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.

Clinical practice recommendations for kidney involvement in tuberous sclerosis complex: a consensus statement by the ERKNet Working Group for Autosomal Dominant Structural Kidney Disorders and the ERA Genes & Kidney Working Group.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the presence of proliferative lesions throughout the body. Management of TSC is challenging because patients have a multifaceted systemic illness with prominent neurological and developmental impact as well as potentially severe kidney, heart and lung phenotypes; however, every organ system can be involved. Adequate care for patients with TSC requires a coordinated effort involving a multidisciplinary team of clinicians and support staff. This clinical practice recommendation was developed by nephrologists, urologists, paediatric radiologists, interventional radiologists, geneticists, pathologists, and patient and family group representatives, with a focus on TSC-associated kidney manifestations. Careful monitoring of kidney function and assessment of kidney structural lesions by imaging enable early interventions that can preserve kidney function through targeted approaches. Here, we summarize the current evidence and present recommendations for the multidisciplinary management of kidney involvement in TSC.

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.

Microscopic Kidney Disease in Tuberous Sclerosis Complex and Treatment With mTOR Inhibition.

Declining kidney function in tuberous sclerosis complex (TSC) is often attributed to large lesions, including angiomyolipomas (AMLs) and cysts, that encroach on the normal parenchyma or that require intervention and loss of parenchyma from surgical debulking or embolization. Consequently, research on inhibitors of the mammalian target of rapamycin (mTOR), a protein complex implicated in TSC pathophysiology for its role in promoting cell growth and proliferation, has largely focused on their ability to reduce AML size. Clinical guidelines distilled from this research limit mTOR inhibition as a first-line treatment to patients with large AMLs. However, chronic kidney disease (CKD) occurs in patients without large AMLs or a history of renal intervention. Alternate mechanisms postulated for CKD in TSC may suggest a role for mTOR inhibition in this population. In this report, we present 2 cases of a microscopic variant of TSC kidney disease causing declining kidney function, as well as anecdotal evidence for the use of mTOR inhibition to improve kidney function in the absence of large AMLs. We highlight the importance of annual kidney function assessment in patients with TSC and suggest a low threshold for kidney biopsy in patients with declining glomerular filtration rate without a clear etiology clinically or radiographically.

Are nephrometry scores accurate for the prediction of outcomes in patients with renal angiomyolipoma treated with robot-assisted partial nephrectomy? A multi-institutional analysis.

BACKGROUND: Prediction of complications and surgical outcomes is of outmost importance even in patients with benign renal masses. The aim of our study is to test the PADUA, SPARE and R.E.N.A.L. scores to predict nephron sparing surgery (NSS) outcomes in patients presenting with renal angiomyolipoma (RAML). METHODS: We retrospectively analyzed the clinical and pathological data of 93 patients with AML treated with robot-assisted partial nephrectomy (RAPN) at three tertiary care referral centers. Renal masses were classified according to the PADUA, SPARE and R.E.N.A.L. nephrometry scores. Surgical success was defined according to the novel Trifecta Score. Logistic regression models (LRM) were fitted to predict the achievement of novel Trifecta and the risk of high-grade Clavien-Dindo (CD) complication. The receiver operating characteristics (ROC) curve analysis was used to estimate the accuracy of LRMs. RESULTS: Of 93 patients, 66 (69.9%) were females; median tumor size was 42 (36-48) mm. Novel Trifecta was achieved in 79 patients (84.9%) and postoperative complications classified as CD>2 occurred in 7 (7.5%) patients. At univariate and multivariate LRMs all three nephrometry scores were significantly associated with novel Trifecta achievement. Similar findings were observed for the prediction of CD>2 complications. The AUCs to predict optimal surgical outcomes and CD>2 complications were 0.791 and 0.912 for PADUA, 0.767 and 0.836 for SPARE and 0.756 and 0.842 for RENAL Score, respectively. CONCLUSIONS: RAPN appears to be a feasible and safe surgical technique for the treatment of RAML. PADUA, SPARE and RENAL scores can be safely adopted to predict surgical outcomes, with the first one showing a higher accuracy.

Leiomyomatosis-like lymphangioleiomyomatosis: A case report of the colonic manifestation of tuberous sclerosis.

INTRODUCTION: Tuberous sclerosis complex is an inherited multisystemic disorder with manifestations in various organ systems as a result of a mutation of 1 of 2 tumor suppressor genes, tuberous sclerosis complex-1 or tuberous sclerosis complex-2. Perivascular epithelioid cell tumors have been shown to be associated with these gene mutations and include a variety of tumors such as angiomyolipomas and lymphangioleiomyomatosis. PATIENT CONCERNS: In this report, we present a case of a 28-year-old woman presenting with symptoms of severe abdominal pain and nausea with a medical history of cardiac rhabdomyoma, adenoma sebaceum, Ash leaf spots, bilateral renal angiomyolipomas, and retinal hamartoma, which are manifestations of tuberous sclerosis complex. The patient was operated twice for colonic perforations in the rectosigmoid and ileocecal regions where the pathologic examination revealed multiple tumoral lesions in both specimens. DIAGNOSIS: The tumor consisted of a myomatous component where the nodules were composed of spindle cells with fascicular array, and a lymphangiomatous component where epithelioid cells could be observed. Immunohistochemically, smooth muscle markers (desmin and SMA) were positive and the epithelioid component showed HMB-45 positivity. A diagnosis of leiomyomatosis-like lymphangioleiomyomatosis was established due to its morphological and immunohistochemical features, the presence of the tumor in multiple foci, and widespread lymphovascular invasion. INTERVENTIONS: The patient had a perforation in her bowel twice during the hospital stay and underwent Hartmann operation and ileocecal resection in 2 different surgical operations. OUTCOMES: After the second operation the patient developed fever and was diagnosed with SARS-CoV-2 infection. No other complication was observed during her stay and the patient's follow-up was unremarkable. CONCLUSION: Perivascular epithelioid cell tumors are associated with tuberous sclerosis and can rarely appear in the colon. Therefore, lymphangioleiomyomatosis should be in the differential diagnosis in a tuberous sclerosis patient presenting with a colonic tumor.

Giant bilateral angiomyolipoma of the kidney.

Angiomyolipoma is a benign solid renal neoplasm. A giant angiomyolipoma is more than 10cm by size, but it can grow to huge proportions. Our case appears to be the third largest angiomyolipoma and the largest among bilateral giant renal angiomyolipoma in the indexed literature. A 26-year-old man presented with large right abdominal swelling for the past three years, which was occupying his right flank and iliac region, extending beyond the midline. Computed tomography of the abdomen revealed a large well-defined mass in the right side of the abdomen, crossing the midline and measuring 35 × 20 × 12cm. The left kidney showed a similar fatty lesion of 14 × 6cm. The findings were consistent with angiomyolipoma. Further evaluation for tuberous sclerosis by magnetic resonance imaging the brain demonstrated multiple subependymal nodules. Giant renal angiomyolipoma is an uncommon tumour with bilateral giant angiomyolipoma being a rare entity. Preoperative embolisation helps in reducing size of the tumour. In case of giant and bilateral angiomyolipoma, evaluation for tuberous sclerosis should always be done.

Kidney Imaging Surveillance in Commercially Insured Patients With Tuberous Sclerosis Complex.

BACKGROUND: Kidney disease has historically been the primary source of early mortality in adults with tuberous sclerosis complex (TSC). Kidney imaging surveillance promotes early detection of lesions requiring intervention. We describe kidney imaging frequency in relationship to patient-level characteristics for commercially insured patients with TSC in the United States. METHODS: This retrospective observational study used 2003 to 2016 enrollment and claims data from a de-identified fully insured commercial health insurer. Patients with TSC less than 65 years were included. The patient-level kidney imaging rate was calculated as the number of kidney imaging procedures divided by length of continuous enrollment. A multiple linear regression model was used to determine the relationship between imaging rate and progression of TSC-associated kidney disease, number of specialists seen, and nephrologist care. RESULTS: At least half of the 70 patients with TSC included in the study were aged 16 years or younger. Over a follow-up period of up to 14 years, the median kidney imaging rate was 0.13 procedures per year with 43% (N = 30) of patients lacking evidence of kidney imaging during the observation period. Imaging frequency increased with progression of TSC-associated kidney disease, more specialists, and nephrologist care (P < 0.05 for all three in regression model). CONCLUSIONS: A substantial percentage of patients with TSC in the United States are at risk for delayed detection of kidney manifestations due to infrequent kidney imaging surveillance. Multispecialty care, including neurologists, may positively affect kidney surveillance rates.

Renal Neoplasia in Tuberous Sclerosis: A Study of 41 Patients.

OBJECTIVE: To study the clinical features and identify unique renal neoplasia subtypes and their prognostic implications in individuals with tuberous sclerosis complex (TSC). PATIENTS AND METHODS: The Mayo Clinic nephrectomy registry included 37 patients with TSC diagnosed between 1970 and 2018. Four additional patients were identified from the pathology consultation and autopsy files. All available renal tumors were further characterized using immunohistochemistry and fluorescence in situ hybridization. Clinicopathologic features and follow-up were obtained from the medical record. The American Association for Cancer Research Project GENIE registry was accessed using cBioPortal for molecular profiling of angiomyolipoma (AML). RESULTS: A total of 276 renal tumors from 41 patients were analyzed. Renal tumors were classified into 9 distinct morphological subtypes, with AML predominating (238 [86%]). Interestingly, all these tumors acted in a benign fashion except one renal cell carcinoma with clear cells and fibromyomatous stroma and one epithelioid AML that metastasized. Molecular profiling studies revealed that epithelioid AMLs were enriched for alterations of TP53, RB1, and ATRX. Eight patients died of direct complications of TSC, including 3 of end-stage renal disease. To date, none have died of a renal epithelial neoplasm. CONCLUSION: The identification of unique renal neoplasia subtypes may provide important clues to establish a diagnosis of TSC, and in the somatic setting, this finding has important implications for accurate prognostication. These tumors tend to be indolent, and only 2 of 276 tumors in our study exhibited metastatic behavior. Our results support multidisciplinary management with a focus on preservation of renal function.

Enhancing disease awareness for tuberous sclerosis complex in patients with radiologic diagnosis of renal angiomyolipoma: an observational study.

BACKGROUND: Tuberous Sclerosis Complex (TSC) is a genetic disorder, with renal manifestations like angiomyolipoma (AML) occurring in 70-80% of patients. AML usually cause more complications in TCS patients than in non-TSC patients. However, AML patients are not routinely investigated for TSC. Our aim was to retrospectively assess the correlation between radiologically diagnosed AML and TSC. METHODS: All patients were stratified into AML related vs. unrelated to TSC. Correlations were calculated to determine the association between age, AML, and TSC. RESULTS: Complete data were available for 521 patients with renal AML, in 7 of which the concurrent diagnosis of TSC was found. Younger age significantly positively correlated with the prevalence of TSC in AML patients (p <  0.01). 37 (7%) of the 521 patients were within the age-range of 18-40 years, in which TSC occurred in 6 cases, 4 (66.7%) of which presented with multiple, bilateral renal AML (p <  0.05), and 2 (33.3%) of which with a single, unilateral AML (p <  0.05). In patients with AML but without TSC, unilateral AML was found in 83.9% and bilateral AML in 16.1% (p <  0.05). Simple binary logistic regression analysis revealed bilateral AML (OR 33.0; 95% CI 3.2-344.0; p = 0.003) (but not unilateral AML (OR 0.09; 95% CI 0.01-0.88; p = 0.04)) to be a risk factor for TSC. CONCLUSIONS: The presence of bilateral AML in patients within the age-range of 18-40 years should raise suspicion for TSC as the underlying cause. Therefore, our advice is to refer patients with multiple bilateral renal AML for further investigations regarding TSC.

The Role of Heat Shock Protein-90 in the Pathogenesis of Birt-Hogg-Dubé and Tuberous Sclerosis Complex Syndromes.

Birt-Hogg-Dubé (BHD) and tuberous sclerosis (TS) syndromes share many clinical features. These two diseases display distinct histologic subtypes of renal tumors: chromophobe renal cell carcinoma and renal angiomyolipoma, respectively. Early work suggested a role for mTOR dysregulation in the pathogenesis of these two diseases, however their detailed molecular link remains elusive. Interestingly, a growing number of case reports describe renal angiomyolipoma in BHD patients, suggesting a common molecular origin. The BHD-associated proteins FNIP1/2 and the TS protein Tsc1 were recently identified as regulators of the molecular chaperone Hsp90. Dysregulation of Hsp90 activity has previously been reported to support tumorigenesis, providing a potential explanation for the overlapping phenotypic manifestations in these two hereditary syndromes.

Renal tumors in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a multisystem hereditary disorder characterized by the growth of benign tumors (hamartomas) in multiple organs, including the kidneys. Renal angiomyolipomas (AML) are a major diagnostic feature of TSC and are present in the majority of patients by adulthood. However, AML are usually asymptomatic during childhood when neurological and developmental manifestations are the main source of morbidity. Kidney manifestations of TSC have historically been the main cause of morbidity and mortality of adults with TSC. The recognition that the complications of TSC are caused by dysregulation of the mammalian target of rapamycin (mTOR) pathway has led to an enormous progress in the management of patients with TSC in the last two decades, the establishment of diagnostic guidelines, and trials which have shown the therapeutic benefit of mTOR inhibitors. Kidney surveillance of children with TSC now provides the opportunity for timely interventions to reduce the impact of TSC in adulthood. In this review, we discuss the current management of kidney tumors associated with TSC, including the diagnosis, surveillance, and treatment options for these lesions. We also present outcome data from international registries demonstrating the effectiveness of the current management strategies. With clear management guidelines and efficient treatment of kidney tumors, we envisage that the long-term outcomes of patients with TSC will further improve in the future.

Sporadic Angiomyolipomas Growth Kinetics While on Everolimus: Results of a Phase II Trial.

PURPOSE: Everolimus decreases tumor volume of renal angiomyolipomas in patients with tuberous sclerosis. No prospective data are available regarding the effect of everolimus on the growth kinetics in patients with sporadic angiomyolipomas. We sought to determine the safety and efficacy of everolimus in the volumetric reduction of sporadic angiomyolipomas. MATERIALS AND METHODS: This multi-institutional, prospective, phase II trial, enrolled patients with 3 cm or larger sporadic angiomyolipomas who were candidates for surgical resection or percutaneous angioembolization. Patients received 10 mg everolimus daily for 4 planned 28-day cycles. Response was defined as a 25% or greater volumetric reduction of patient angiomyolipoma. Baseline, 4, 6 and 12-month volumetric analyses were performed using magnetic resonance imaging. Everolimus was discontinued in those with less than 25% volumetric reduction after 4 cycles. Those with 25% or greater volumetric reduction received 2 additional cycles. The primary outcomes were the efficacy of everolimus in the volumetric reduction of angiomyolipomas by 25% or more, and the safety and tolerability of everolimus. RESULTS: Overall 20 patients were enrolled at 5 centers. Of these patients 11 (55%) completed 4 cycles and 7 (35%) completed 6 cycles. Efficacy was demonstrated, with 10 of 18 (55.6%) patients exhibiting a 25% or greater reduction in tumor volume at 4 months (median 58.5%) and 10 of 14 (71.4%) patients exhibiting a 25% or greater reduction in tumor volume at 6 months (median 58.2%). Four (20%) patients were withdrawn due to protocol defined toxicities and 8 (40%) self-withdrew from the study due to side effects. CONCLUSIONS: Everolimus was effective in causing volumetric reduction of angiomyolipomas by 25% or greater in most patients but was associated with a high rate of treatment discontinuation.

Fate of Pediatric Renal Angiomyolipoma During mTOR Inhibitor Treatment in Tuberous Sclerosis Complex.

OBJECTIVE: To evaluate the clinical and radiographic follow-up of renal angiomyolipoma (AML) in pediatric patients with tuberous sclerosis complex (TSC) on mTOR inhibitors. METHODS: We performed retrospective chart review of children who were diagnosed with TSC between 2000 and 2019 and prescribed everolimus at age ≤18 years. Treatment assessment was performed in patients who were medically-compliant by serum drug trough levels and who had at least a baseline and one subsequent renal imaging study. RESULTS: Nineteen patients were analyzed. Average age of everolimus initiation was 9 years, and indication was neurologic in 17 (90%). Fourteen patients (73.6%) had AML with average size of 1.9 (0.4-5) cm. Medication was discontinued due to side effects in 3 (16%) patients. Treatment assessment was analyzed for 15 patients with median medication exposure 5.1 (0.8-8.5) years. Among 13 with AML, the dominant lesion decreased in size in 9 (69%) and stayed stable in 4 (31%). Greatest absolute size decrease was seen for lesions ≥2 cm. No new AML lesions formed during treatment. CONCLUSION: Although not currently approved for this indication, everolimus appears to be well-tolerated with similar efficacy for pediatric AML as in adult AML. Use may be most warranted in children with AML ≥2 cm.

Selective Arterial Embolization for Large or Symptomatic Renal Angiomyolipoma: 10 Years of Follow-up.

OBJECTIVE: To assess long-term outcome after selective arterial embolization (SAE) as first-line treatment for large or symptomatic AML. DESIGN, SETTING, AND PARTICIPANTS: Data from a prospectively maintained database on 71 patients who underwent SAE for large or symptomatic AML were reviewed. Patients with sporadic and tuberous-sclerosis-complex (TSC) were included. OUTCOME MEASUREMENTS: The main endpoints were re-embolization rates, occurrence of clinical events related to AML, size of AML, and renal function. RESULTS: Thirteen (19.1%) patients reported at least 1 major clinical event. Major complications affected 2 patients (2.9%), both ending in complete loss of renal unit function. Four renal units (5.9%) were eventually treated surgically. The re-embolization rate was 41.1%, with an average time from the initial to a repeat SAE of 2.18 years (range 0.31-10.65 years). The size of the tumor prior to SAE and after 5 and 10 years of follow-up were 8.9 cm (7-12), 6.5 cm (4-7.5), 7 cm (4-7.8), respectively [median (IQR)]. These results are translated to a size reduction of 27% in 10 years follow-up. Patients with TSC had larger tumors on long-term follow-up (77.8 vs 41.3 mm, P = .045). The long-term follow-up estimated average glomerular filtration rate was 81.97 (range 26-196). No patient needed renal replacement therapy, and disease-specific survival was 100%. CONCLUSIONS: SAE is a safe treatment option for patients with symptomatic or large AML. It represents a minimally invasive intervention with good long-term outcome. SAE may be offered as first-line treatment in most cases, though, it is associated with high retreatment rates.

How many surgically-treated angiomyolipomas are related to tuberous sclerosis complex? Insights from a retrospective multicenter study.

BACKGROUND: Patients with TSC - related renal angiomyolipoma (AML) are eligible for targeted therapy with mTOR inhibitors, avoiding the morbidity of interventional management. Despite clinical criteria for TSC diagnosis have been defined, their use in routine clinical practice is likely suboptimal, leading to potential misclassification of TSC-related AML. The study aims to assess the proportion and characteristics of surgically-treated patients with putative sporadic AML that would have been re-classified as TSC-related. METHODS: We retrospectively reviewed a prospectively collected multi-institutional database to select patients with suspected TSC-related AML among those undergoing surgery at three referral Centers over 11-years (2005-2015). Possible diagnosis of TSC was defined according to the 2012 International Tuberous Sclerosis Complex Consensus (ITSCC) criteria. The proportion and characteristics of patients with possible TSC-related AML (as compared to those of patients with sporadic AML) were considered the main study endpoints. RESULTS: Overall, 132 patients were included. Of these, 10 (7.6%) were considered TSC-related. Most patients (84%) were female. Patients with TSC-related AML were likely to be younger (median age 53 vs. 56 years, P=0.29), symptomatic at diagnosis (70% vs. 21%, P=0.002), with slightly worse preoperative physical status (median ASA score 2 vs. 1, P=0.001) and bilateral disease (30% vs. 7.4%, P=0.04) as compared to patients with sporadic AML. Anatomic complexity and tumor size were also higher among TSC-related AMLs. CONCLUSIONS: A non-negligible proportion of surgically-treated, putative sporadic AMLs were reclassified as potentially hereditary (TSC-related). As TSC patients may be treated with targeted therapies, our findings may increase urologists' awareness of TSC-related AML and prompt the design of future studies evaluating targeted diagnostic pathways for these patients.

[Rapamycin in the treatment of renal diseases associated with tuberous sclerosis complex].

Objective: To investigate the efficacy and safety of rapamycin in children with tuberous sclerosis complex (TSC) associated renal disease. Methods: A prospective self-control study was conducted. The clinical data of 92 children diagnosed with tuberous sclerosis complex associated kidney disease at the People's Liberation Army General Hospital from January 2011 to January 2019 were collected. The long-term rapamycin treatment for all patients initiated at 1 mg/(m(2)·d), which was gradually adjusted to reach a blood concentration of 5-10 µg/L. The changes of the maximum diameter of renal lesions in children after rapamycin treatment were observed and analyzed with Wilcoxon test. Results: Ninety-two children, including 52 males and 40 females, who met the criteria were analyzed. Sixty patients had only renal angiomyolipoma(RAML), while 24 patients had only multiple renal cysts(MRC), and 8 patients had both lesions. The age of TSC diagnosis was 16.0 (7.0, 42.0) months, and the age of initial treatment with rapamycin was 63.5 (21.0, 103.0) months. The follow-up lasted for 12.0 (4.0, 23.0) months. Sequencing of TSC1 and TSC2 genes was performed in 54 children with TSC, including 3 patients (6%) with mutations in TSC1 gene and 51 patients (94%) with mutations in TSC2 gene. The maximum RAML diameter before treatment was 7.0 (4.0, 9.0) mm. The best effect reached at 3 months of treatment, with the diameter of 4.0 (0,7.0) mm. The maximum diameters at 6 months, 1 year and 1-2 years were 5.0 (0,9.8) mm, 5.0 (1.5, 8.5) mm, 5.5 (3.0, 9.0) mm, respectively, and were significantly different from the baseline (Z=-2.404,-2.350,-2.750,P=0.016,0.019,0.006, respectively). The maximum diameter after 2-3 years, and ≥3 years were 5.0 (3.9,7.0) mm and 6.0 (1.0, 11.0) mm, without significant difference from the baseline (Z=-0.856,-0.102,P=0.393,0.919, respectively).The maximum diameters of MRC after 3 months, 6 months, 1 year,1-2 years, 2-3 years, and ≥3 years were 11.0 (5.0, 14.0) mm,3.0 (0.0,11.0) mm,5.0 (0,21.0) mm,0 (0,14.0) mm,0 (0,10.0) mm, and 0 (0,18.3) mm, respectively, but were not significantly different rom the baseline (7.0 (5.0, 15.7) mm)(Z=-0.944,-1.214,-1.035,-1.896,-1.603,-1.214,P=0.345,0.225,0.301,0.058,0.109,0.225, respectively).Twenty-nine patients (32%) had oral ulcers during the entire treatment period, and no serious adverse reactions were observed. Conclusions: Rapamycin could decrease the diameter of TSC-related RAML, but could not inhibit the growth of cysts. It is well tolerated in the treatment of renal diseases associated with tuberous sclerosis complex.