Tuberous sclerosis complex and the kidney

Introduction

Tuberous sclerosis complex (TSC) is an often underdiagnosed and misunderstood disease affecting more than one million patients worldwide. Disruptions in the TSC axis lead to cellular abnormalities that result in abnormal development and postpartum cellular growth. TSC affects every organ system and is often thought of as a tumor predisposition syndrome, although the lesions often seem to share characteristics of more benign lesions, and in some ways a dysplastic process. There has been an attribution to “malignant degeneration” of TSC renal lesions, although this seems to be more of a historical footnote rather than a well-studied phenomenon. There is also confusion regarding the true risk of fat-poor renal lesions being malignant. This chapter will address these issues.

Genetics of tuberous sclerosis complex renal disease

TSC is an autosomal dominant genetic disorder that has a birth incidence of around 1:5800. ^, Proper diagnosis can be certain if the International Guidelines are followed, but diagnosis can be missed if one relies on the Vogt’s triad for TSC (facial angiofibromas, developmental delay, and intractable epilepsy) because less than 40% of affected patients have these classic features. Approximately half of the patients demonstrate cognitive impairment, autism, or behavioral disorders.

There are two gene loci associated with TSC: TSC1 , located on chromosome 9, and TSC2 , located on chromosome 16. The identification of the TSC2 gene location was assisted because of an observation in a family with autosomal dominant polycystic kidney disease caused by a balanced translocation in the PKD1 gene. A child in this family had autosomal dominant polycystic kidney disease and TSC, which helped in the positional cloning of the TSC2 gene.

TSC may occur by the loss of expression of the nonmutant allele. Both TSC and autosomal dominant polycystic kidney disease are phenotypically expressed because of a second-hit, or somatic mutation mechanism. The kidney disease associated with the PKD1 and the TSC2 loci account for a majority of their respective diseases, and both exhibit a more severe phenotype compared with the disease associated with the PKD2 and TSC1 loci. This association with more severe disease may have a molecular underpinning. The PKD1 and TSC2 loci are immediately adjacent, in a tail-to-tail orientation, on chromosome 16p. The proximity of the genes may be important because the PKD1 gene contains an intronic sequence with unique structural properties ^, that would predispose to mutation because this tract interferes with deoxyribonucleic acid (DNA) replication and leads to double-strand breaks and an array of somatic mutational effects. This predisposition to DNA double-strand breaks is synergized by the renal microenvironment, which inhibits DNA damage recognition. ^, This renal microenvironmental predisposition to disease may also help explain the multifocal and bilateral nature of the TSC cystic disease and the angiomyolipomata.

Tuberous sclerosis complex and renal function

Premature impairment of glomerular filtration rate (GFR) is reported in up to 40% of patients with TSC. ^, This reduction in function occurs in the absence of overt bleeding from angiomyolipomata or interventions, suggesting an intrinsic renal disease, and underscores the need to preserve kidney function by treating hypertension aggressively and avoiding surgical intervention when treating angiomyolipomata preemptively to prevent hemorrhage. Renal function should be assessed at the time of diagnosis and on an annual basis using blood tests to estimate GFR using creatinine ^, or cystatin C equations. Renal function in patients with TSC is of critical importance because many of the drugs commonly used to treat epilepsy in patients with TSC are renally cleared.

Biology of tuberous sclerosis complex renal disease

Angiomyolipomata

The cell giving rise to the angiomyolipomata, categorized a perivascular epithelial cell tumor (PEComa), has been unknown until recently. Vascular associations with TSC, including aneurysms in the angiomyolipomata, aorta, and brain, along with immunohistochemical staining reveal that angiomyolipomata may arise from vascular mural cells. This origin helps explain the angiomyolipomata propensity to hemorrhage and the proclivity of the cells to home to lung, leading to lymphangioleiomyomatosis. ^,

Although the typical TSC-associated angiomyolipoma contains fat, these lesions can also contain spindle cells, epithelioid cells, or a mix of both that express smooth muscle actin and melanocyte markers, such as gp100, a splice variant of Pmel17, and even melanin A ( Fig. 27.1 ). Expression of these melanocyte-associated genes results from MitF family transcription factor activity. This increased MITF transcription factor activity has caused confusion between TSC-associated PEComas and those caused by translocations involving TFE3 or TFEB, such as more aggressive renal cell carcinomas (RCCs) and malignant PEComas. ^,

Because approximately one-third of TSC-associated angiomyolipomata have fat-poor components ( Fig. 27.2 ), and because at least half of the patients affected with TSC will have cystic disease, it is common for some patients to have a solid mass that is associated with cystic components. These findings should raise concern for RCC in the general population but should not raise the same level of concern in the population with TSC, because RCC is actually very rare in the population of TSC patients. Such lesions can be serially measured and assessed for growth characteristics that can help sort the fat-poor angiomyolipoma from the malignancy. Current research focuses on noninvasive approaches to help better delineate malignancy from fat-poor angiomyolipoma.

Cystic disease: Intersection of cilial cystogenic and oncogenic signaling pathways

TSC proteins regulate cell growth and proliferation, which are important for organogenesis, organ maintenance, and malignancy. The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway integrates intra- and extracellular environmental information to properly regulate metabolism, protein translation, growth, proliferation, autophagy, and survival. The TSC2 protein is reported to interact with cleaved C-terminal tail of polycystin-1 (PC-1) to control the mTORC1 pathway. AKT phosphorylation of TSC2 causes its retention at the cell membrane for this regulation of mTORC1. This phosphorylation step is inhibited by the uncleaved, membrane bound C-terminal tail of PC-1. Without this phosphorylation, TSC2 complexes with TSC1 to downregulate mTORC1 activity.

The mTORC1 activation also may involve a nuance involving the PC-1 in explaining the cystogenesis that could help explain why the PKD1/TSC2 contiguous gene syndrome has such a severe phenotype ( Fig. 27.3 ). mTORC1 activity also negatively regulates the biogenesis of PC-1 and proper trafficking of the PC-1/2 complex to cilia. PC-1 is located on the cilia of principal cells, but it is also found on other cell membranes, including intercalated cells, and is strongly expressed on extracellular vesicles. Genetic interaction studies have revealed that PC-1 downregulation by mTORC1 leads to cystogenesis in Tsc1 mutants. These findings may explain the severe renal manifestations of the PKD1/TSC2 contiguous gene syndrome.