Crystalline nephropathies

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 A cute uric acid nephropathy, C hronic urate nephropathy U ric 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.