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Renal disease in tuberous sclerosis complex: pathogenesis and therapy

  • Review Article
  • Published:

From Nature Reviews Nephrology

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Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by hamartomatous tumours of the brain, heart, skin, lung and kidney. Patients with TSC show a diverse range of neurological features (including seizures, cognitive disability and autism) and renal manifestations (including angiomyolipomas, epithelial cysts and renal cell carcinoma (RCC)). TSC is caused by inactivating mutations in TSC1 and TSC2, which encode hamartin and tuberin, respectively. These two proteins form a complex that negatively regulates mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cellular growth and metabolism. In clinical trials, allosteric inhibitors of mTORC1 decrease angiomyolipoma size, but the tumours regrow after treatment cessation. Therefore, the development of strategies to eliminate rather than suppress angiomyolipomas remains a high priority. This Review describes important advances in the TSC field and highlights several remaining critical knowledge gaps: the factors that promote aggressive behaviour by a subset of TSC-associated RCCs; the molecular mechanisms underlying early-onset cystogenesis in TSC2–PKD1 contiguous gene deletion syndrome; the effect of early, long-term mTORC1 inhibition on the development of TSC renal disease; and the identification of the cell or cells of origin of angiomyolipomas.

Key points

  • Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome caused by germline inactivating mutations in either allele of the tumour suppressor genes TSC1 or TSC2.

  • Annual surveillance of renal disease is recommended for most patients with TSC.

  • Nephron-sparing treatments for TSC-related renal disease (rapalogues, embolization and partial nephrectomy) should always be prioritized.

  • Activation of mechanistic target of rapamycin complex 1 (mTORC1) promotes TSC by accelerating cell growth and inhibiting autophagy.

  • mTORC1 hyperactivation increases oxidative stress, rendering TSC-related tumour cells vulnerable to agents that increase oxidative stress or inhibit antioxidant biosynthesis.

  • The interactions of TSC-related tumour cells with their microenvironment remain a key area of research; for example, tumour cells might be responsive to immune checkpoint inhibition.

  • Critical knowledge gaps include the angiomyolipoma cell of origin, aggressive behaviour of renal cell carcinomas and molecular mechanisms underlying early-onset cystic disease in PKD1–TSC2 contiguous gene deletion syndrome.

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Fig. 1: The hamartin–tuberin complex regulates mTORC1 signalling by integrating extracellular and intracellular signals that promote metabolic homeostasis.
Fig. 2: Renal manifestations of TSC.
Fig. 3: Metabolic and molecular changes associated with mTORC1 hyperactivation in TSC.
Fig. 4: Role of oxidative stress in the pathogenesis of TSC.
Fig. 5: Possible therapies for TSC that target immune pathways.

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Acknowledgements

The authors thank J. Nijmeh, N. Alesi and C. Filippakis (Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA) for critical help in table generation, image acquisition and proofreading.

Reviewer information

Nature Reviews Nephrology thanks I. Frew, J. Kingswood and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Hilaire C. Lam & Elizabeth P. Henske

  2. Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Brian J. Siroky

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Glossary

Tuberous sclerosis complex

(TSC). A rare tumour suppressor genetic disorder that causes benign tumours in various organs, primarily the brain, eyes, heart, kidneys, skin and lungs; this disorder is also the leading genetic cause of both epilepsy and autism.

Renal cell carcinoma

(RCC). The most common kidney cancer, originating in the lining of the proximal convoluted tubes in the kidney. Occurs in both adults and children with tuberous sclerosis complex.

Lymphangioleiomyomatosis

A rare progressive lung disease that is the pulmonary manifestation of tuberous sclerois complex, primarily affecting women of childbearing age, that typically results in cystic lung destruction.

Mechanistic target of rapamycin (mTOR) complex 1

(mTORC1). A protein complex that functions as a master regulator. This complex senses and integrates nutrient, energy and redox signals and either potentiates growth and anabolic processes or limits catabolic processes, such as autophagy.

GTP-binding protein Rheb

Also known as Ras homologue enriched in brain, this protein is ubiquitously expressed in humans and other mammals and is principally involved in the mechanistic target of rapamycin pathway and in regulation of the cell cycle.

Autophagy

A conserved regulated intracellular process for degradation and recycling of the cellular components in enzyme-filled compartments, known as autophagosomes.

Knudson two-hit hypothesis

Most loss-of-function mutations in tumour suppressor genes are recessive, meaning that both alleles of the gene must be mutated for function to be lost and for the cell to become cancerous. The germline mutation is the first hit, but disease onset requires a second-hit event affecting the other allele.

Angiomyolipomas

A form of perivascular epithelioid cell tumour characterized by varying contributions of adipocytes, smooth muscle cells and abnormal vasculature.

Mosaicism

The presence, within the same individual, of different cell populations with distinct genetic make-up.

Pneumothorax

A condition in which air is trapped between the lungs and chest wall, leading a portion or all of the lung to collapse.

Multifocal micronodular pneumocyte hyperplasia

A subtype of pneumocytic hyperplasia that presents as a diffuse, benign nodular proliferation of epithelial cells and occurs in many patients with tuberous sclerosis.

Sirolimus

An FDA-approved drug with immunosuppressive and antiproliferative properties due to inhibition of mechanistic target of rapamycin.

Everolimus

An FDA-approved mechanistic target of rapamycin inhibitor that is a derivative of sirolimus and has a similar mechanism of action.

Autosomal dominant polycystic kidney disease

(ADPKD). One of the most common, life-threatening genetic diseases. It causes small, fluid-filled sacs called cysts to develop and enlarge in the kidneys, which eventually leads to kidney failure.

Mizoribine

An FDA-approved selective inhibitor of inosine monophosphate synthetase and GMP synthetase, resulting in the inhibition of de novo nucleotide synthesis, which inhibits DNA synthesis. Also has immunosuppressive properties.

Simvastatin

An FDA-approved statin that works by slowing the production of cholesterol in the body to prevent atherosclerosis-related complications.

Celecoxib

An FDA-approved nonsteroidal anti-inflammatory drug (NSAID), specifically a cyclooxygenase 2 inhibitor, that relieves pain and swelling by reducing prostaglandins.

Endoplasmic reticulum stress

An accumulation of unfolded proteins in the endoplasmic reticulum that overloads its peptide processing and recycling capacity.

Unfolded protein response

An adaptive mechanism, initiated in response to the accumulation of unfolded proteins, that involves transcriptional activation of genes responsible for enhancing the protein-folding capacity of the endoplasmic reticulum and promotes endoplasmic reticulum-associated misfolded protein degradation.

l-Buthionine sulfoximine

(BSO). A compound that inhibits γ-glutamyl cysteine synthetase, the enzyme required in the first step of glutathione synthesis, thus reducing glutathione levels.

Chelerythrine chloride

A potent and selective inhibitor of protein kinase C.

Nelfinavir

An FDA-approved antiretroviral drug that belongs to the protease inhibitor family.

Salinomycin

An antibacterial drug that has been shown in mice to kill cancer stem cells.

Chloroquine

An FDA-approved drug that neutralizes lysosomal acidification, thus blocking autophagosomal degradation, and mildly suppresses the immune system.

Pentose phosphate pathway

An alternative to the glucose-oxidizing metabolic pathway. It is the major source to generate NADPH but also generates pentoses (five-carbon sugars) as well as ribose 5-phosphate, a precursor for the synthesis of nucleotides.

6-Aminonicotinamide

An inhibitor of 6-phosphogluconate dehydrogenase, thus used to block the pentose phosphate pathway.

Resveratrol

A type of natural phenol found in plants that acts as an antioxidant.

T cell exhaustion

The loss of T cells’ ability to perform their effector functions efficiently, which leads to low proliferative capacity and poor survival following antigen stimulation. Exhausted T cells co-express multiple inhibitory receptors that negatively regulate their function, such as programmed cell death protein 1, a major target of clinical immunotherapy.

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Lam, H.C., Siroky, B.J. & Henske, E.P. Renal disease in tuberous sclerosis complex: pathogenesis and therapy. Nat Rev Nephrol 14, 704–716 (2018). https://doi.org/10.1038/s41581-018-0059-6

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