Faculty Bibliography

OBJECTIVE: We review the imaging of renal angiomyolipomas, including differentiation of tuberous sclerosis complex (TSC)-associated and sporadic renal angiomyolipomas and other solid renal tumors. We also focus on radiologic interventions and molecular targeting of the TSC genetic pathway. CONCLUSION: Imaging plays a central role in the diagnosis and management of renal angiomyolipomas. It provides essential information to make the best therapeutic decisions about the interventional and pharmacologic options to help prevent bleeding and preserve functional parenchyma.

BACKGROUND: Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. METHODS: We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. RESULTS: 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1-2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline). CONCLUSIONS: Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC. TRIAL REGISTRATION: Clinicaltrials.gov NCT00126672

BACKGROUND: Social hornets attack victims in swarms in Asia, Africa and the Middle East. The venom consists of multiple proteins with myotoxin, haemotoxin, vasodilatory and anticoagulant effects. METHODS: We reviewed the records of 65 patients at Cho Ray Hospital (Ho Chi Minh City, Vietnam) attacked by swarms of the lesser banded hornet, Vespa affinis. Patients were divided into four groups. Groups A and B presented within 3 days of attack and C and D after 3 days with 50 stings, respectively. RESULTS: Varying degrees of acute kidney injury (AKI) were seen in 38 (58.5%) patients in all groups. Twenty nine required renal replacement therapy. AKI was likely to be myoglobin and toxin induced with a clinical course consistent with acute tubular injury. The prognosis for renal recovery is excellent in those who survive. Seven patients (one from Group A and six from Group B) developed non-anaphylactic shock which led to four deaths. The predominant finding in Groups C and D who sought delayed tertiary care is renal failure. CONCLUSIONS: This cases which illustrate the varied effects of hornet venom and the need to be vigilant for shock within the first 2 days and persistent AKI beyond 3 days of attack.

Purpose: Renal angiomyolipoma (AML) is a benign neoplasm with a propensity to bleed proportional to tumor size. Transarterial embolization prevents hemorrhage by decreasing the angiogenic component of AML. We sought to determine whether baseline vascularity and lipid content of AML measured by MRI techniques can predict embolization response, as measured by changes in volume and vascularity on MRI. Materials and Methods: A retrospective review using an electronic database, over a consecutive 3 year period, identified 38 AMLs that underwent embolization in 22 patients. 15 AMLs had both preembolization and postembolization MRIs. 11 AMLs were in females, 4 in males. Median age was 29 years, range 21-73 years. 13 AMLs occurred in the setting of tuberous sclerosis (TS), and 2 occurred sporadically. Mean interval between baseline MRI and embolization was 86 days (range 7, 324), and mean interval between embolization and follow-up MRI was 331 days (range 35, 876). Baseline vascularity was measured by percent enhancement, with higher enhancement signifying higher vascularity. Baseline lipid content was measured by AML to psoas signal ratio on T1 fat saturation images, with a higher ratio signifying lower lipid content. Response characteristics were percent change in volume and percent change in enhancement. Results: No correlation was seen between change in volume and change in enhancement (R=0.104). Embolization resulted in a mean change in volume of -28% (range -82,+10), and a mean change in enhancement of -41% (range -97,+17). Poor correlations were seen between baseline enhancement and change in volume (R=-0.033), and between baseline enhancement and change in enhancement (R=-0.345). Moderately good correlations were seen between baseline lipid content and change in volume (R=0.625), and between baseline lipid content and change in enhancement (R=0.463). Conclusion: Embolization is effective in decreasing AML size and vascularity, which can be regarded as independent MRI markers of response. Lower baseline lipid content on MRI may predict greater response to embolization. No significant correlation was detected between baseline vascularity and response

Despite initial evidence suggesting a relatively benign safety profile, several subsequent case reports have detailed nephrotoxicity in patients using tenofovir disoproxil fumarate for the treatment of HIV. We report a case of rapid renal failure that developed into an HIV-naive patient initiated on an antiretroviral regimen that included tenofovir

Fish gallbladders are consumed in rural areas of Asia as a traditional medicine to improve symptoms of arthritis, decreased visual acuity, and impotence. Consumption of large amounts of this traditional medicine can result in systemic toxicities; in particular, acute renal failure. We reviewed records of all admissions to Cho Ray Hospital (Ho Chi Minh City, Vietnam) between January 1995 and December 2000 after this ingestion. Clinical courses and outcomes were similar in 16 of 17 patients. Within hours, patients experienced profuse vomiting (n = 16) and diarrhea (n = 15). All developed acute renal failure, with a mean serum creatinine concentration of 14.7 +/- 3.9 mg/dL (1,299.5 +/- 344.8 micromol/L). Four patients administered intravenous fluid (IVF) developed extracellular fluid volume overload, as did 1 patient not administered IVF. Time to peak creatinine concentration was 8.6 +/- 3.0 days, which was accompanied by decreased urine volume (174.7 +/- 161.6 mL/24 h). Blood pressure remained normal, with a mean arterial pressure of 91 +/- 12 mm Hg. Twelve patients required renal replacement therapy. A mean of 1.9 +/- 1.1 hemodialysis sessions was performed per patient. Sixteen patients recovered renal function; 1 patient died of fulminant hepatic failure. Kidney biopsies showed features of acute tubular injury. Acute renal failure after fish gallbladder ingestion is characterized by a failure to respond to IVF, an 8.6-day interval to peak creatinine level, frequent need for dialysis therapy, and findings on renal biopsy consistent with acute tubular necrosis. Acute renal failure after fish gallbladder ingestion has an excellent prognosis. However, death from fulminant hepatic failure can occur

The human serum protein transthyretin (TTR) is highly fibrillogenic in vitro and is the fibril precursor in both autosomal dominant (familial amyloidotic polyneuropathy [FAP] and familial amyloidotic cardiomyopathy [FAC]) and sporadic (senile systemic amyloidosis [SSA]) forms of human cardiac amyloidosis. We have produced mouse strains transgenic for either wild-type or mutant (TTRLeu55Pro) human TTR genes. Eighty-four percent of C57BI/6xDBA/2 mice older than 18 months, transgenic for the wild-type human TTR gene, develop TTR deposits that occur primarily in heart and kidney. In most of the animals, the deposits are nonfibrillar and non-Congophilic, but 20% of animals older than 18 months that bear the transgene have human TTR cardiac amyloid deposits identical to the lesions seen in SSA. Amino terminal amino acid sequence analysis and mass spectrometry of the major component extracted from amyloid and nonamyloid deposits revealed that both were intact human TTR monomers with no evidence of proteolysis or codeposition of murine TTR. This is the first instance in which the proteins from amyloid and nonfibrillar deposits in the same or syngeneic animals have been shown to be identical by sequence analysis. It is also the first time in any form of amyloidosis that nonfibrillar deposits have been shown to systematically occur temporally before the appearance of fibrils derived from the same precursor in the same tissues. These findings suggest, but do not prove, that the nonamyloid deposits represent a precursor of the fibril. The differences in the ultrastructure and binding properties of the deposits, despite the identical sizes and amino terminal amino acid sequences of the TTR and the dissociation of deposition and fibril formation, provide evidence that in vivo factors, perhaps associated with aging, impact on both systemic precursor deposition and amyloid fibril formation