Crystalline nephropathies

1. Crystalline Nephropathies
Leal C. Herlitz, MD; Vivette D. D’Agati,
MD; Glen S. Markowitz, MD
Arch Pathol Lab Med—Vol 136, July 2012, 713-721

2. • Crystal is a homogeneous solid composed of
atoms, ions, or molecules that have a fixed
distance between the constituent parts,
forming an orderly, repeating, 3- dimensional
pattern.

3. • The kidney is a favored site for crystal
deposition because of the high concentration
of ions and molecules reached at the level of
the renal tubules in the course of filtration

4. • Crystalline nephropathy is a term applied to
patterns of renal injury that share the
distinctive finding of abundant crystals, most
frequently involving the tubules and
interstitium.

5. • The clinical presentation of the crystalline
nephropathies may be acute or chronic
• Characterized mainly by the development of
renal insufficiency, which is often largely
irreversible.
• The proteinuria is typically subnephrotic, and the
hematuria is not accompanied by the formation
of red blood cell casts

6. • The crystalline nephropathies are divided into
4 broad categories based
– on either the composition of the crystals or
– the clinical setting in which they are formed

7. • The 4 categories include
– (1) crystalline nephropathies seen in the setting of
dysproteinemia
– (2) drug-induced crystalline nephropathies
– (3) crystalline nephropathies related to calcium
deposition, and
– (4) metabolic and genetic forms of crystalline
nephropathy.

8. DYSPROTEINEMIA-RELATED
CRYSTALLINE NEPHROPATHIES

9. • Dysproteinemia is the clinical state
characterized by excessive synthesis of
immunoglobulin molecules or subunits,
resulting from clonal plasma cell proliferations
or B-cell lymphoproliferative disorders
• There are only 3 crystalline nephropathies
seen in this setting.

10. Light chain cast nephropathy
• Myeloma cast nephropathy
• Most common dysproteinemia-related renal
disease and it can have a distinctly ‘‘crystalline’’
appearance
• Casts are composed predominantly of a single
monoclonal light chain, which is typically admixed
with Tamm-Horsfall protein secreted by the thick
ascending limb of Henle.

11. • Patients with light chain cast nephropathy
usually present with acute kidney injury, and
approximately 90% of patients meet the
criteria for multiple myeloma

12. Light chain casts are located within distal tubules, appear hypereosinophilic, and
range from needle shaped crystals to irregular, polygonal shapes with sharp edges
and lines of fracture. Several of the casts are partially engulfed by giant cells.
The distinctive casts of light chain cast nephropathy stain minimally with periodic
acid–Schiff (B)

13. Appear polychromatic (mixed red and blue) with the Masson trichrome stain (C).
Proximal tubules show acute tubular injury with loss of apical brush border.
D, Immunofluorescence staining for k light chain reveals strong positivity in a cast that
has been fractured during sectioning, producing the sharp edges often seen in light chain
cast nephropathy.

14. Light chain Fanconi syndrome (LCFS)
• Rare condition, characterized by accumulation of light
chain crystals within proximal tubular cells.
• The clinical onset is often insidious, and the proximal
tubular damage caused by the crystals typically
manifests with features of Fanconi syndrome, including
– normoglycemic glycosuria,
– aminoaciduria,
– hyperuricosuria,
– hyperphosphaturia, and
– type II renal tubular acidosis.

15. • In the absence of documented clinical
evidence of full or partial Fanconi syndrome,
the alternative term light chain proximal
tubulopathy may be applied.

16. • Light chain Fanconi syndrome is a difficult
diagnosis to establish because the light
microscopic findings are often subtle.
• Nonspecific findings, such as mild acute
tubular injury and tubular atrophy with
interstitial fibrosis, may be the only changes
evident by light microscopy

17. Proximal tubular cells are distended by needle-shaped, eosinophilic, cytoplasmic
crystals.
Immunofluorescence staining for k light chain, performed after pronase digestion on
paraffin sections, shows abundant intratubular needle-shaped crystals that stain strongly
and solely for k light chain.

18. C, Electron microscopy reveals electron-dense, geometric crystals within the
cytoplasm of proximal tubular epithelial cells.
D, High-power, ultrastructural examination of the light chain crystals frequently
reveals an organized, repeating substructure, such as the regularly spaced vertical
striations seen in this crystal. The crystal appears to be at least partially membrane
bound, possibly lying within a phagolysosome

19. • Light chain Fanconi syndrome predominantly
occurs in patients with plasma cell dyscrasias,
– most of whom have smoldering myeloma or,
– less commonly, ‘‘high mass’’ multiple myeloma or
monoclonal gammopathy of undetermined
significance.
• Rarely,
– chronic lymphocytic leukemia/small lymphocytic
lymphoma
– diffuse large B-cell lymphoma.

20. • Almost universally, crystals of LCFS are composed
of monoclonal k light chains,
– typically derived from the Vk1 variability subgroup
– are resistant to proteolysis by lysosomal enzymes of
the proximal tubule, in particular cathepsin

21. Crystal-storing histiocytosis
• Rare condition associated with
dysproteinemia
• Significant overlap with LCFS.

22. Crystal storing histiocytosis. A, Histiocytes with hypereosinophilic, cytoplasmic light chain
crystals are seen infiltrating the renal interstitium. B, Electron microscopy reveals interstitial
histiocytes containing electron dense, needle-shaped crystals

23. • As in LCFS, most cases are caused by monoclonal
k light chains.
• Further evidence supporting the relatedness of
these conditions derives from case reports of
patients who simultaneously manifest both
crystal-storing histiocytosis and LCFS.
• The pathomechanism of crystal-storing
histiocytosis is likely similar to that of LCFS

24. DRUG-INDUCED CRYSTALLINE
NEPHROPATHIES

25. • May develop during the use of medications
that are excreted by the kidney.
• Intratubular precipitation of exogenously
administered medications or their metabolites
is typically influenced by
– degree of supersaturation within distal tubules
(dependent on hydration and drug dosage)
– urine pH

26. Sulfadiazine
• Recent years have witnessed a resurgence in
its use as a result of the HIV
• Low urinary solubility, especially in acidic
urine and can crystallize
• Obstruction at any level in the urinary tract
from renal tubules to the bladder.

27. • Sulfadiazine crystals typically resemble
sheaves of wheat, with an hourglass shape
that shows prominent radial striations.
• Monitoring the urine for evidence of
crystalluria has been recommended to detect
potential toxicity before the development of
serious renal injury

28. Acyclovir
• Widely used antiviral drug
• Cause crystalluria and crystal nephropathy,
particularly when administered through rapid
intravenous infusion or in high doses.
• Typically needle-shaped, polarizable, and are
visible in the renal tubules and urine of patients
with acyclovir-induced crystalline nephropathy

29. Indinavir
• Protease inhibitor
• Well-documented cause of crystal induced
acute kidney injury and chronic kidney disease
• Crystals in the urine range from irregular plate
forms to needle-shaped crystals and starburst
aggregates

30. Distal tubular casts composed of abundant, clear, needle-shaped
crystals, some of which appear to have dissolved in processing. Many of
the individual crystals are surrounded by intratubular macrophages

31. CALCIUM-CONTAINING
CRYSTALLINE NEPHROPATHIES

32. • Phosphate and oxalate are the 2 calcium salts
that commonly crystallize in the kidney.
• Calcium phosphate and calcium oxalate
crystals can be distinguished by their tinctorial
properties.

33. A case of phosphate nephropathy with abundant, basophilic, calcium phosphate crystals
in distal tubules. B, Calcium phosphate crystals show a positive reaction with the von
Kossa stain. Calcium oxalate crystals are translucent when viewed by standard light
microscopy (C) but are strongly birefringent under polarized light (D)

34. • Nephrocalcinosis is a crystalline nephropathy
characterized by
– abundant tubular and interstitial deposits of
calcium phosphate
– varying degrees of acute tubular injury and
chronic tubulointerstitial scarring

35. • The finding of abundant calcium phosphate
deposits in renal biopsy or nephrectomy
specimens should prompt careful clinical
correlation to identify underlying diseases
associated with
– hypercalcemia,
– excessive dietary calcium intake, or
– exposure to bowel preparations containing high
levels of phosphate.

36. • Histologic findings of nephrocalcinosis most
commonly result from exposure to the high-phosphate
content of oral sodium phosphate
bowel purgatives used for bowel cleansing before
colonoscopy.
• In this setting, the term phosphate nephropathy
(rather than nephrocalcinosis) is preferred
• Most patients with phosphate nephropathy
develop irreversible renal failure

37. Oxalate nephropathy
• seen in a variety of clinical settings
• may result from
– Enteric hyperoxaluria
– Toxic exposures
– Excessive dietary intake of oxalate
– Inborn errors of metabolism.

38. • Enteric hyperoxaluria
– the most common etiology of oxalate
nephropathy
– caused by fat and/or bile acid malabsorption,
leading to steatorrhea

39. • In the setting of fat malabsorption, high levels of
free fatty acids are present in the intestinal lumen
and bind calcium, thereby reducing the amount
of free calcium available to bind oxalate.
• This results in high intestinal levels of free
oxalate, which is readily absorbed by the colonic
epithelium and ultimately precipitates as calcium
oxalate crystals in the kidney.

40. • In addition, the presence of high levels of free
fatty acids and bile salts enhances colonic
mucosal permeability to oxalate, further
promoting oxalate absorption.
• Enteric hyperoxaluria resulting from chronic
steatorrhea can be seen in patients with
– inflammatory bowel disease,
– pancreatic insufficiency, or
– following bowel surgery

41. • Oxalate nephropathy is a well-described
complication of jejunoileal bypass and roux-en-
Y gastric bypass.
• Gastrointestinal lipase inhibitors, such as
orlistat, used to induce weight loss in obese
patients can also produce sufficient
steatorrhea to cause enteric hyperoxaluria and
oxalate nephropathy

42. • The most common toxic exposure associated with the
development of acute and largely irreversible oxalate
nephropathy is ingestion of ethylene glycol (antifreeze)
• Ethylene glycol is metabolized predominantly by
alcohol dehydrogenase and aldehyde dehydrogenase
to produce metabolites,
– glycolate, which causes acute tubular injury, and
– oxalic acid, which binds calcium to form calcium oxalate
that precipitates in the kidney

43. • Excessive intake of vitamin C, which is
metabolized to oxalate, can also result in oxalate
nephropathy.
• Oxalate nephropathy can also be seen in several
hereditary enzymatic defects known collectively
as the primary hyperoxalurias.
– considered in pediatric patients and in individuals who
lack an alternative explanation for the development of
hyperoxaluria

44. CRYSTALLINE NEPHROPATHIES
RELATED TO
METABOLIC DISORDERS

45. Uric acid nephropathy
• Crystalline nephropathies can be observed in a
variety of inherited or acquired metabolic
disorders.
• Urate crystal deposition in the kidney is the
most common
– Acute uric acid nephropathy,
– Chronic urate nephropathy
– Uric acid nephrolithiasis

46. • Acute uric acid nephropathy typically presents as
– oliguric or anuric acute renal failure
– frequently seen in the setting of massive tissue
destruction
• Histologically there is diffuse acute tubular injury
accompanied by uric acid crystals located
predominantly in the collecting tubules

47. • If frozen sections or alcohol-fixed specimens
are examined, the urate crystals stain blue
with hematoxylin and are birefringent under
polarized light.
• The crystals are typically needle-shaped or
rectangular and occasionally incite an
interstitial inflammatory response.

48. • Chronic urate nephropathy is seen in both
primary and secondary forms of gout
• To adequately evaluate for the presence or
absence of gouty nephropathy, a biopsy must
include renal medulla, the site where urate
crystals predominate.

49. • The medullary interstitium is often scarred
and collecting tubules typically contain
elongated or rectangular urate crystals.

50. Chronic uric acid nephropathy is characterized by urate granulomas composed of
aggregates of crystals surrounded by palisading histiocytes, with or without
accompanying multinucleated giant cells.

51. • The crystals are best preserved in alcohol-fixed
specimens, where they appear
basophilic and birefringent under polarized
light.
• Formalin fixation dissolves most of the crystals
leaving empty lacunae with only rare, faintly
blue crystals that usually fail to polarize well

52. Cystinosis
• Cystinosis
– inherited disorder
– characterized by defective transport of cystine across
lysosomal membranes resulting in systemic accumulation.
• In the kidney, this produces tubular dysfunction,
sometimes manifesting as Fanconi syndrome.
• Manifest either in infancy or adolescence
– mutations in the same gene, CTNS, which encodes
cystinosin, appear to be involved in all forms of the
disease.

53. • The crystals of cystinosis can be identified in
– glomerular podocytes,
– mesangial cells,
– interstitial macrophages,
– tubular cells and tubular lumina. (occasional )
• Intracellular crystals are typically small and needle-shaped
or rhomboidal.
• Crystals are typically dissolved during processing with
aqueous solutions
– may be seen in frozen sections of unfixed tissues and are
strongly birefringent under polarized light

54. The finding of a multinucleated podocyte (at the 3-o’clock position) is a clue to the
diagnosis of cystinosis, which is a difficult diagnosis to establish because the
crystals typically dissolve in routine processing.

55. 2,8-dihydroxyadeninuria
• Crystalline nephropathy due to 2,8-dihydroxyadeninuria
– rare autosomal recessive disorder
– characterized by complete loss of adenine
phosphoribosyltransferase.
• Accurate diagnosis is essential because treatment with
allopurinol may improve renal function and prevent further
crystal deposition.
• If the diagnosis is suspected,
– testing to confirm the absence of adenine
phosphoribosyltransferase in red blood cells
– presence of 2,8-dihydroxyadeninuria in the urine

56. Mistaken for oxalate nephropathy owing to the similar, strong birefringence of the crystals
under polarized light. In contrast to oxalate crystals, which are optically clear, 2,8-
dihydroxyadeninuria crystals are typically tinted brownish-green

57. CONCLUSION
• Many crystals have overlapping histologic
features and a variety of clinical entities can
produce a single crystalline nephropathy,
careful clinical-pathologic correlation is
essential in the interpretation of crystalline
nephropathies.