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

• Crystal is a homogeneous solid composed ofatoms, ions, or molecules that have a fixeddistance between the constituent parts,forming an orderly, repeating, 3- dimensionalpattern.

• The kidney is a favored site for crystaldeposition because of the high concentrationof ions and molecules reached at the level ofthe renal tubules in the course of filtration

• Crystalline nephropathy is a term applied topatterns of renal injury that share thedistinctive finding of abundant crystals, mostfrequently involving the tubules andinterstitium.

• 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

• The crystalline nephropathies are divided into4 broad categories based

– on either the composition of the crystals or

– the clinical setting in which they are formed

• 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.

DYSPROTEINEMIA-RELATEDCRYSTALLINE NEPHROPATHIES

• Dysproteinemia is the clinical statecharacterized by excessive synthesis ofimmunoglobulin molecules or subunits,resulting from clonal plasma cell proliferationsor B-cell lymphoproliferative disorders

• There are only 3 crystalline nephropathiesseen in this setting.

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.

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

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

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.

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.

• In the absence of documented clinicalevidence of full or partial Fanconi syndrome,the alternative term light chain proximaltubulopathy may be applied.

• 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

Proximal tubular cells are distended by needle-shaped, eosinophilic, cytoplasmiccrystals. 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.

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

• 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.

• Almost universally, crystals of LCFS are composedof monoclonal k light chains,

– typically derived from the Vk1 variability subgroup

– are resistant to proteolysis by lysosomal enzymes ofthe proximal tubule, in particular cathepsin

Crystal-storing histiocytosis

• Rare condition associated with dysproteinemia

• Significant overlap with LCFS.

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

• As in LCFS, most cases are caused by monoclonalk light chains.

• Further evidence supporting the relatedness ofthese conditions derives from case reports ofpatients who simultaneously manifest bothcrystal-storing histiocytosis and LCFS.

• The pathomechanism of crystal-storinghistiocytosis is likely similar to that of LCFS

DRUG-INDUCED CRYSTALLINE NEPHROPATHIES

• May develop during the use of medicationsthat are excreted by the kidney.

• Intratubular precipitation of exogenouslyadministered medications or their metabolitesis typically influenced by– degree of supersaturation within distal tubules

(dependent on hydration and drug dosage)

– urine pH

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.

• 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

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

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

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

CALCIUM-CONTAININGCRYSTALLINE NEPHROPATHIES

• 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 tinctorialproperties.

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

• 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

• The finding of abundant calcium phosphatedeposits in renal biopsy or nephrectomyspecimens should prompt careful clinicalcorrelation to identify underlying diseasesassociated with

– hypercalcemia,

– excessive dietary calcium intake, or

– exposure to bowel preparations containing highlevels of phosphate.

• Histologic findings of nephrocalcinosis mostcommonly result from exposure to the high-phosphate content of oral sodium phosphatebowel purgatives used for bowel cleansing beforecolonoscopy.

• In this setting, the term phosphate nephropathy(rather than nephrocalcinosis) is preferred

• Most patients with phosphate nephropathydevelop irreversible renal failure

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.

• Enteric hyperoxaluria

– the most common etiology of oxalate nephropathy

– caused by fat and/or bile acid malabsorption, leading to steatorrhea

• 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.

• 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

• Oxalate nephropathy is a well-describedcomplication of jejunoileal bypass and roux-en-Y gastric bypass.

• Gastrointestinal lipase inhibitors, such asorlistat, used to induce weight loss in obesepatients can also produce sufficientsteatorrhea to cause enteric hyperoxaluria andoxalate nephropathy

• The most common toxic exposure associated with thedevelopment of acute and largely irreversible oxalatenephropathy is ingestion of ethylene glycol (antifreeze)

• Ethylene glycol is metabolized predominantly byalcohol dehydrogenase and aldehyde dehydrogenaseto produce metabolites,– glycolate, which causes acute tubular injury, and

– oxalic acid, which binds calcium to form calcium oxalatethat precipitates in the kidney

• Excessive intake of vitamin C, which ismetabolized to oxalate, can also result in oxalatenephropathy.

• Oxalate nephropathy can also be seen in severalhereditary enzymatic defects known collectivelyas the primary hyperoxalurias.– considered in pediatric patients and in individuals who

lack an alternative explanation for the development ofhyperoxaluria

CRYSTALLINE NEPHROPATHIES RELATED TO

METABOLIC DISORDERS

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

• 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

• 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.

• 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 uratecrystals predominate.

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

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

• 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

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.

• 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

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 thecrystals typically dissolve in routine processing.

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

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

CONCLUSION

• Many crystals have overlapping histologicfeatures and a variety of clinical entities canproduce a single crystalline nephropathy,careful clinical-pathologic correlation isessential in the interpretation of crystallinenephropathies.