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Crystalline nephropathies.

A 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. Because the kidney functions as a filtering organ that receives 25% of the cardiac output and concentrates ions and molecules in the renal tubules in the course of plasma filtration and urine formation, the kidney is a prime site for crystal deposition. 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. The clinical presentation of the crystalline nephropathies may be acute or chronic and is characterized mainly by the development of renal insufficiency, which is often largely irreversible. Although proteinuria and hematuria may occur, the proteinuria is typically subnephrotic, and the hematuria is not accompanied by the formation of red blood cell casts.

This review will focus on the major crystalline nephropathies encountered by pathologists in renal biopsy, nephrectomy, or autopsy specimens. The crystalline nephropathies will be divided into 4 broad categories based on either the composition of the crystals or the clinical setting in which they are formed, with the goal of helping the pathologist accurately identify the material and suggest the appropriate differential diagnosis. 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. These disorders are particularly challenging because they require the pathologist to deduce the nature of the crystals from a variety of clues, rather than by direct chemical identification.

DYSPROTEINEMIA-RELATED CRYSTALLINE NEPHROPATHIES

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. Although dysproteinemia can cause a diverse spectrum of renal disease, there are only 3 crystalline nephropathies seen in this setting.

Light chain cast nephropathy, also known as myeloma cast nephropathy, merits brief discussion because it is the most common dysproteinemia-related renal disease, (1) and it can have a distinctly "crystalline" appearance. The 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. (2) By light microscopy, the proximal tubules often show diffuse acute tubular injury, although in early cases, this injury may be mild and localized. The distal tubules contain distinctive, atypical casts that typically appear hypereosinophilic, pale with periodic acid-Schiff stain, and polychromatic (mixed red and blue) and lamellated with Masson trichrome stain. Light chain casts have a hard texture and often fracture when cut with a microtome, resulting in sharp or jagged edges and internal lines of fracture. Occasionally, light chain casts assume rhomboidal, needle-shaped, or other striking geometric forms. These atypical casts often elicit a "cellular reaction" and may be surrounded by leukocytes or engulfed by multinucleated giant cells (Figure 1, A through C). Immunofluorescence plays a critical role in the diagnosis of light chain cast nephropathy and usually reveals dominant staining for either [kappa] or [lambda] light chain with minimal or absent staining for the reciprocal light chain (Figure 1, D). In rare cases, mutated monoclonal light chains fail to bind to commercially available antibodies, leading to false-negative immunofluorescence staining. By electron microscopy, the light chain casts are highly electron dense and may exhibit sharp edges, geometric shapes, and cellular reaction by dehisced tubular epithelial cells, infiltrating leukocytes, and giant cells.

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Light chain Fanconi syndrome (LCFS) is a clinical-pathologic entity 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 clinical evidence of full or partial Fanconi syndrome, the alternative term light chain proximal tubulopathy 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. On high-power examination, proximal tubular epithelial cells may show intracytoplasmic accumulations of needle-shaped crystals that are eosinophilic, typically pale with periodic acid-Schiff and red with Masson trichrome (Figure 2, A). To complicate matters, standard direct immunofluorescence performed on frozen tissue often fails to demonstrate the light chain composition of the crystals because the highly crystallized light chains are relatively inaccessible to antibody binding. Better results can be obtained when immunofluorescence is performed on formalin-fixed, paraffin-embedded sections, following antigen retrieval by digestion with pronase or another protease (Figure 2, B). (3) When light-microscopic findings are subtle and immunofluorescence findings are inconclusive, LCFS may not be evident until electron microscopy is performed. Ultrastructural examination of the proximal tubular cells reveals abundant intracytoplasmic electron dense crystals (Figure 2, C), some of which may appear membrane-bound, suggesting incorporation into phagolysosomes (Figure 2, D).

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Because of the rarity of the condition, the literature on LCFS is limited to case reports and small case series. (4-6) 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. Rare cases of LCFS have also been reported in the setting of chronic lymphocytic leukemia/small lymphocytic lymphoma (7,8) and diffuse large B-cell lymphoma. (9) Almost universally, crystals of LCFS are composed of monoclonal [kappa] light chains, typically derived from the V[kappa]1 variability subgroup and are resistant to proteolysis by lysosomal enzymes of the proximal tubule, in particular cathepsin B. (6,10,11) In a transgenic murine model of LCFS, the mouse JK region was replaced by the VK-JK gene from a patient with LCFS. The mice developed proximal tubular crystals similar to those seen in the original patient, supporting the concept that the development of light-chain crystals is determined by the physical and chemical properties unique to the amino acid sequence of the monoclonal light chain. (12)

Crystal-storing histiocytosis is another rare condition associated with dysproteinemia, and it has significant overlap with LCFS. Crystal-storing histiocytosis is characterized by accumulation of light chain crystals within histiocytes and is typically seen in the bone marrow but often involves extramedullary sites, including the kidney. The crystals typically stain in the same manner as those described for LCFS and have a similar ultrastructural appearance but are located in histiocytes, rather than proximal tubular cells (Figure 3, A and B). 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. (13-15) The pathomechanism of crystal-storing histiocytosis is likely similar to that of LCFS. Lebeau and colleagues (16) reported a case of crystal-storing histiocytosis caused by a light chain from the V[kappa]1 variability subgroup with several unusual amino acid substitutions that appeared to promote crystal-logenesis and prevent intralysosomal degradation.

DRUG-INDUCED CRYSTALLINE NEPHROPATHIES

Crystalline nephropathy 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 the degree of supersaturation within distal tubules (dependent on hydration and drug dosage) and urine pH. Yarlagadda and Perazella (17) have reviewed medication-induced crystal nephropathy comprehensively. Here, we restrict our discussion to 3 of the most common agents associated with this condition.

[FIGURE 3 OMITTED]

Sulfadiazine, one of the oldest sulfa drugs, was widely used in the mid-1900s and has been a well-documented cause of crystalluria since the 1940s. Its usage declined sharply as more soluble sulfa derivatives became available. Recent years have witnessed a resurgence in its use as a result of the HIV epidemic because sulfadiazine paired with pyrimethamine is the treatment of choice for Toxoplasma encephalitis. Accordingly, the renal toxicity of sulfadiazine has been "rediscovered." (18) Sulfadiazine and its metabolites have low urinary solubility, especially in acidic urine and can crystallize, causing 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. (19)

Acyclovir is a widely used antiviral drug that can cause crystalluria and crystal nephropathy, particularly when administered through rapid intravenous infusion or in high doses. Oral therapy and low-dose infusions almost never result in crystal precipitation, unless the patient is profoundly dehydrated or the oral dose is excessive. (17) The crystals are typically needle-shaped, polarizable, and are visible in the renal tubules and urine of patients with acyclovir-induced crystalline nephropathy. (20)

Indinavir, a protease inhibitor used in the treatment of HIV infection, is a well-documented cause of crystal-induced acute kidney injury and chronic kidney disease. (21,22) Kopp et al (23) reported crystalluria in 20% of patients on indinavir and urologic symptoms in 8%. Crystals in the urine range from irregular plate forms to needle-shaped crystals and starburst aggregates. (23) Needle-shaped crystals may aggregate in collecting ducts forming obstructive casts (Figure 4). Discontinuation of indinavir, coupled with increased hydration and acidification of the urine, generally reverses the nephrotoxicity; however, late recognition may result in irreversible kidney damage. (17)

CALCIUM-CONTAINING CRYSTALLINE 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 tinctorial properties. Oxalate crystals typically appear translucent, whereas calcium phosphate crystals often appear blue or purple in sections stained with hematoxylin-eosin (Figure 5, A and C). Furthermore, the von Kossa stain reacts with the phosphate moiety of calcium phosphate and, therefore, does not stain calcium oxalate (Figure 5, B), whereas only calcium oxalate crystals are birefringent under polarized light (Figure 5, D). Alizarin red S stains calcium specifically, reacting with calcium phosphate at pH 7 and pH 4.2 and reacting with calcium oxalate at pH 7 (but not at pH 4.2). (24) Sparse tubular or interstitial calcifications are frequently encountered as a nonspecific, incidental finding in many clinical settings. However, when tubular and/or interstitial calcifications are numerous and diffuse, the diagnoses of nephrocalcinosis, phosphate nephropathy, and oxalate nephropathy must be considered.

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[FIGURE 5 OMITTED]

Nephrocalcinosis is a crystalline nephropathy characterized by abundant tubular and interstitial deposits of calcium phosphate, accompanied by varying degrees of acute tubular injury and chronic tubulointerstitial scarring. 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. The most common conditions associated with hypercalcemia are primary hyperparathyroidism, malignancy, milk alkali syndrome, (25) and chronic granulomatous diseases, such as sarcoidosis. (26) Heritable diseases, including Dent disease, may present with nephrocalcinosis in childhood and should be clinically investigated in the pediatric population. (27)

In our experience at Columbia University, 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. (28) In this setting, the term phosphate nephropathy (rather than nephrocalcinosis) is preferred. The pathophysiology of phosphate nephropathy likely relates to both massive phosphate intake and the diarrhea and resultant dehydration that accompany the use of oral sodium phosphate bowel purgatives. Proximal tubular phosphate reabsorption is rapidly reduced in the setting of high serum phosphate levels, resulting in increased delivery of phosphate to the distal nephron. If hypovolemia is present, water and other salts are avidly reabsorbed in the proximal nephron, which is relatively impermeable to calcium and phosphate. The net effect is to concentrate calcium and phosphate to high levels in the lumen of the distal nephron, which is the site where calcium phosphate crystals precipitate in phosphate nephropathy. (29) Most patients with phosphate nephropathy develop irreversible renal failure. (30) In December 2008, the US Food and Drug Administration issued an alert that over-the-counter oral sodium phosphate solutions should no longer be used for bowel cleansing, and the products were subsequently, voluntarily withdrawn from the market. Oral sodium phosphate remains available in tablet form, by prescription only.

Oxalate nephropathy is seen in a variety of clinical settings and may result from enteric hyperoxaluria, toxic exposures, excessive dietary intake of oxalate, and inborn errors of metabolism. Enteric hyperoxaluria, the most common etiology of oxalate nephropathy, is caused by fat and/or bile acid malabsorption, leading to steatorrhea. Under normal conditions, calcium and oxalate complex with each other in the colonic lumen and are excreted in the feces. 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. (31) In addition, the presence of high levels of free fatty acids and bile salts enhances colonic mucosal permeability to oxalate, further promoting oxalate absorption. (32) Enteric hyperoxaluria resulting from chronic steatorrhea can be seen in patients with inflammatory bowel disease, pancreatic insufficiency, or following bowel surgery. Oxalate nephropathy leading to irreversible renal failure is a well-described complication of jejunoileal bypass, one of the early surgical approaches for correction of morbid obesity, (33) and continues to be seen as a complication of roux-en-Y gastric bypass. (34) 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. (35)

The most common toxic exposure associated with the development of acute and largely irreversible oxalate nephropathy is ingestion of ethylene glycol (antifreeze). (36,37) Ethylene glycol is metabolized predominantly by alcohol dehydrogenase and aldehyde dehydrogenase to produce metabolites, including glycolate, which causes acute tubular injury, and oxalic acid, which binds calcium to form calcium oxalate that precipitates in the kidney. (38) Excessive intake of vitamin C, which is metabolized to oxalate, can also result in oxalate nephropathy. (39) Oxalate nephropathy can also be seen in several hereditary enzymatic defects known collectively as the primary hyperoxalurias. (40) These metabolic defects should be considered in pediatric patients and in individuals who lack an alternative explanation for the development of hyperoxaluria.

CRYSTALLINE NEPHROPATHIES RELATED TO METABOLIC DISORDERS

Crystalline nephropathies can be observed in a variety of inherited or acquired metabolic disorders. Urate crystal deposition in the kidney is the most common and can present as acute uric acid nephropathy, chronic urate nephropathy, or uric acid nephrolithiasis. Acute uric acid nephropathy typically presents as oliguric or anuric acute renal failure and is most frequently seen in the setting of massive tissue destruction because of tumor lysis syndrome. (41) Histologically there is diffuse acute tubular injury accompanied by uric acid crystals located predominantly in the collecting tubules. In formalin-fixed tissue, urate crystals are largely dissolved in processing, leaving behind empty lacunae. 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. Acute uric acid nephropathy is largely preventable with aggressive hydration, urine alkalinization, and treatment with either recombinant urate oxidase (which converts uric acid to allantoin, which is water soluble) or allopurinol (which inhibits xanthine oxidase, thereby reducing uric acid production). (42)

Chronic urate nephropathy is seen in both primary and secondary forms of gout. Clinically, it is difficult to separate chronic kidney disease due to urate nephropathy from chronic kidney disease due to other chronic medical conditions, such as hypertension. With improved management of chronic hyperuricemia, the incidence and severity of chronic urate (gouty) nephropathy have decreased. (43) To adequately evaluate for the presence or absence of gouty nephropathy, a biopsy must include renal medulla, the site where urate crystals predominate. The medullary interstitium is often scarred and collecting tubules typically contain elongated or rectangular urate crystals. Crystalline deposits resembling microtophi seen elsewhere in the body may form in the medullary interstitium, consisting of radially oriented crystals of uric acid or monosodium urate, which evoke an inflammatory reaction, often with granulomatous features (Figure 6, A). 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 is an 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. Although cystinosis can 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. In fact, both infantile and adolescent presentations can occur in different members of the same family. (44) The crystals of cystinosis can be identified in glomerular podocytes, mesangial cells, interstitial macrophages, and occasionally in tubular cells and tubular lumina. Intracellular crystals are typically small and needle-shaped or rhomboidal. Crystals are typically dissolved during processing with aqueous solutions but may be seen in frozen sections of unfixed tissues and are strongly birefringent under polarized light. (45) The finding of multinucleated podocytes is often a helpful clue to the diagnosis (Figure 6, B). (46)

Crystalline nephropathy due to 2,8-dihydroxyadeninuria results from a rare autosomal recessive disorder characterized by complete loss of adenine phosphoribosyltransferase. This nephropathy is probably underrecognized because it is readily 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 (Figure 6, C and D). Accurate diagnosis is essential because treatment with allopurinol may improve renal function and prevent further crystal deposition. (47) If the diagnosis is suspected, testing to confirm the absence of adenine phosphoribosyltransferase in red blood cells and the presence of 2,8-dihydroxyadeninuria in the urine is available.

[FIGURE 6 OMITTED]

CONCLUSION

Accurate classification of crystalline nephropathies can provide essential information enabling the diagnosis of conditions ranging from hematologic malignancy to drug toxicity to metabolic disorders. Because 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.

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Leal C. Herlitz, MD; Vivette D. D'Agati, MD; Glen S. Markowitz, MD

Accepted for publication January 10, 2012.

From the Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital, New York.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Leal C. Herlitz, MD, Department of Pathology and Cell Biology, Columbia University Medical Center, 630 W 168th St, VC14-224, New York, NY 10032 (e-mail: LB684@columbia.edu).
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Author:Herlitz, Leal C.; D'Agati, Vivette D.; Markowitz, Glen S.
Publication:Archives of Pathology & Laboratory Medicine
Date:Jul 1, 2012
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