Renal Manifestations of Tuberous Sclerosis Complex: Key Findings From the Final Analysis of the TOSCA Study Focussing Mainly on Renal Angiomyolipomas.

J Chris Kingswood,Vincent Cottin,Matthias Sauter,Martha Feucht,Maria Dahlin,Elena Belousova,Yukitoshi Takahashi,Rima Nabbout,Christoph Hertzberg,John A Lawson,Alfons Macaya,Seema Shah,Valentin Sander,Petrus J De Vries,Paolo Curatolo,Sotiris Youroukos,Finbar O'Callaghan,Jiong Qin,Renaud Touraine,Carla Fladrowski,Bernard A Zonnenberg ,Lisa D’amato ,Thomas Carter ,José Carlos Ferreira ,Mirjana P Benedik ,Guillaume Beaure D’augères ,Anna Jansen ,Rúben Marques ,Sergiusz Jóźwiak

doi:10.3389/fneur.2020.00972

Abstract

Renal angiomyolipomas are one of the most common renal manifestations in patients with tuberous sclerosis complex (TSC), with potentially life-threatening complications and a poor prognosis. Despite the considerable progress in understanding TSC-associated renal angiomyolipomas, there are no large scale real-world data. The aim of our present study was to describe in detail the prevalence and outcome of renal angiomyolipomas in patients with TSC, enrolled into the TuberOus SClerosis registry to increase disease Awareness (TOSCA) from 170 sites across 31 countries worldwide. We also sought to evaluate the relationship of TSC-associated renal angiomyolipomas with age, gender and genotype. The potential risk factors for renal angiomyolipoma-related bleeding and chronic kidney disease (CKD) were studied in patients who participated in the TOSCA renal angiomyolipoma substudy. Of the 2,211 eligible patients, 1,062 (48%) reported a history of renal angiomyolipomas. The median age of TSC diagnosis for the all subjects (n = 2,211) was 1 year. The median age of diagnosis of renal angiomyolipoma in the 1,062 patients was 13 years. Renal angiomyolipomas were significantly more prevalent in female patients (p < 0.0001). Rates of angiomyolipomas >3 cm (p = 0.0119), growing lesions (p = 0.0439), and interventions for angiomyolipomas (p = 0.0058) were also higher in females than males. Pre-emptive intervention for renal angiomyolipomas with embolisation, surgery, or mammalian target of rapamycin (mTOR) inhibitor may have abolished the gender difference in impaired renal function, hypertension, and other complications. The rate of interventions for angiomyolipomas was less common in children than in adults, but interventions were reported in all age groups. In the substudy of 76 patients the complication rate was too low to be useful in predicting risk for more severe CKD. In addition, in this substudy no patient had a renal hemorrhage after commencing on an mTOR inhibitor. Our findings confirmed that renal angiomyolipomas in subjects with TSC1 mutations develop on average at the later age, are relatively smaller in size and less likely to be growing; however, by age 40 years, no difference was observed in the percentage of patients with TSC1 and TSC2 mutations needing intervention. The peak of appearance of new renal angiomyolipomas was observed in patients aged between 18 and 40 years, but, given that angiomyolipomas can occur later, lifelong surveillance is necessary. We found that pre-emptive intervention was dramatically successful in altering the outcome compared to historical controls; with high pre-emptive intervention rates but low rates of bleeding and other complications. This validates the policy of surveillance and pre-emptive intervention recommended by clinical guidelines.

Highlights

Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disorder characterized by hamartomatous lesions in multiple organs such as brain, kidneys, skin, lungs, eyes, and heart [1, 2]
In our previous publication from the TOSCA core section interim analysis [13], we reported that the occurrence rate of renal angiomyolipomas was lower in the TOSCA cohort compared to other published literature [8, 9]
Rates of haematuria and hypertension were lower compared with those reported in TSC patients in other studies [6, 7, 21, 22], this may be a reflection of the age relatively young age of our subjects and possibly under-ascertainment. These lower rates of occurrence of renal angiomyolipomas and angiomyolipomarelated complications could be explained by a different age range of our population; the current analysis shows that angiomyolipoma prevalence rose progressively with age, to 77.7% in those over 40 years of age, whereas complication rates remained much lower than in other studies

Summary

Introduction

Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disorder characterized by hamartomatous lesions in multiple organs such as brain, kidneys, skin, lungs, eyes, and heart [1, 2]. Renal angiomyolipomas are the most common renal manifestations in patients with TSC, with an estimated prevalence ranging from 55 to 80% [8,9,10,11]. They are usually multiple and bilateral, progress with age and cause more problems in females [12, 13]. A retrospective cohort study showed that modifiable factors such as hypertension, proteinuria, and hyperfiltration occur frequently and early in patients with TSC and could play an important role in the development of chronic kidney disease (CKD) in these patients [15]. Mutation studies have shown the occurrence and severity of TSCassociated renal angiomyolipomas and cysts to be higher among patients with TSC2 mutation than those with TSC1 mutation [8, 17]

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