Cystic kidney disease in tuberous sclerosis complex: current knowledge and unresolved questions.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with an estimated incidence of one in 5000 to 10,000 live births worldwide. Two million people of all races and genders are estimated to have TSC secondary to mutations in one of two tumor suppressor genes, TSC1 or TSC2. The respective TSC1 and 2 gene products - hamartin and tuberin - form cytoplasmic heterodimers that inhibit mTOR-mediated cell growth and division. When mTOR inhibition is lost, people with TSC develop characteristic and usually benign tumors in various organ systems. Kidney tumors and cysts are common, particularly in the setting of TSC2 gene mutations. In most TSC patients, the number of kidney cysts is limited, their morphology is simple, their size is small, and their clinical significance is negligible. In some, cyst morphology progresses from simple to complex with the risk of malignant transformation. In others, aggressive accumulation and growth of kidney cysts can cause hypertension, impaired kidney function, and progression to kidney failure. This educational review summarizes current knowledge and remaining open questions regarding cystic kidney disease in TSC, emphasizing detection, classification, surveillance, and treatment options.

Sporadic versus Tuberous Sclerosis Complex-Associated Angiomyolipomas: Predictors for Long-Term Outcomes following Transcatheter Embolization.

PURPOSE: To evaluate risk factors for long-term outcomes following embolization of sporadic versus tuberous sclerosis complex (TSC)-associated angiomyolipomas (AMLs). MATERIALS AND METHODS: A retrospective review of consecutive transcatheter embolizations of renal AMLs between 2002 and 2014 was performed. Tumor volumetrics including density analysis were obtained. Treatment outcomes were assessed at 1 year after embolization using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 and volumetric RECIST criteria. A total of 56 patients, 70% (39/56) of whom had TSC, underwent embolization of 72 renal AMLs. Embolization was most commonly performed (70/72, 97%) using microspheres (300-500 µm or 500-700 µm Embosphere). RESULTS: Between the sporadic and TSC-associated populations, there was no difference in follow-up time (648 d vs 583 d, P = .78), initial tumor diameter (6.68 cm vs 5.71 cm, P = .09), or percent tumoral fat content (39.5% vs 8.6%, P = .35). Progressive disease was noted in 9 TSC-associated AMLs by volume and 3 TSC-associated AMLs by diameter but in no sporadic AMLs. Growth suppression curves were remarkable for rebound growth in TSC patients, particularly in TSC patients younger than 18 years. Patient age (P = .007) and tumor volume (P = .03) were found to correlate with tumor regrowth within the TSC population. No difference was found in median change in total volume after embolization based on fat content (-57.9% vs -54.2%, P = .68). CONCLUSIONS: TSC, patient age, and tumoral volume before embolization are risk factors for AML growth following embolization. Intratumoral fat content was not found to predict response to embolization.

Angiographic and volumetric effects of mammalian target of rapamycin inhibitors on angiomyolipomas in tuberous sclerosis.

AIM: To investigate the angiographic and volumetric effects of mammalian target of rapamycin (mTOR) inhibitors on angiomyolipomas (AMLs) in a case series of patients with tuberous sclerosis complex. METHODS: All patients who underwent catheter angiography prior to and following mTOR inhibitor therapy (n = 3) were evaluated. All cross-sectional imaging studies were analyzed with three-dimensional volumetrics, and tumor volume curves for all three tissue compartments (soft tissue, vascular, and fat) were generated. Segmentation analysis tools were used to automatically create a region of interest (ROI) circumscribing the AML. On magnetic resonance images, the "fat only" map calculated from the in- and opposed-phase gradient recalled echo sequences was used to quantify fat volume within tumors. Tumor vascularity was measured by applying a thresholding tool within the ROI on post-contrast subtraction images. On computed tomography images, volume histogram analysis of Hounsfield unit was performed to quantify tumor tissue composition. The angiography procedures were also reviewed, and tumor vascularity based on pre-embolization angiography was characterized in a semi-quantitative manner. RESULTS: Patient 1 presented at the age of 15 with a 6.8 cm right lower pole AML and a 4.0 cm right upper pole AML. Embolization was performed of both tumors, and after a few years of size control, the tumors began to grow, and the patient was initiated on mTOR inhibitor therapy. There was an immediate reduction in the size of both lesions. The patient then underwent repeat embolization and discontinuation of mTOR inhibition, after which point there was a substantial regrowth in both tumors across all tissue compartments. Patient 2 presented at the age of 18 with a right renal AML. Following a brief period of tumor reduction after embolization, she was initiated on mTOR inhibitor therapy, with successful reduction in tumor size across all tissue compartments. As with patient 1, however, there was immediate rebound growth following discontinuation of inhibitor therapy, without sustained control despite repeat embolization. patient 3 presented at the age of 5 with a left renal AML and underwent two embolization procedures without lasting effect prior to starting mTOR inhibition. As with patients 1 and 2, following discontinuation of therapy, there was immediate rebound growth of the tumor. Repeat embolization, however, was notable for a substantial reduction in intratumoral aneurysms and vascularity. CONCLUSION: AML volume reduction as well as post-treatment rebound growth due to mTOR inhibitors involves all three tissue components of the tumor.

Safety considerations of mammalian target of rapamycin inhibitors in tuberous sclerosis complex and renal transplantation.

Rapamycin-related mTOR inhibitors (rapalogs) possess immunosuppressive and antiproliferative properties. Their mechanism of action makes them attractive therapies for several disease states but also potentiates adverse effects associated with these drugs. The oral mTOR inhibitor everolimus was recently approved for the treatment of tuberous sclerosis complex (TSC)-associated renal angiomyolipoma. As clinical use of rapalogs for the treatment of TSC increases, nephrologists and urologists who treat both children and adults with renal masses, as well as internists and geneticists with an interest in renal disease, should be aware of their safety profiles. This review presents the clinical experience of rapamycin-related mTOR inhibitors in patients with TSC and summarizes their toxicity profiles in renal transplant and TSC populations. Increased usage of rapalogs in a variety of patient populations demands vigilant monitoring of their safety profiles and rigorous differentiation between disease-specific and drug-specific toxicities.

Renal cell carcinoma in tuberous sclerosis complex.

Renal cell carcinoma (RCC) occurs in 2% to 4% of patients with tuberous sclerosis complex (TSC). Previous reports have noted a variety of histologic appearances in these cancers, but the full spectrum of morphologic and molecular features has not been fully elucidated. We encountered 46 renal epithelial neoplasms from 19 TSC patients and analyzed their clinical, pathologic, and molecular features, enabling separation of these 46 tumors into 3 groups. The largest subset of tumors (n=24) had a distinct morphologic, immunologic, and molecular profile, including prominent papillary architecture and uniformly deficient succinate dehydrogenase subunit B (SDHB) expression prompting the novel term "TSC-associated papillary RCC (PRCC)." The second group (n=15) were morphologically similar to a hybrid oncocytic/chromophobe tumor (HOCT), whereas the last 7 renal epithelial neoplasms of group 3 remained unclassifiable. The TSC-associated PRCCs had prominent papillary architecture lined by clear cells with delicate eosinophilic cytoplasmic thread-like strands that occasionally appeared more prominent and aggregated to form eosinophilic globules. All 24 (100%) of these tumors were International Society of Urological Pathology (ISUP) nucleolar grade 2 or 3 with mostly basally located nuclei. Tumor cells from 17 of 24 TSC-associated PRCCs showed strong, diffuse labeling for carbonic anhydrase IX (100%), CK7 (94%), vimentin (88%), and CD10 (83%) and were uniformly negative for SDHB, TFE3, and AMACR. Gains of chromosomes 7 and 17 were found in 2 tumors, whereas chromosome 3p deletion and TFE3 translocations were not detected. In this study, we reported a sizable cohort of renal tumors seen in TSC and were able to identify them as different morphotypes, which may help to expand the morphologic spectrum of TSC-associated RCC.

Selective regulation of autoreactive B cells by FcgammaRIIB.

FcgammaRIIB is an inhibitory receptor which plays a role in limiting B cell and DC activation. Since FcgammaRIIB is known to dampen the signaling strength of the BCR, we wished to determine the impact of FcgammaRIIB on the regulation of BCRs which differ in their affinity for DNA. For these studies, FcgammaRIIB deficient BALB/c mice were bred with mice expressing the transgene-encoded H chain of the R4A anti-DNA antibody which gives rise to BCRs which express high, low or no affinity for DNA. The deletion of FcgammaRIIB in R4A BALB/c mice led to an alteration in the B cell repertoire, allowing for the expansion and activation of high affinity DNA-reactive B cells. By 6-8 months of age, R4A x FcgammaRIIB-/- BALB/c mice spontaneously developed anti-DNA antibody titers. These mice also displayed an induction of IFN-inducible genes and an elevation in levels of the B cell survival factor, BAFF. These data demonstrate that FcgammaRIIB preferentially limits activation of high affinity autoreactive B cells and can influence the activation of DC through an immune complex-mediated mechanism.

Follicular exclusion of autoreactive B cells requires FcgammaRIIb.

In non-autoimmune mice, the 3H9 transgenic Ig heavy chain can pair with endogenous Iglambda1 light chains to generate B cells with specificity for DNA. These autoreactive cells are actively regulated in vivo, as indicated by the exclusion of lambda1 cells from the splenic B cell follicle and the absence of auto-antibody production. To study the role of Fcgamma receptor IIb (FcgammaRIIb) in peripheral B cell tolerance, FcgammaRIIb(-/-) mice were crossed with C57BL/6 mice bearing a site-directed knock-in of the 3H9 transgene. 3H9FcgammaRIIb(-/-) mice become autoreactive, lose the follicular exclusion of anti-DNA B cells and instead have lambda1 B cells located within splenic germinal centers. They have increased frequencies of splenic auto-antibody-producing cells and elevated titers of IgG anti-DNA auto-antibody. The data implicate an FcgammaRIIb-dependent checkpoint that can exclude autoreactive B cells from splenic follicles. By restricting their participation in germinal center reactions, this putative checkpoint helps attenuate the production of potentially pathogenic auto-antibodies. The data further suggest that this FcgammaRIIb-dependent regulation is B cell autonomous.