An update on tuberous sclerosis complex from a renal perspective

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterised by the presence of benign, non-invasive tumours throughout the body.¹ It can result in the formation of hamartomas in any organ, including the brain, kidneys, lungs, heart, liver, eyes, and on the skin. Differences in location, distribution, size, and number of tumours cause various clinical presentations, even between relatives.²

The disease is brought on by inactivating variants of TSC1 or TSC2 genes, with TSC2 gene variants being more common and resulting in a more severe disease profile. The TSC1 gene is located on chromosome 9 and encodes for hamartin,³ while the TSC2 gene is located on chromosome 16 and encodes for tuberin.⁴ Following the discovery of TSC1 and TSC2, along with proteins encoded by those genes, several potentially impacted downstream protein cascades have now been identified, including the mammalian target of rapamycin (mTOR) pathway.² This has opened therapeutic options for TSC, with mTOR inhibitors now indicated in certain clinical situations.⁵

Manifestations of TSC

The most common childhood clinical manifestations of TSC are neurological, caused by tumour formation in the brain. Around 60-90 per cent of patients experience seizures in their lifetime⁶ and 90 per cent present with neurodevelopmental delays and behavioural problems.⁷

Cardiac rhabdomyomas are commonly seen prenatally in patients with TSC, and although they usually regress in childhood, they remain a cause of neonatal mortality. Moreover, they can recur in adolescence, especially in girls, but usually remain asymptomatic.⁵

Pulmonary manifestations encompass cysts and lymphangioleiomyomatosis. This presentation occurs almost exclusively in women of childbearing age.⁸ Other manifestations include skin and nail lesions, retinal hamartomas, and oral manifestations, such as gingival fibromas and dental enamel pits.⁹

Renal manifestations of TSC

Renal manifestations of TSC are common, with large studies indicating an incidence between 60 and 75 per cent, with varying severity.¹⁰ The most common renal pathology observed in TSC is angiomyolipoma (AML) formation, estimated to occur in 34-80 per cent of patients.¹⁰

AMLs are benign tumours composed of adipocytes, smooth muscle cells, and abnormal vasculature. Complications may include haemorrhage and mass effects, which can cause pain or discomfort and compromise renal function by compressing urine outflow or altering normal renal parenchyma.¹⁰ This can further lead to development of hypertension due to dysregulation of blood pressure.

The second commonest renal pathology observed in the TSC population is the presence of renal cysts, which happens in 14-32 per cent of patients.¹⁰ Especially detrimental is the presence of renal cysts when TSC co-exists with polycystic kidney disease. The TSC2 locus is located next to the PKD1 gene, and contiguous deletions can result in a combined presentation of both phenotypes.¹¹ In these cases, cysts can be large and multiple and can cause end-stage renal failure in early adult life.

Moreover, renal cell carcinoma incidence amongst TSC patients is reported to occur with greater frequency than in the general population.¹⁰ Importantly, renal complications have been reported to be the leading cause of mortality in adults living with TSC,¹² and often require collaborative input from nephrology, urology, and radiology teams.

Prevalence

The prevalence of TSC is not rigorously defined, with UK population-based studies reporting a frequency of between one in 12,000 to one in 14,000 in children under the age of 10,¹³ but considering that some individuals might be less severely impacted by the disease and therefore undiagnosed, the estimated birth rate of the disorder is one in 6,000.^14,15 Based on those estimates, there are thought to be around 600-800 individuals living with TSC in the Republic of Ireland.¹⁶ Medical care for these patients is historically fragmented between hospitals and specialities, and it is likely that some cases are unaccounted for.

Managing renal TSC

Comprehensive consensus guidelines describing the diagnosis, surveillance, and management of TSC have been published regularly since 1993,¹⁷ with the most recent iterations published in 2021 in the US and 2019 in the UK. The most recent clinical recommendations for kidney involvement were published in 2024 in Nature.¹ Renal guidelines recommend annual measurement of blood pressure, renal function, and urinary protein quantification as well as renal imaging every one to three years.

In Ireland, care for patients living with TSC has been historically fragmented, leading to difficulty in delivering comprehensive and equitable care, management, and treatment.¹⁶ The most common primary points of care for TSC patients are epilepsy clinics. In recent years, a monthly sub-clinic specialising in care for patients with TSC was developed by the epilepsy clinic at St James’s Hospital, Dublin. However, to address TSC manifestations outside of neurological involvement, patients are referred to other specialist clinics.

In order to streamline care for TSC patients, a dedicated nephrology TSC service was established in 2023. There are also quarterly multidisciplinary team (MDT) meetings for discussion of complex cases with representation from neurology, nephrology, genetics, respiratory, and an intellectual disability liaison nurse.

We recently reviewed the clinical care given to all adult patients with TSC attending the new nephrology service in St James’s Hospital since formalising this care pathway, and compared delivered care to guideline recommendations.

A total of 23 patients attended this service (nine female, 14 male) with an age range of 16-56 years. Three reported a family history of TSC. The majority (n=11) had normal renal function; several required anti-hypertensives or mTOR inhibitors for renal indications. There was an improvement in renal guideline adherence following entry into the dedicated service (compared to the year prior to entry into this service).

Annual creatinine checks were done in all patients (compared to 76 per cent prior to entry into this service), annual urinary protein quantification was performed in 67 per cent (compared to 9 per cent previously), and annual blood pressure check was done in all (compared to 34 per cent previously). Adherence to imaging guidelines was seen in all patients after entry into the service (compared to 43 per cent prior). To summarise, the development of a dedicated nephrology pathway for TSC patients led to improved renal guideline adherence.

Conclusion

This review highlights the medical complexity of this patient cohort. Establishment of a TSC MDT resulted in improved renal guideline adherence, as well as more streamlined care. The future vision, if resources allow, involves expansion of the existing dedicated services across specialties, with more combined clinics and inclusion of urology, radiology, genetics, dermatology, and other pertinent specialities in the MDT to facilitate more streamlined care for these patients.