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Crystal nephropathies: mechanisms of crystal-induced kidney injury

Nature Reviews Nephrology volume 13, pages 226–240 (2017)Cite this article

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Key Points

  • Crystals cause several types of kidney injury: renovascular damage (type 1), tubular damage (type 2), and urolithiasis (type 3)

  • Renovascular damage (type 1) due to cholesterol crystals (from plaques in cholesterol embolism, for example) leads to ischaemic renal necrosis; stenotic atherosclerosis of renal arteries causes renal atrophy owing to chronic ischaemia

  • Tubular crystallopathy type 2 involves crystals of endogenous metabolites, minerals or proteins or exogenous drugs and toxins and causes acute necroinflammation, tubule obstruction or crystal granuloma formation and chronic tissue remodelling

  • In urolithiasis (type 3 crystallopathy), crystals form at the papilla or in the ducts of Bellini and grow to form calculi and stones, which cause colic, infections, and obstruction-related nephron loss

  • The molecular mechanisms of crystal-induced tissue injury and remodeling have become an exciting area of basic and translational research

Abstract

Crystals can trigger a wide range of kidney injuries that can lead to acute kidney injury, chronic kidney disease, renal colic or nephrocalcinosis, depending on the localization and dynamics of crystal deposition. Studies of the biology of crystal handling by the kidney have shown that the formation of different crystals and other microparticles and the associated mechanisms of renal damage share molecular mechanisms, such as stimulation of the NLRP3 inflammasome or direct cytotoxicity through activation of the necroptosis signalling pathway. By contrast, crystal granuloma formation is limited to chronic crystallopathies that lead to chronic kidney disease and renal fibrosis. Here, we discuss current understanding of the pathomechanisms underlying the different types of crystal-induced kidney injury and propose a classification of crystal nephropathies based on the localization of crystal deposits in the renal vasculature (type 1), the nephron (type 2), or the draining urinary tract (type 3). Further exploration of the molecular mechanisms of crystal-induced kidney injury and renal remodelling might aid the development of innovative cures for these diseases.

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Figure 1: Histopathological changes in vascular crystal nephropathies (type 1).
Figure 2: Histopathological changes in nephron-associated crystal nephropathies (type 2).
Figure 3: Molecular mechanisms of crystal-induced necroinflammation.
Figure 4: Tissular changes in crystalline CKD.
Figure 5: Mechanisms of crystal granuloma formation.
Figure 6: Endoscopic and histopathologic changes in papillary biopsy samples from stone formers.
Figure 7: Overview of crystal deposition in the different compartments of the kidney and segments of the nephron.

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Change history

  • 01 March 2017

    In the html version of this article originally published online, Dr Helen Liapis was not acknowledged for the images that she supplied (FIG. 1a,b,c; FIG.2a–i; FIG. 4b,c) in the respective figure legends. This error has now been corrected.

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Acknowledgements

S.R.M and H.-J.A. are supported by the Deutsche Forschungsgemeinschaft (MU 3906/1-1, AN372/14-3, AN372/16-1, AN372/20-1, and AN372/23-1).

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  1. Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU Munich, Ziemssenstrasse 1, 80336, München, Germany

    Shrikant R. Mulay & Hans-Joachim Anders

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  1. Shrikant R. Mulay
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Both authors contributed equally to researching data for the article, discussing the article's content, writing the article and reviewing and editing of the manuscript before submission.

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Correspondence to Hans-Joachim Anders.

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H.-J.A. has received consultancy fees from Roche, Bayer, Janssen, and lecture fees from Novartis, Amgen, Fresenius, and Roche. S.R.M. declares no competing interests.

PowerPoint slides

Glossary

Crystallization

Periodic self-aggregation of atoms, ions or misfolded proteins into a highly ordered solid structure consisting atoms, molecules or ions.

Crystalluria

Presence of crystals in urine.

Inflammasome

Multiprotein oligomer complex present in the cytosol that activates the inflammatory caspase 1 and sometimes caspase 5 (in mice caspase 11) to cleave pro-IL-1β and pro-IL-18 into respective mature forms and eventually induce pyroptosis, a form of regulated necrosis that mainly occurs upon recognition of bacterial endotoxin inside the cytoplasm of infected macrophages.

Crystallopathies

Diseases caused by crystals or crystal-like microparticles.

Cholesterol embolism

Obstruction of a blood vessel by cholesterol crystals that are released from an atherosclerotic plaque in veins.

Acral ischaemia

Ischaemia of the tips of the fingers or toes due to the obstruction of terminal arteries.

Necroptosis

Form of regulated necrosis that involves the RIPK3/MLKL pathway triggered by TNFR1, TLR4/TRIF, TLR3/TRIF, CD95 or IFNγ/STAT3 signalling pathways.

Niemann–Pick disease

Inherited metabolic disorder caused by sphingomyelin accumulation in lysosomes.

Crystalglobulinaemia

Presence of cryoglobulin crystals in serum.

Crystal-storing histiocytosis

Presence of cryoglobulin crystals in histiocytes (tissue macrophages).

Hepatorenal syndrome

Particular type of kidney failure that affects patients with hepatic dysfunction (cirrosis, fulminant liver failure or portal hypertension and ascites).

Rhabdomyolysis

Condition involving rapid break down of damaged skeletal muscles.

Nephrocalcinosis

Deposition of calcium salts such as calcium phosphate and calcium oxalate in the parenchyma of the kidney.

Necroinflammation

Amplification loop between cell necrosis and inflammation.

Ferroptosis

Iron-dependent form of regulated necrosis that involves impaired glutathione peroxidase 4 function and leads to lethal accumulation of lipid peroxides.

Damage-associated molecular pattern

(DAMP). Intracellular components that induce inflammation by activating receptors of the innate immune system on other cells when released into extracellular space after cell necrosis.

Cystinosis

Genetic metabolic disease involving accumulation of cystine in various organs.

Extratubulation

Process of translocation of crystal plugs from the tubular lumen to the interstitium.

Tubule plugs

Cast-like plugs of crystals that form inside the lumen of renal tubules.

Brushite

Phosphate mineral in complex with calcium (CaHPO4·2H2O).

Hydroxyapatite

Crystals of calcium phosphate usually present in bones, kidney stones, and vascular calcifications.

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Mulay, S., Anders, HJ. Crystal nephropathies: mechanisms of crystal-induced kidney injury. Nat Rev Nephrol 13, 226–240 (2017). https://doi.org/10.1038/nrneph.2017.10

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