Tuberous Sclerosis Complex Kidney Research Articles

Nutritional status as a predictive factor for paediatric tuberous sclerosis complex-associated kidney angiomyolipomas: a retrospective analysis

The purpose of this study is to determine the predictive factors of tuberous sclerosis complex (TSC)-associated kidney disease and its progression in children. Retrospective review of children with TSC in a tertiary children’s hospital was performed. Relevant data were extracted, and Cox proportional hazards regression was used to establish predictors of kidney lesions. Logistic regression was conducted to identify factors predicting chronic kidney disease (CKD) and high-risk angiomyolipomas (above 3 cm). Kidney imaging data were available in 145 children with TSC; of these, 79% (114/145) had abnormal findings. The only significant predictive factor for cyst development was being female (HR = 0.503, 95% CI 0.264–0.956). Being female (HR = 0.505, 95% CI 0.272–0.937) and underweight (HR = 0.092, 95% CI 0.011–0.800) both lowers the risk of having angiomyolipomas, but TSC2 mutations (HR = 2.568, 95% CI 1.101–5.989) and being obese (HR = 2.555, 95%CI 1.243–5.255) increases risks. Ten (12%) of 81 children with kidney function tested demonstrate CKD stages II–V, and only angiomyolipomas above 3 cm predict CKD. Additionally, 13/145 (9%) children had high-risk angiomyolipomas, whereby current age (adjusted odds ratio (aOR) 1.015, 95% CI 1.004–1.026) and being overweight/obese (aOR 7.129, 95% CI 1.940–26.202) were significantly associated with angiomyolipomas above 3 cm.Conclusions: While gender and genotype are known predictors, this study includes the novel finding of nutritional status as a predictor of TSC-associated kidney disease. This study sheds light on a possible complex interplay of hormonal influences, obesity, and kidney angiomyolipomas growth, and further investigations focusing on the impact of nutritional status on TSC-associated kidney disease are warranted.What is Known:• Gender and genotype are well-studied predictive factors in TSC kidney disease.What is New:• Nutritional status may influence the development and the progression of kidney lesions in children with TSC and should not be overlooked.• Management guidelines of TSC-associated kidney disease can address nutritional aspects.

Not all kidney cysts are created equal: a distinct renal cystogenic mechanism in tuberous sclerosis complex (TSC).

Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disease caused by mutations in either TSC1 or TSC2 genes. Approximately, two million individuals suffer from this disorder worldwide. TSC1 and TSC2 code for the proteins harmartin and tuberin, respectively, which form a complex that regulates the mechanistic target of rapamycin complex 1 (mTORC1) and prevents uncontrollable cell growth. In the kidney, TSC presents with the enlargement of benign tumors (angiomyolipomas) and cysts whose presence eventually causes kidney failure. The factors promoting cyst formation and tumor growth in TSC are poorly understood. Recent studies on kidney cysts in various mouse models of TSC, including mice with principal cell- or pericyte-specific inactivation of TSC1 or TSC2, have identified a unique cystogenic mechanism. These studies demonstrate the development of numerous cortical cysts that are predominantly comprised of hyperproliferating A-intercalated (A-IC) cells that express both TSC1 and TSC2. An analogous cellular phenotype in cystic epithelium is observed in both humans with TSC and in TSC2+/- mice, confirming a similar kidney cystogenesis mechanism in TSC. This cellular phenotype profoundly contrasts with kidney cysts found in Autosomal Dominant Polycystic Kidney Disease (ADPKD), which do not show any notable evidence of A-IC cells participating in the cyst lining or expansion. RNA sequencing (RNA-Seq) and confirmatory expression studies demonstrate robust expression of Forkhead Box I1 (FOXI1) transcription factor and its downstream targets, including apical H+-ATPase and cytoplasmic carbonic anhydrase 2 (CAII), in the cyst epithelia of Tsc1 (or Tsc2) knockout (KO) mice, but not in Polycystic Kidney Disease (Pkd1) mutant mice. Deletion of FOXI1, which is vital to H+-ATPase expression and intercalated (IC) cell viability, completely inhibited mTORC1 activation and abrogated the cyst burden in the kidneys of Tsc1 KO mice. These results unequivocally demonstrate the critical role that FOXI1 and A-IC cells, along with H+-ATPase, play in TSC kidney cystogenesis. This review article will discuss the latest research into the causes of kidney cystogenesis in TSC with a focus on possible therapeutic options for this devastating disease.

Renal organoid modeling of tuberous sclerosis complex reveals lesion features arise from diverse developmental processes.

Tuberous sclerosis complex (TSC) is a multisystem tumor-forming disorder caused by loss of TSC1 or TSC2. Renal manifestations predominately include cysts and angiomyolipomas. Despite a well-described monogenic etiology, the cellular pathogenesis remains elusive. We report a genetically engineered human renal organoid model that recapitulates pleiotropic features of TSC kidney disease invitro and upon orthotopic xenotransplantation. Time course single-cell RNA sequencing demonstrates that loss of TSC1 or TSC2 affects multiple developmental processes in the renal epithelial, stromal, and glial compartments. First, TSC1 or TSC2 ablation induces transitional upregulation of stromal-associated genes. Second, epithelial cells in the TSC1-/- and TSC2-/- organoids exhibit a rapamycin-insensitive epithelial-to-mesenchymal transition. Third, a melanocytic population forms exclusively in TSC1-/- and TSC2-/- organoids, branching from MITF+ Schwann cell precursors. Together, these results illustrate the pleiotropic developmental consequences of biallelic inactivation of TSC1 or TSC2 and offer insight into TSC kidney lesion pathogenesis.

Causes of mortality in individuals with tuberous sclerosis complex.

The causes of death in patients with tuberous sclerosis complex (TSC) have rarely been studied, with only one published account, which was reported from the Mayo Clinic in 1991. We aimed to investigate mortality in a large cohort of patients with TSC from one of two national referral clinics in the UK. We identified 284 patients who attended Bath TSC clinic between 1981 and 2015, and ascertained causes of death by reviewing medical records, death certificates, and postmortem reports. Sixteen patients died from complications of TSC: eight from TSC kidney diseases; four from sudden unexpected death in epilepsy (SUDEP); two from lymphangioleiomyomatosis; one from a subependymal giant cell astrocytoma; and one from a pancreatic malignancy. The median age of death was 33 years (interquartile range [IQR] 26-46). Mortality was significantly more common in patients with learning disabilities than in those without (13/135 [9%] vs 3/131 [2%]; two-tailed Fisher exact test p=0.020). Renal disease is a major cause of mortality in TSC. Lifelong surveillance and early intervention is warranted. SUDEP is also an important cause of mortality. Patients with learning disabilities are at significantly greater risk of early mortality and this implies the need for greater vigilance for TSC-related complications in this group. Female patients are vulnerable to pulmonary and renal disease. Pancreatic lesions are a rare but potentially treatable cause of mortality.

Similar Trends in Serum VEGF-D Levels and Kidney Angiomyolipoma Responses with Longer Duration Sirolimus Treatment in Adults with Tuberous Sclerosis

ContextWe have previously shown that serum VEGF-D is elevated at baseline, correlates with kidney angiomyolipoma size at baseline and 12 months, and decreases with sirolimus treatment in adults with tuberous sclerosis complex (TSC). To further investigate the utility of serum VEGF-D for longer term monitoring of TSC kidney disease, we present VEGF-D level results with 24 month follow-up.ObjectiveTo compare 24 month VEGF-D levels in two subgroups of sirolimus treated patients (OFF SIROLIMUS AFTER 12 MONTHS or ON SIROLIMUS AFTER 12 MONTHS).Design and Intervention(s)Serum VEGF-D was measured in samples collected from subjects enrolled in a phase 2 multicenter trial evaluating sirolimus for the treatment of kidney angiomyolipomas associated with TSC or TSC/LAM. All participants were treated with sirolimus from 0–12 months. During months 12–24, sirolimus was discontinued in one subgroup. The other subgroup was treated with additional sirolimus.SettingAdult TSC participants were recruited from six clinical sites in the United States (comprehensive TSC clinics, 5; urology clinic, 1).PatientsThere were 28 TSC patients who completed all 24 months of the study and serum samples were available at 24 months from 18/28 patients.Main Outcome Measure(s)We compared the percent change in VEGF-D levels (baseline to 24 months) in patients from the two treatment subgroups.ResultsAt 24 months, VEGF-D levels decreased by 67% compared with baseline (to 787±426 pg/ml) in the ON SIROLIMUS AFTER 12 MONTHS group versus a 13% decrease (to 2971±4014 pg/ml) in the OFF SIROLIMUS AFTER 12 MONTHS group (p = 0.013, Mann-Whitney test). A similar trend was observed in kidney angiomyolipoma size but not in pulmonary function tests. Conclusions Serum VEGF-D may be useful for monitoring response to treatment with sirolimus and kidney angiomyolipoma size in patients with TSC, but confirmation is needed.Trial RegistrationClinical trials.gov NCT00126672.