New treatment paradigms for ADPKD: moving towards precision medicine

Key Points

  • Clinicians are now able to identify which patients with autosomal dominant polycystic kidney disease (ADPKD) are at highest risk of progression and most likely to benefit from early therapy

  • MRI measurement of total kidney volume (TKV) is a valuable method to predict future rate of increase in TKV, rate of decline in kidney function and risk of end-stage renal disease (ESRD)

  • The availability of genetic testing will continue to increase and can provide a diagnosis in unusual or atypical cases or in young (<30 years of age) patients being assessed for kidney donation

  • ADPKD is typically the result of germline PKD1 or PKD2 mutations, with somatic mutations, genetic mosaicism and modifier mutations occasionally contributing to the ADPKD phenotype

  • Disruption of polycystin trafficking and signalling, environmental exposures and the compounding 'snowball' effects of regional ischaemia, inflammation and tubular obstruction further contribute to disease progression

  • Novel strategies intended to limit cyst burden have provided encouraging results, whereas treatment of hypertension and proteinuria remain the mainstays of medical management of ADPKD

  • Assessment and treatment of ADPKD-related complications, including cyst haemorrhage, cyst infection, nephrolithiasis and chronic pain, require special consideration and attention

Abstract

The natural history of autosomal dominant polycystic kidney disease (ADPKD) is characterized by a variable rate of cyst development and increase in total kidney volume (TKV), variable kidney function decline and age of onset of end-stage renal disease (ESRD), and variable presentation of renal and extrarenal manifestations. Precision medicine is proposed to improve patient outcomes by tailoring therapy to the specific genetic background, pathophysiology, disease burden, prognosis and status of each individual. This approach to the management of patients with ADPKD is nearing clinical implementation owing to advances in genetics, imaging, biomarker development and therapeutics. In this Review, we discuss pharmacological and non-pharmacological interventions for the treatment of hypertension and proteinuria, and for slowing the rate of cyst growth in patients with ADPKD before the development of ESRD. We provide recommendations for the management of renal complications, including cyst infection, nephrolithiasis, haematuria and chronic pain. The early treatment of patients with ADPKD who are largely asymptomatic is associated with a therapeutic burden but slows cyst growth and delays subsequent loss of kidney function, which ultimately delays the need for renal replacement therapy and has a positive effect on the quality of life of patients.

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Figure 1: Pathogenic mechanisms and pathways in ADPKD.
Figure 2: Sources of data to characterize the ADPKD clinical phenotype.
Figure 3: Theoretical relationship between total kidney volume (TKV) and kidney function.
Figure 4: The theoretical contribution of genetic and environmental factors to polycystin protein dosage explains the rate of cyst progression in patients with autosomal dominant polycystic kidney disease (ADPKD).

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Acknowledgements

M.B.L. is supported by the American Society of Nephrology Jared J. Grantham fellowship.

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Correspondence to Arlene B. Chapman.

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A.B.C. declares an association with Otsuka Pharmaceutical Group through membership of the TEMPO steering committee. M.B.L. declares no competing interests.

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Lanktree, M., Chapman, A. New treatment paradigms for ADPKD: moving towards precision medicine. Nat Rev Nephrol 13, 750–768 (2017). https://doi.org/10.1038/nrneph.2017.127

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