because clinical or imaging findings of TSC may not manifest in the young child, the radiologist can be the first to suggest a diagnosis of TSC2/ADPKD1 contiguous gene syndrome and recommend thorough skin examination and imaging in search of TSC findings. The radiologist should be able to suggest the diagnosis of TSC2/ADPKD1 contiguous gene syndrome in children with TSC who have large cysts occupying a large portion of an enlarged kidney. This should not be dismissed as renal cystic disease of TSC or as ADPKD because the diagnosis of TSC2/ADPKD1 contiguous gene syndrome has implications for patient management and prognosis.

Exome sequencing and in vitro studies identified podocalyxin as a candidate gene for focal and segmental glomerulosclerosis.

Our understanding of focal and segmental glomerulosclerosis (FSGS) has advanced significantly from the studies of rare, monogenic forms of the disease. These studies have demonstrated the critical roles of multiple aspects of podocyte function in maintaining glomerular function. A substantial body of research has suggested that the integral membrane protein podocalyxin (PODXL) is required for proper functioning of podocytes, possibly by preserving the patency of the slit diaphragm by negative charge-based repulsion. Exome sequencing of affected cousins from an autosomal dominant pedigree with FSGS identified a cosegregating private variant, PODXL p.L442R, affecting the transmembrane region of the protein. Of the remaining 11 shared gene variants, two segregated with disease, but their gene products were not detected in the glomerulus. In comparison with wild type, this disease-segregating PODXL variant facilitated dimerization. By contrast, this change does not alter protein stability, extracellular domain glycosylation, cell surface expression, global subcellular localization, or interaction with its intracellular binding partner ezrin. Thus, a variant form of PODXL remains the most likely candidate causing FSGS in one family with autosomal dominant inheritance, but its full effect on protein function remains unknown. Our work highlights the challenge faced in the clinical interpretation of whole-exome data for small pedigrees with autosomal dominant diseases.

Nephrotic syndrome associated with tyrosine kinase inhibitors for pediatric malignancy: case series and review of the literature.

BACKGROUND: Tyrosine kinase (TK) inhibitors are increasingly being used to treat a variety of pediatric malignancies. Reports in adult patients describe a range of effects of TK inhibitors on the kidney, including hypertension, proteinuria, acute kidney injury, and thrombotic microangiopathy (TMA); however, there are only a few reports of TK-inhibitor-associated nephrotic syndrome. METHODS: We report four pediatric patients with various malignancies (chronic myelogenous leukemia, acute lymphoblastic leukemia, and glioma/renal cell carcinoma) who developed nephrotic syndrome during treatment with TK inhibitors (imatinib, sunitinib, dasatinib, and quizartinib). One of the four patients also had clinical features of TMA. RESULTS: Three of the four patients achieved complete remission of nephrotic syndrome with discontinuation of the TK inhibitor and have had no additional nephrotic syndrome relapses to date. The temporal relationship of nephrotic syndrome onset to TK-inhibitor therapy and resolution of nephrotic syndrome with cessation of therapy strongly imply an association in these patients. CONCLUSIONS: TK inhibitors are important therapies in pediatric cancer, and their use is expanding. Nephrotic syndrome with or without features of TMA is a potential complication of these therapies in children.

Streptococcal infection as possible trigger for dense deposit disease (C3 glomerulopathy).

UNLABELLED: Dense deposit disease (DDD, formerly known as membranoproliferative glomerulonephritis (MPGN) type II) is a subtype of C3 glomerulopathy (C3G). Electron-dense deposits in the glomerular basement membrane characterize this glomerulonephritis. DDD typically presents with a nephritic syndrome that progresses to end-stage renal failure in 50 % of patients despite treatment. The pathogenic basis of DDD is uncontrolled activation of the alternative complement cascade although the potential triggering events that precipitate the development of complement dysregulation are typically unknown. There are isolated reports of an apparent association between streptococcal infection and DDD, as well as with MPGN types I and III. However, this association has not been deemed compelling, perhaps because so few cases have been reported or because of a current lack of evidence for a plausible hypothesis to connect a streptococcal infection with subsequent disease. In this report, we describe two patients with DDD who definitely had an antecedent streptococcal infection with the phenotype of acute post-streptococcal glomerulonephritis and whose initial kidney biopsy findings on light microscopy were indistinguishable from acute post-streptococcal glomerulonephritis. These patients had additional points of interest: recurrence of gross hematuria with recurrent streptococcal infections, slowly progressive course, persistently low serum C3 concentration, positive C3 nephritic factor, and positive risk alleles in the complement factor H (CFH) gene. CONCLUSION: We suggest that streptococcal infection may trigger DDD in individuals genetically predisposed by virtue of a disorder in complement regulation.

Renal transplantation into a diverted urinary system-is it safe in children?

PURPOSE: Historically surgeons caring for children with urinary diversion for bladder outlet obstruction have routinely performed undiversion before renal transplantation. We hypothesized that patients undergoing transplantation into a diverted system would have outcomes similar to those undergoing transplantation into a normal bladder. We review the outcomes of patients with and without diversion undergoing kidney transplantation at our institution. MATERIALS AND METHODS: We retrospectively studied a cohort of children undergoing renal transplant between 1993 and 2006. Patients whose etiology of end-stage renal disease was either obstructive uropathy or renal dysplasia were included. Patients with less than 5 years of followup were excluded from the analysis. Four groups were assembled, ie controls with renal dysplasia and no history of obstructive uropathy undergoing transplant (group 1), patients with obstructive uropathy not diverted at transplant (group 2), patients with obstructive uropathy diverted at transplant (group 3) and patients with obstructive uropathy augmented before transplant (group 4). The groups were compared for outcomes of frequency of urinary tract infection, renal graft function and graft loss. RESULTS: Of the 80 subjects eligible based on diagnostic criteria 43 had completed 5 years of followup. There was no significant difference between groups based on age (p = 0.508), renal function as measured by glomerular filtration rate (p = 0.526) or creatinine (p = 0.612), or frequency of urinary tract infections (p = 0.083). Only 1 patient in the cohort suffered graft loss. CONCLUSIONS: Based on frequency of urinary tract infection, renal function and graft loss 5 years after transplant, there appears to be no added risk to transplanting a kidney into a diverted system.

Renal-hepatic-pancreatic dysplasia: a sibship with skeletal and central nervous system anomalies and NPHP3 mutation.

We report on five consecutive sibs three with fatal renal-hepatic-pancreatic dysplastic (RHPD) syndrome and two pregnancies ending in early abortion. Three of the fetuses reached term and two survived for 15 and 58 days. They had diffusely cystic kidneys with absence of the distal collecting tubules, hepatic fibrosis, bile duct paucity, and pancreatic fibrosis with irregularly dilated ducts. These findings correspond to many of those reported by Ivemark et al. [Ivemark et al. (1959); Acta Paediat Scand 48: 1-11] as part of the RHPD syndrome. There are several notable differences in this family: one patient had hypocalvaria and a choroid plexus cyst at the right foramen of Luschka, multiple bone abnormalities including widened growth plates and abnormal development of the trabeculae of the ribs, "handle-bar" clavicles, wedge defects of the inferior margin of several thoracic vertebrae; the second patient had hypocalvaria and abnormally developed brain with bilateral exposure of the insulae; and a third patient had anencephaly. Mutational analysis of the two who survived beyond post-delivery demonstrated compound heterozygous novel frameshift mutations in the nephronophthisis type 3 gene (NPHP3).

Update on Streptococcus pneumoniae associated hemolytic uremic syndrome.

PURPOSE OF REVIEW: Streptococcus pneumoniae associated hemolytic uremic syndrome (SpHUS) is defined by the occurrence of acute hemolytic anemia, thrombocytopenia and acute kidney injury in a patient with a S. pneumoniae infection. We review the pathophysiology, clinical course, treatment and prognosis for SpHUS. We also describe an expanded classification system that uses additional diagnostic criteria to identify more patients with a high likelihood of having SpHUS. RECENT FINDINGS: SpHUS often may be underdiagnosed because of overlapping features with disseminated intravascular coagulation (DIC) and the lack of strict diagnostic criteria. The epidemiology has changed with the emergence of different pneumococcal serotypes as newer pneumococcal vaccines have been introduced. SUMMARY: SpHUS accounts for 5-15% of all HUS cases. The majority of SpHUS patients have pneumonia and a low mortality rate in contrast to those with meningitis, who have a more severe clinical course. Although the pathogenesis of SpHUS remains unknown, the Thomsen-Friedenreich antigen seems to play a central role. S. pneumoniae produces neuraminidase, thereby exposing the Thomsen-Friedenreich antigen on the surface of cell membranes. Thomsen-Friedenreich antigen exposure can result in hemolysis and direct endothelial injury leading to HUS phenotype. Early identification of these patients is critical so that fresh frozen plasma may be avoided.

Long-term outcomes of Shiga toxin hemolytic uremic syndrome.

Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) is an important cause of acute kidney injury (AKI). The outcomes of STEC HUS have improved, and the acute mortality rate in children is 1-4%. About 70% of patients recover completely from the acute episode and the remainder have varying degrees of sequelae. Only a few retrospective studies have reviewed these patients over long periods. Methodological flaws include a lack of strict definitions, changing modes of treatment, ascertainment bias and loss of subjects to follow-up. The kidneys bear the brunt of the long-term damage: proteinuria (15-30% of cases); hypertension (5-15%); chronic kidney disease (CKD; 9-18%); and end-stage kidney disease (ESKD; 3%). A smaller number have extra-renal sequelae: colonic strictures, cholelithiasis, diabetes mellitus or brain injury. Most renal sequelae are minor abnormalities, such as treatable hypertension and/or variable proteinuria. Most of the patients who progress to ESKD do not recover normal renal function after the acute episode. Length of anuria (more than 10 days) and prolonged dialysis are the most important risk factors for a poor acute and long-term renal outcome. After the acute episode all patients must be followed for at least 5 years, and severely affected patients should be followed indefinitely if there is proteinuria, hypertension or a reduced glomerular filtration rate (GFR).

Atypical glomerulopathy associated with the cblE inborn error of vitamin B12 metabolism.

BACKGROUND: The cblE disorder is an inherited disorder of vitamin B12 metabolism that results in elevated levels of homocysteine and decreased methionine in body fluids. Renal complications have been reported in patients with cblC disease, but not in those with cblE disease. The renal complications of cblC disease include thrombotic microangiopathy (TMA), neonatal hemolytic uremic syndrome, chronic renal failure, tubulointerstitial nephritis and proximal renal tubular acidosis. Previously, we reported a patient with cblC disease who had an atypical glomerulopathy that manifested with proteinuria and progressive renal insufficiency. CASE-DIAGNOSIS/TREATMENT: Studies were done on cultured fibroblasts. Renal biopsy tissue was examined by light and electron microscopy. There was decreased incorporation of labeled methyltetrahydrofolate and decreased synthesis of methylcobalamin. Complementation analysis placed the patient into the cblE complementation group. The findings from the histological and ultrastructural studies of renal biopsy were similar, but not identical, to those of idiopathic membranoproliferative glomerulonephritis (MPGN) and overlapped with those of TMA. CONCLUSIONS: We describe a patient with cblE disease who had an atypical glomerulopathy similar to MPGN. Additional findings included migraine headaches, hypothyroidism and livedo reticularis.

Renin-angiotensin-aldosterone system inhibitors in pediatric focal segmental glomerulosclerosis.

BACKGROUND: Conventional immunosuppressive therapy for primary pediatric focal segmental glomerulosclerosis (FSGS) is potentially toxic and only moderate evidence supports its effectiveness. Renin-angiotensin-aldosterone (RAAS) inhibition monotherapy is anecdotally used in selected patients as an alternative to conventional therapy. METHODS: We performed a retrospective cohort study of children with primary FSGS seen at a tertiary care academic hospital between 1986 and 2008. We classified patients into two groups based upon initial treatment: RAAS inhibition monotherapy (RIM) and conventional therapy (CT). The primary endpoint was progression to end-stage renal disease (ESRD). Secondary endpoints were remission of proteinuria, relapse, and death. RESULTS: The cohort consisted of 67 patients. Mean baseline urine protein/creatinine ratio (Up/c) was 8.0 (5.2, 10.7) mg/mg, and mean baseline estimated glomerular filtration rate (eGFR) was 115.0 (101.8, 128.1) mL/min/1.73 m(2). Patients in the RIM group were more likely to have lower eGFR (100.8 mL/min/1.73 m(2) vs 132.9 mL/min/1.73 m(2), p = 0.01) and less proteinuria (4.4 vs.14.4, p < 0.01). Renal failure occurred in 22.9% of the RIM group vs 40.6% in the CT group (log-rank p = 0.07). After adjustment for African-American race, time period of presentation, baseline age, eGFR, and Up/c, patients in the RIM group had a 0.11 hazard ratio of progressing to renal failure compared with patients in the CT group (p < 0.01). CONCLUSIONS: Children treated initially with RIM may have better outcomes than those treated with CT.

A time for reappraisal of "atypical" hemolytic uremic syndrome: should all patients be treated the same?

UNLABELLED: Atypical hemolytic uremic syndrome (HUS) refers to the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury in the absence of Shiga toxin-producing Escherichia coli exposure or Streptococcus pneumoniae infection. Currently, approximately 50 % of the atypical cases have demonstrable mutations in complement regulatory proteins. Historically, the diagnosis of atypical HUS portends a poor prognosis with a high rate of disease recurrence, progression to end-stage renal disease, and death. However, it is now evident that atypical HUS actually encompasses a heterogeneous group of disorders, and there are reports suggesting that some cases of atypical HUS have a favorable prognosis, similar to that of diarrhea-associated disease. We present three patients with the atypical HUS phenotype who had complete renal recovery and no disease recurrence. We believe it is important to distinguish those cases of atypical HUS associated with disorders of complement regulatory proteins from other idiopathic causes of nondiarrheal HUS given the implications for prognosis and treatment. CONCLUSION: Given the heterogeneous nature and variable prognosis of atypical HUS, treatment should be carefully considered prior to the use of long-term plasma therapy and/or eculizumab.

Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband.

OBJECTIVE: An infant was investigated because of megaloblastic anaemia, atypical hemolytic uraemic syndrome, severe combined immune deficiency, elevated blood levels of homocysteine and methylmalonic acid, and a selective decreased synthesis of methylcobalamin in cultured fibroblasts. METHODS: Exome sequencing was performed on patient genomic DNA. RESULTS: Two mutations were identified in the MTHFD1 gene, which encodes a protein that catalyses three reactions involved in cellular folate metabolism. This protein is essential for the generation of formyltetrahydrofolate and methylenetetrahydrofolate and important for nucleotide and homocysteine metabolism. One mutation (c.727+1G>A) affects the splice acceptor site of intron 8. The second mutation, c.517C>T (p.R173C), changes a critical arginine residue in the NADP-binding site of the protein. Mutations affecting this arginine have previously been shown to affect enzyme activity. Both parents carry a single mutation and an unaffected sibling carries neither mutation. The combination of two mutations in the MTHFRD1 gene, predicted to have severe consequences, in the patient and their absence in the unaffected sibling, supports causality. CONCLUSION: This patient represents the first case of an inborn error of folate metabolism affecting the trifunctional MTHFD1 protein. This report reinforces the power of exome capture and sequencing for the discovery of novel genes, even when only a single proband is available for study.

Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation. In approximately 50% of patients, mutations have been described in the genes encoding the complement regulators factor H, MCP, and factor I or the activator factor B. We report here mutations in the central component of the complement cascade, C3, in association with aHUS. We describe 9 novel C3 mutations in 14 aHUS patients with a persistently low serum C3 level. We have demonstrated that 5 of these mutations are gain-of-function and 2 are inactivating. This establishes C3 as a susceptibility factor for aHUS.

Vascular involvement in tuberous sclerosis.

Vascular involvement in tuberous sclerosis (TS) is rare. Central and peripheral aneurysms and large and medium size arterial stenotic-occlusive disease have been reported in patients with TS. We present here three pediatric patients with TS and severe vascular abnormalities, followed by a review of the literature. The three cases include a 14-month-old girl with polycystic kidneys and cerebral tubers who had a large asymptomatic abdominal aortic aneurysm, a 2-year-old boy with multiple features of TS who had hypertension and was found to have mid-aortic syndrome with bilateral renal artery stenosis, and an 18-year-old girl with abdominal pain and TS features who had greater than 70% celiac artery stenosis. In all cases, noninvasive vascular imaging modalities were utilized for either initial diagnosis, surveillance, or both. These cases highlight the collaborative roles of the pediatric nephrologist and cardiovascular imager in the diagnosis and management of the vascular complications in TS patients. Appropriate care can only be made through a high index of suspicion.