Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know / Complexo da Esclerose Tuberosa e rins: o que os nefrologistas devem saber

Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the development of hamartomas in the central nervous system, heart, skin, lungs, and kidneys and other manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability. The disease is associated with pathogenic variants in the TSC1 or TSC2 genes, resulting in the hyperactivation of the mTOR pathway, a key regulator of cell growth and metabolism. Consequently, the hyperactivation of the mTOR pathway leads to abnormal tissue proliferation and the development of solid tumors. Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas, which may progress and cause pain, bleeding, and loss of kidney function. Over the past years, there has been a notable shift in the therapeutic approach to TSC, particularly in addressing renal manifestations. mTOR inhibitors have emerged as the primary therapeutic option, whereas surgical interventions like nephrectomy and embolization being reserved primarily for complications unresponsive to clinical treatment, such as severe renal hemorrhage. This review focuses on the main clinical characteristics of TSC, the mechanisms underlying kidney involvement, the recent advances in therapy for kidney lesions, and the future perspectives.

Resumo O complexo da esclerose tuberosa (CET) é uma doença autossômica dominante caracterizada pelo desenvolvimento de hamartomas no sistema nervoso central, coração, pele, pulmões e rins e outras manifestações, incluindo convulsões, tubérculos corticais, linhas de migração radial, autismo e deficiência cognitiva. A doença está associada a variantes patogênicas nos genes TSC1 ou TSC2, resultando na hiperativação da via mTOR, um importante regulador do crescimento e metabolismo celular. Consequentemente, a hiperativação da via mTOR leva à proliferação anormal do tecido e ao desenvolvimento de tumores sólidos. O envolvimento renal no CET é caracterizado pelo desenvolvimento de lesões císticas, carcinoma de células renais e angiomiolipomas renais, que podem progredir e causar dor, sangramento e perda da função renal. Nos últimos anos, houve uma mudança notável na abordagem terapêutica do CET, especialmente no tratamento das manifestações renais. Os inibidores de mTOR surgiram como a principal opção terapêutica, enquanto intervenções cirúrgicas como nefrectomia e embolização são reservadas principalmente para complicações que não respondem ao tratamento clínico, como hemorragia renal grave. Esta revisão se concentra nas principais características clínicas do CET, nos mecanismos subjacentes ao envolvimento renal, nos recentes avanços na terapia para lesões renais e nas perspectivas futuras.

Concomitant Wilms tumor and autosomal dominant polycystic kidney disease.

BACKGROUND: Concomitant Wilms tumor (WT) and autosomal dominant polycystic kidney disease (ADPKD) is exceedingly rare, presenting a diagnostic and technical challenge to pediatric surgical oncologists. The simultaneous workup and management of these disease processes are incompletely described. PROCEDURE: We performed a retrospective analysis of patients treated at our institution with concomitant diagnoses of WT and ADPKD. We also review the literature on the underlying biology and management principles of these conditions. RESULTS: We present three diverse cases of concomitant unilateral WT and ADPKD who underwent nephrectomy. One patient had preoperative imaging consistent with ADPKD with confirmatory testing postoperatively, one was found to have contralateral renal cysts intraoperatively with confirmatory imaging post nephrectomy, and one was diagnosed in childhood post nephrectomy. All patients are alive at last follow-up, and the patient with longest follow-up has progressed to end-stage kidney failure requiring transplantation and dialysis in adulthood. All patients underwent germline testing and were found to have no cancer predisposition syndrome or pathogenic or likely pathogenic variants for WT. CONCLUSION: Concomitant inheritance of ADPKD and development of WT are extremely rare, and manifestations of ADPKD may not present until late childhood or adulthood. ADPKD is not a known predisposing condition for WT. When ADPKD diagnosis is made by family history, imaging, and/or genetic testing before WT diagnosis and treatment, the need for extensive preoperative characterization of cystic kidney lesions in children and increased risk of post-nephrectomy kidney failure warrant further discussion of surgical approach and perioperative management strategies.

Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know.

Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the development of hamartomas in the central nervous system, heart, skin, lungs, and kidneys and other manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability. The disease is associated with pathogenic variants in the TSC1 or TSC2 genes, resulting in the hyperactivation of the mTOR pathway, a key regulator of cell growth and metabolism. Consequently, the hyperactivation of the mTOR pathway leads to abnormal tissue proliferation and the development of solid tumors. Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas, which may progress and cause pain, bleeding, and loss of kidney function. Over the past years, there has been a notable shift in the therapeutic approach to TSC, particularly in addressing renal manifestations. mTOR inhibitors have emerged as the primary therapeutic option, whereas surgical interventions like nephrectomy and embolization being reserved primarily for complications unresponsive to clinical treatment, such as severe renal hemorrhage. This review focuses on the main clinical characteristics of TSC, the mechanisms underlying kidney involvement, the recent advances in therapy for kidney lesions, and the future perspectives.

Physiologically Based Pharmacokinetic Modeling of Extracellular Vesicles.

Extracellular vesicles (EVs) are lipid membrane bound-cell-derived structures that are a key player in intercellular communication and facilitate numerous cellular functions such as tumor growth, metastasis, immunosuppression, and angiogenesis. They can be used as a drug delivery platform because they can protect drugs from degradation and target specific cells or tissues. With the advancement in the technologies and methods in EV research, EV-therapeutics are one of the fast-growing domains in the human health sector. Therapeutic translation of EVs in clinics requires assessing the quality, safety, and efficacy of the EVs, in which pharmacokinetics is very crucial. We report here the application of physiologically based pharmacokinetic (PBPK) modeling as a principal tool for the prediction of absorption, distribution, metabolism, and excretion of EVs. To create a PBPK model of EVs, researchers would need to gather data on the size, shape, and composition of the EVs, as well as the physiological processes that affect their behavior in the body. The PBPK model would then be used to predict the pharmacokinetics of drugs delivered via EVs, such as the rate at which the drug is absorbed and distributed throughout the body, the rate at which it is metabolized and eliminated, and the maximum concentration of the drug in the body. This information can be used to optimize the design of EV-based drug delivery systems, including the size and composition of the EVs, the route of administration, and the dose of the drug. There has not been any dedicated review article that describes the PBPK modeling of EV. This review provides an overview of the absorption, distribution, metabolism, and excretion (ADME) phenomena of EVs. In addition, we will briefly describe the different computer-based modeling approaches that may help in the future of EV-based therapeutic research.

Single Gene Mutations in Pkd1 or Tsc2 Alter Extracellular Vesicle Production and Trafficking.

Patients with autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis complex (TSC) are born with normal or near-normal kidneys that later develop cysts and prematurely lose function. Both renal cystic diseases appear to be mediated, at least in part, by disease-promoting extracellular vesicles (EVs) that induce genetically intact cells to participate in the renal disease process. We used centrifugation and size exclusion chromatography to isolate the EVs for study. We characterized the EVs using tunable resistive pulse sensing, dynamic light scattering, transmission electron microscopy, and Western blot analysis. We performed EV trafficking studies using a dye approach in both tissue culture and in vivo studies. We have previously reported that loss of the Tsc2 gene significantly increased EV production and here demonstrate that the loss of the Pkd1 gene also significantly increases EV production. Using a cell culture system, we also show that loss of either the Tsc2 or Pkd1 gene results in EVs that exhibit an enhanced uptake by renal epithelial cells and a prolonged half-life. Loss of the primary cilia significantly reduces EV production in renal collecting duct cells. Cells that have a disrupted Pkd1 gene produce EVs that have altered kinetics and a prolonged half-life, possibly impacting the duration of the EV cargo effect on the recipient cell. These results demonstrate the interplay between primary cilia and EVs and support a role for EVs in polycystic kidney disease pathogenesis.

Tsc2 mutation induces renal tubular cell nonautonomous disease.

TSC renal cystic disease is poorly understood and has no approved treatment. In a new principal cell-targeted murine model of Tsc cystic disease, the renal cystic epithelium is mostly composed of type A intercalated cells with an intact Tsc2 gene confirmed by sequencing, although these cells exhibit a Tsc-mutant disease phenotype. We used a newly derived targeted murine model in lineage tracing and extracellular vesicle (EV) characterization experiments and a cell culture model in EV characterization and cellular induction experiments to understand TSC cystogenesis. Using lineage tracing experiments, we found principal cells undergo clonal expansion but contribute very few cells to the cyst. We determined that cystic kidneys contain more interstitial EVs than noncystic kidneys, excrete fewer EVs in urine, and contain EVs in cyst fluid. Moreover, the loss of Tsc2 gene in EV-producing cells greatly changes the effect of EVs on renal tubular epithelium, such that the epithelium develops increased secretory and proliferative pathway activity. We demonstate that the mTORC1 pathway activity is independent form the EV production, and that the EV effects for a single cell line can vary significantly. TSC cystogenesis involves significant contribution from genetically intact cells conscripted to the mutant phenotype by mutant cell derived EVs.

Indocyanine green-guided nephron-sparing surgery for pediatric renal tumors.

BACKGROUND: Indocyanine green (ICG), a water-soluble tricarbocyanine fluorophore, is being increasingly used for tumor localization based on its passive intra-tumoral accumulation due to enhanced permeability and retention in tumor tissue. Therefore, we hypothesized that ICG can provide contrast to facilitate accurate, real-time recognition of renal tumors at the time of nephron-sparing surgery in children. METHODS: This retrospective study examined the feasibility of ICG in guiding nephron-sparing surgery for pediatric renal tumors. RESULTS: We reviewed the medical records of 8 pediatric patients with renal tumors in 12 kidneys. Intraoperative localization of tumor with near infrared guidance was successful in all 12 kidneys. However, we consistently found an inverse pattern of near infrared signal in which the normal kidney demonstrated increased fluorescent signal relative to the kidney tumor. CONCLUSIONS: Fluorescence-guided renal tumor delineation is unique because it has an inverse pattern of near infrared signal in which the normal kidney demonstrates increased signal relative to the adjacent tumor. Nevertheless fluorescence-guided distinguishing of renal tumor from surrounding normal kidney is feasible.

Progress in Tuberous Sclerosis Complex Renal Disease.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects both fetal development and postnatal tissue growth, resulting in altered brain structures and a tumor predisposition syndrome. Although every organ system is affected by the disease, kidney involvement is a leading cause of death in adults with TSC. Over the past decade, significant progress has been made in understanding the renal disease. This review focuses on the cystic and solid renal lesions in TSC, including their pathobiology and treatment.

Renal cystic disease in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is associated with TSC1 or TSC2 gene mutations resulting in hyperactivation of the mTORC1 pathway. This mTORC1 activation is associated with abnormal tissue development and proliferation such that in the kidney there are both solid tumors and cystic lesions. This review summarizes recent advances in tuberous sclerosis complex nephrology and focuses on the genetics and cell biology of tuberous sclerosis complex renal disease, highlighting a role of extracellular vesicles and the innate immune system in disease pathogenesis.