—  SPECIALTY CONFERENCE  —

Renal Pathology

Case 3 - Megalocytic Interstitial Nephritis

Cynthia C. Nast
Cedars-Sinai Medical Center and UCLA School of Medicine
Los Angeles, CA


Click on each slide thumbnail image for an enlarged view
Clinical History
The patient is a 29 year old Vietnamese woman who initially presented with an elevated serum creatinine level of 2.3 mg/dl and hypertension. At that time she had normal size kidneys by ultrasound and a normal serologic profile. She was treated with atenolol. One month later she developed nausea, vomiting and generalized fatigue, and was admitted. She had developed hematuria and dysuria 2 days prior to admission. She denied arthralgias, hemoptysis and rash.

Her physical exam was unremarkable with a well controlled blood pressure.

Laboratory studies at the time of admission revealed renal failure with a serum creatinine of 7.3 mg/dl and BUN 75 mg/dl. She was anemic with hematocrit 19 mg/dl. Serologic studies included ANA < 1:40, anti-double-stranded DNA < 1:5, C3 170 mg/dl and C4 42 mg/dl. Urine analysis showed pH 5.0, 3+ protein, large occult blood, TNTC RBCs and WBCs, and no casts. A renal biopsy was performed.


Case 3 - Figure 1 - The interstitium contains a diffuse infiltrate of large polygonal cell. There is acute tubular injury with cellular debris within tubular lumina. (Periodic acid-Schiff x 10)
Case 3 - Figure 2 - The infiltrating interstitial cells have PAS + cytoplasm and replace the renal parenchyma in this field. A tubule is ruptured with degenerating cellular material in the disrupted lumen. (Periodic acid-Schiff x 20)
Case 3 - Figure 3 - There is a heterogeneous interstitial infiltrate composed of histiocytes, lymphocytes and scattered neutrophils. (Hematoxylin and eosin x 20)


Case 3 - Figure 4 - The interstitial histiocytes have abundant cytoplasm with PAS + fine granules. A portion of a completely sclerotic glomerulus is present. (Periodic acid-Schiff x 40)
Case 3 - Figure 5 - The glomerulus is intact and shows mesangial expansion with mild segmental hypercellularity. The surrounding interstitium has a heterogeneous inflammatory infiltrate. (Periodic acid-Schiff x 20)
Case 3 - Figure 6 - Granular mesangial staining for IgA. (x 20)


Case 3 - Figure 7 - Transmission EM of an interstitial histiocyte. There are few cytoplasmic lipid vacuoles and electron dense lysosome-like structures. (x 5000)
Case 3 - Figure 8 - Transmission EM of a glomerulus. There are electron dense deposits in the mesangium beneath the paramesangial basement membrane. (x 5000)

Renal Biopsy Findings

Light microscopy
The specimen shows abnormalities of the tubulo-interstitium and glomeruli. The interstitium is diffusely edematous and infiltrated with a variety of leukocytes including neutrophils, lymphocytes and monocyte/histiocytes. The latter cells are forming large aggregates in focal areas, although more often are diffusely distributed. The histiocyte cytoplasm is abundant and frequently contains numerous fine PAS positive granules. Neutrophils are within tubules as well as the interstitium. Tubular cells often are necrotic, tubular lumina contain cellular debris, and few tubules are ruptured with extravasation of extra-tubular Tamm Horsfall protein. Focal tubular atrophy with interstitial fibrosis is evident. Sixty percent of the 15 glomeruli are completely sclerotic, and the remainder have mesangial widening with hypercellularity. PAS and Gram stains fail to reveal microorganisms.

Immunofluorescence microscopy
Glomeruli have mesangial staining for IgA, C3, and kappa and lambda light chains in a granular pattern.

Electron microscopy
The interstitial histiocytes focally contain lysosomal granules with variably electron dense material, but no bacteria or Michaelis-Gutmann bodies are observed. Glomeruli have electron dense deposits in mesangial regions

Diagnoses
Megalocytic interstitial nephritis
IgA nephropathy

Differential Diagnosis and Discussion
Megalocytic interstitial nephritis (MIN) is an uncommon inflammatory disease of the kidney. Grossly, it appears as focal gray or gray-yellow areas which may be discrete and nodular or confluent predominantly within the cortex. [1] Microscopically it is characterized by interstitial infiltration with large histiocytes of macrophage origin which have abundant eosinophilic cytoplasm, usually containing fine PAS positive granules. [2, 3] Ultrastructurally, these granules are phagolysosomes composed of electron dense granular material; electron lucent crystals similar to cholesterol and lipid vacuoles have been described in these cells as well. [4] No bacteria or fragments thereof are present. The interstitium also has variable numbers of lymphocytes, neutrophils and plasma cells, which may have the pattern of acute infectious interstitial nephritis. Glomeruli are spared

The differential diagnosis includes neoplastic and inflammatory conditions of the kidney. In reference to the former, megalocytic interstitial nephritis (MIN) may present as renal enlargement which on imaging studies appears as discrete cortical nodules imitating renal cell carcinoma. [5, 6] On core biopsy the large polygonal histiocytes, which frequently contain variable amounts of lipid histologically, may mimic this carcinoma as well. Alternatively, the kidneys often are bilaterally enlarged [7] and patients develop acute renal failure. In this setting the clinical impression is of an infiltrative process; in cases where the histiocyte intracytoplasmic granules are infrequent, the picture may emulate a large cell or histiocytic lymphoma.

MIN has many clinical and morphologic similarities to two related inflammatory lesions, malakoplakia and xanthogranulomatous interstitial nephritis (xanthogranulomatous pyelonephritis) (XGP). Differentiating between these processes is not always easy; however, there are some distinctions and it may be clinically relevant to do so. All three lesions appear to be an unusual inflammatory response and may have pathogenetic mechanisms in common. However, it is not clear to what extent they overlap.

Megalocytic interstitial nephritis first was described in 1945 by Zollinger [8], characterized by Ramsperger [3] in 1949 and related to malakoplakia in a series of cases by Ravel [9] in 1967. Many investigators are of the opinion that these lesions, particularly MIN and malakoplakia, are different stages of same disease. [5, 10, 11] Arguments in support of this concept include their often similar clinical presentation, bilaterality in both entities, similar prognosis, and their occurrence in patients with some form of immunologic compromise and/or gram negative bacillary infection. There are similar histologic features, particularly the diagnostic cell which is the large histiocyte containing PAS positive granules. The difference in malakoplakia, which defines this disease, is the presence in the histiocytes of Michaelis-Gutmann bodies which are intracytoplasmic concentrically lamellated inclusions containing calcium, phosphate and sometimes iron. [11] Experimental studies also suggest MIN and malakoplakia are within the same disease spectrum. Csapo induced a form of malakoplakia by injecting concentrated crude endotoxin-antigen complex of 075 Escherichia coli (Boivin antigen) into the kidneys and testes of rats; histiocytic infiltrates with Michaelis-Gutmann bodies were evident by 8 days following injection. [12] In further studies, Garret achieved similar results with Michaelis-Gutmann bodies appearing by 5 weeks. However, a lesion with the appearance of MIN was obtained using dilute Boivin antigen, suggesting MIN represents a similar host response dependent on varying magnitudes and time of injury. [13] MIN may have pathogenetic links to XGP as well, although similarities to malakoplakia are more pronounced. Both MIN and XGP contain histiocytes with intracytoplasmic lipid and PAS positive granules, although the former is far more apparent in XGP and the latter in MIN. Additionally, both lesions are found within the cortex.

To the contrary, there are factors indicating these entities may represent similar but distinct diseases. The clinical presentations may differ, with MIN more often resulting in renal failure. Malakoplakia occurs in extra-renal locations including the male and female reproductive tracts, breast and bladder while MIN is restricted to the kidney. Additionally, MIN is a cortical lesion which usually is bilateral while malakoplakia is found in the renal pelvis and is bilateral in only 40% of cases. XGP almost always is unilateral. Histiocytes have intracellular bacterial components and resulting formation of Michaelis-Gutmann bodies in malakoplakia [14], whereas in MIN they contain phagolysosomes with electron dense granular material and intracytoplasmic electron lucent crystalline structures similar to cholesterolbut without bacterial components. [4, 15] Therefore, it is not clear whether these are part of the same disease process or not, although most investigators favor a close relationship, suggesting MIN is a "prediagnostic" stage of malakoplakia and/or XGP.

The pathogenesis of MIN is not completely understood The underlying mechanisms likely are similar to those in malakoplakia, but no definitive studies have been done due to the infrequent incidence of MIN. There appears to be an unusual host response to bacterial infection, thought to be a form of aberrant bactericidal function by histiocytes and/or other inflammatory cells. In malakoplakia a number of leukocyte abnormalities have been described including dysfunctional cGMP affecting microtubules and microfilaments with aberrant phagocytic function, histiocytic elevated alpha-1 anti-trypsin, and transitory or persistently abnormal leukocyte function studies. [16, 17] Cledes has shown a transitory deficiency in the bactericidal function of neutrophils exposed to S. aureus in a patient with MIN who recovered renal function following antibiotic therapy. [18] This further supports the concept of impaired leukocyte function in both MIN and malakoplakia resulting in an atypical exuberant inflammatory response to infection.

The therapy of MIN is similar to that for malakoplakia and comprises antibiotics for the presumed underlying infection, with or without steroids to reduce the inflammatory component. The use of intracellularly active and cholinergic antibiotics has been advocated based on the possible pathogenetic mechanism of abnormal bactericidal activity. [19 ]Steroid therapy is controversial with varying results when this approach is used. [17]The short term response to treatment is variable, with some patients fully recovering. However, the prognosis is not as optimistic over the long term with chronic renal failure often ensuing. The sooner treatment is initiated, the more likely renal function will improve.

References

  1. Ravel R: Megalocytic interstitial nephritis: An entity probably related to malakoplakia. Am J Clin Pathol 47:781-789, 1967.
  2. Krupp G, Schneider W, Gobel U, Muller V, Haller H, Luft FC: Tumefactive megalocytic interstitial nephritis in a patient with Escherichia coli bacteremia. Am J Kidney Dis 25:928-933, 1995.
  3. Ramsperger W: Die grosszellig-interstitielle nephritis; doctoral thesis: University of Zurich, 1949.
  4. Kelley DR, Murad TM: Megalocytic interstitial nephritis, xanthogranulomatous pyelonephritis, and malakoplakia. An ultrastructural comparison. Am J Clin Pathol : 333-344, 1981.
  5. Esparza AR, McKay DB, Cronan JJ, Chazan JA: Renal parenchymal malakoplakia. Am J Surg Pathol 13:225-236, 1989.
  6. Gonzalez AC, Karcioglu Z, Waters BB, Weens HS: Megalocytic interstitial nephritis: ultrasonic and radiographic changes. Radiology 133:449-450, 1979.
  7. Jander HP, Pujara S, Murad TM: Tumefactive megalocytic interstitial nephritis. Radiology 129:635-636, 1978.
  8. Zollinger HU: Die interstitiell nephritis. Basel, Karger 1945, pp149-150.
  9. Ravel R: Megalocytic interstitial nephritis. An entity probably related to malakoplakia. Am J Clin Pathol 17:781-789, 1967.
  10. Jo S-K, Yun J-W, Cha D-R, Cho W-Y, Kim H-K, Won NH: Anuric acute renal failure secondary to magalocytic interstitial nephritis ina a patient with Behcet's disease. Clin Nephrol 54:498-500, 2000.
  11. Griggs WP, Hemstreet GP: Pathologic and immunologic considerations in malakoplakia. Urology 16:638-645, 1980.
  12. Al-Sulaiman MH, Al-Khader AA, Mousa DH, Al-Swailem RY, Dhar J, Haleem A: Renal parenchymal malacoplakia and megalocytic interstitial nephritis: clinical and histologic features. Am J Nephrol 13:483-488, 1993.
  13. Csapo Z, Kuithy E, Lantos J, Ormos J: Experimantally induced malakoplakia. Am J Pathol 79:453-464, 1975.
  14. Garrett IR, McClure J: Renal malakoplakia – experimental production and evidence of a link with interstitial megalocytic nephritis. J Pathol 236:111-122, 1982.
  15. Schreiber AG, Maderazo EG: Leukocytic function in malakoplakia. Arch Pathol Lab Med 102:534-537, 1978.
  16. Abdou NI, NaPombejara C, Sagawa A, Ragland C, Stechschulte DJ, Nilsson U, Gourley W, Watanabe I, Lindsey NJ, Allen MS: Malakoplakia: evidence for monocyte lysosomal abnormality correctable by cholinergic agonist in vitro and in vivo. N Engl J Med 297:1413-1419, 1977.
  17. Biggar WD, Crawford L, Cardella C, Bear RA, Gladman D, Reynolds WJ. Malakoplakia and immunosuppressive therapy. Reversal of clinical and leukocyte abnormalities after withdrawal of prednisone and azathioprine. Am J Pathol 119:5-11, 1985.
  18. Cledes J, Herve JP, Le Roy JP, Ferec C, Youinou P: Diminished bactericidal activity in megalocytic interstitial nephritis. Clin Nephrol 23:101-104, 1985.
  19. Dobyan DC, Truong LD, Eknoyan G: Renal malacopakia reappraised. Am J Kidney Dis 2:243-252, 1993.