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Why kidneys fail in autosomal dominant polycystic kidney disease

Nature Reviews Nephrology volume 7, pages 556–566 (2011)Cite this article

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Abstract

The weight of evidence gathered from studies in humans with hereditary polycystic kidney disease (PKD)1 and PKD2 disorders, as well as from experimental animal models, indicates that cysts are primarily responsible for the decline in glomerular filtration rate that occurs fairly late in the course of the disease. The processes underlying this decline include anatomic disruption of glomerular filtration and urinary concentration mechanisms on a massive scale, coupled with compression and obstruction by cysts of adjacent nephrons in the cortex, medulla and papilla. Cysts prevent the drainage of urine from upstream tributaries, which leads to tubule atrophy and loss of functioning kidney parenchyma by mechanisms similar to those found in ureteral obstruction. Cyst-derived chemokines, cytokines and growth factors result in a progression to fibrosis that is comparable with the development of other progressive end-stage renal diseases. Treatment of renal cystic disorders early enough to prevent or reduce cyst formation or slow cyst growth, before the secondary changes become widespread, is a reasonable strategy to prolong the useful function of kidneys in patients with autosomal dominant polycystic kidney disease.

Key Points

  • In patients with autosomal dominant polycystic kidney disease (ADPKD), cysts develop in a minority of cortical and medullary tubules, enlarge exponentially and compress adjacent normal parenchyma

  • Individual expanding cysts displace normal tubules, blood vessels and lymphatics, obstruct their flow and promote apoptosis, atrophy and fibrosis of functioning parenchyma

  • Owing to dichotomous branching of the ureteric bud, cysts forming in medullary collecting ducts will probably impair the function of more upstream nephrons than cysts developing in the cortex

  • Despite the pernicious loss of functioning nephrons, glomerular filtration rate (GFR) does not decline until fairly late in the course of ADPKD, probably because of compensatory hyperfiltration in surviving nephrons

  • In the third to fourth decades of life, spreading nephron obstruction, together with interstitial inflammation and fibrosis, widens the devastation of residual parenchyma, promoting the inexorable loss of renal function

  • Potential therapies that target cyst growth mechanisms and are initiated early in the disease course (stage 1 chronic kidney disease) will probably be more effective than treatments starting after GFR has declined

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Figure 1: End-stage polycystic kidneys.
Figure 2: Schematic illustration of the early stages of cyst formation and enlargement.
Figure 3: Early stage cyst formation.
Figure 4: Effect of removing AVP on the development and growth of cysts in Pkhd1 rats (autosomal recessive polycystic kidney disease ortholog).
Figure 5: Evidence of tubule obstruction by cysts.
Figure 6: Topography of renal cyst formation in ADPKD.
Figure 7: How cysts decrease GFR.

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Acknowledgements

We thank James Calvet PhD, Robin Maser PhD and Darren Wallace PhD for helpful discussions and manuscript critique.

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Authors and Affiliations

  1. Departments of Medicine and Anatomy and Cell Biology, The Kidney Institute, 3901 Rainbow Boulevard, University of Kansas Medical Center, Kansas City, 66160, KS, USA

    Jared J. Grantham, Sumanth Mulamalla & Katherine I. Swenson-Fields

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  1. Jared J. Grantham
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  2. Sumanth Mulamalla
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  3. Katherine I. Swenson-Fields
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All authors contributed equally to all aspects of this Review.

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Correspondence to Jared J. Grantham.

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Competing interests

J. J. Grantham has been a consultant for Otsuka Pharmaceutical Group. The other authors declare no competing interests.

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Grantham, J., Mulamalla, S. & Swenson-Fields, K. Why kidneys fail in autosomal dominant polycystic kidney disease. Nat Rev Nephrol 7, 556–566 (2011). https://doi.org/10.1038/nrneph.2011.109

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