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Although almost all pathological diagnoses made from a native kidney

biopsy come from careful examination of the renal cortex, certain dis-

eases have a characteristic medullary component. Medullary angiitis

has histological features of interstitial hemorrhage in the medulla with

an associated polymorphonuclear leukocyte infiltrate. These findings

are primarily found in the setting of antineutrophil cytoplasmic antibody-

associated vasculitis. Medullary angiitis identified in the setting of nega-

tive immunofluorescence is most suggestive of pauci-immune crescentic

glomerulonephritis, as presented in this case.

The gold standard for evaluation and proper classifi cation of kidney disease is microscopic examination of renal tis-sue. As noted by Pirani, “the adequacy of a needle biopsy is determined not by size (length) but by the presence

of renal cortex” (1). Glomerulonephritis can have characteristic cortical fi ndings, namely in the glomeruli. However, certain disease entities remain elusive without close inspection of the medulla. Medullary angiitis is an uncommon fi nding on renal biopsies with rare descriptions in the literature (2, 3). Th ese fi nd-ings are thought to be due to thrombosis of the vasa recta with subsequent medullary hemorrhage. Medullary angiitis is most commonly associated with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Increased awareness of this pathologic fi nding is needed, as medullary angiitis can be ignored or misdiagnosed as acute interstitial nephritis (4). Th is case describes the association between medullary angiitis and systemic vasculitis with a discussion of the underlying etiology.

CASE DESCRIPTIONA 64-year-old man with prior hypertension, obesity, gout,

and chronic kidney disease was admitted for evaluation of a rising creatinine. Two years earlier, his baseline creatinine was 1.2 to 1.5 mg/dL with 132 mg of albumin in a 24-hour urine collection. Th ese fi ndings remained stable until his creatinine increased from 1.5 to 2.2 mg/dL with 2+ hematuria over a 1-month period. Th e patient admitted to frequent use of nonsteroidal antiinfl amma-tory drugs (NSAIDs) for gout during that period. At that time, his allopurinol was decreased from 450 mg to 300 mg daily and the patient remained off NSAIDs. Th ree weeks later, the creatinine was 3.5 mg/dL with 5.2 g of protein in a 24-hour urine collection.

From the Division of Nephrology (Klein, Szerlip) and the Department of Pathology

(Kuperman), Baylor University Medical Center, Dallas, Texas; and Austin Kidney

Associates, Austin, Texas (Rodriguez). Dr. Klein is now at the University of Kansas.

Corresponding author: Jeffrey Klein, MD, Division of Nephrology and Hypertension,

Department of Internal Medicine, University of Kansas Medical Center, 3901

Rainbow Blvd., Mail Stop 3002, Kansas City, KS 66160 (e-mail: jklein@kumc.edu).

A kidney biopsy disclosed 12 glomeruli. None were glob-ally sclerosed; one had a cellular crescent, two had fi brocellular crescents, and three had fi brous crescents. Th e glomeruli had normal size and cellularity. Th ere was severe acute tubular injury consisting of tubular cell necrosis with sloughing and apical blebbing. Th e medulla had extensive interstitial hemorrhage and leukocytoclasia of neutrophils (Figure 1). Tubular atrophy and interstitial fi brosis involved 40% to 50% of the cortex. Im-munofl uorescence was negative. Electron microscopy revealed normal glomerular basement membrane thickness without de-posits. Approximately 80% of the glomerular basement mem-brane surface had podocyte foot process eff acement.

Based on the kidney biopsy fi ndings, the patient was diag-nosed with pauci-immune glomerulonephritis with medullary angiitis. ANCA was positive with a titer of 1:320. Antigen test-ing was positive for myeloperoxidase.

Th e induction regimen included intravenous cyclophospha-mide 1000 mg with intravenous Solu-Medrol 500 mg. After 6 doses of monthly cyclophosphamide and prednisone taper, his serum creatinine fell to 1.7 mg/dL with 2 g of proteinuria. Due to persistent proteinuria, the patient was transitioned to intravenous rituximab 1000 mg monthly with reduction of proteinuria to 200 mg after the second dose. After 4 doses of rituximab, he remains off corticosteroids with continued mi-croalbuminuria and stable kidney function.

DISCUSSIONMedullary angiitis found on renal biopsy warranted further

diagnostic testing in this patient with acutely worsening renal function and heavy NSAID use (5–7). Less than 20% of AAV specimens describe fi ndings of necrotizing arteritis on histology (2, 7, 8). Watanabe et al originally described necrosis of the renal papilla in 5 of 23 cases of granulomatosis with polyangiitis (3). In addition to the classic necrotizing crescentic lesions typical of the cortex, these 5 cases demonstrated fi brinoid necrosis of

Medullary angiitis and pauci-immune crescentic glomerulonephritisJeffrey Klein, MD, William Rodriguez, MD, Michael Kuperman, MD, and Harold Szerlip, MD

Proc (Bayl Univ Med Cent) 2017;30(3):351–352

352 Baylor University Medical Center Proceedings Volume 30, Number 3

the vasa recta. Of the 18 cases without papillary necrosis, only 3 had both medullary interstitial changes and classic glomerular lesions.

Th e histologic diagnosis may prove invaluable, as medullary angiitis may be the only hint of severe systemic disease. Bonsib et al noted necrotizing medullary lesions in 8 of 56 renal pa-thology specimens with known AAV (2). Unlike the original descriptions by Watanabe, some glomerular lesions did not cor-relate with the severity of the medullary lesions. Further, cortical sampling may be insuffi cient or nondiagnostic, so medullary angiitis may be the only fi nding to suggest systemic vasculitis and thus lead to proper therapy (9–11).

Medullary angiitis is associated with ANCA positivity, IgA nephropathy, and drug-induced interstitial nephritis (2). Hen-dricks et al reviewed 38 patients with medullary angiitis, and 19 of the 30 patients (67%) were identifi ed as having AAV (4). Th e remaining 11 patients had IgA nephropathy (20%) and 17% had various infections treated with associated antibiotics (4). Similar to crescentic glomerulonephritis, the fi nding of medul-lary angiitis on renal biopsy should provoke further serologic testing (12). If no immunologic factor is identifi ed (ANCA or IgA), then drug-induced etiologies should be considered (9). While NSAID use with minimal change disease was a diff eren-tial consideration, it has not been implicated in AAV.

Diminished renal perfusion with relative medullary hypoxia has been proposed for medulla-specifi c peritubular capillary involvement (4). More recent investigation into endothelial cell dysregulation has revealed complex microvascular interplay (13). Th e neutrophils stimulated by ANCA lead to endothelial cell activation and vessel destruction (14, 15). Th is process ap-

pears to be regulated by endothelial-specifi c angiopoietins (Ang). Ang-2 can be used to measure the extent of endothelial cell detachment, with a strong correlation between ac-tive AAV with renal involvement as measured by Birmingham Vasculitis Activity Score and Ang-2 levels (16). Th ese complex processes are areas of ongoing research.

1. Piranni C. Evaluation of kidney biopsy specimens. In Tisher CC, Brenner BM, eds. Renal Pathology with Clinical and Functional Correlations. Philadelphia: John Wiley & Sons, 1989:11–42.

2. Bonsib SM, Goeken JA, Fandel T, Houghton DC. Necrotizing medullary lesions in patients with ANCA associated renal disease. Mod Pathol 1994;7(2):181–185.

3. Watanabe T, Nagafuchi Y, Yoshikawa Y, Toyoshima H. Renal papillary necrosis as-sociated with Wegener’s granulomatosis. Hum Pathol 1983;14(6):551–557.

4. Hendricks AR, Harris AA, Walker PD, Larsen CP. Renal medullary angiitis: a case series from a single institution. Hum Pathol 2013;44(4):521–525.

5. Hedger N, Stevens J, Drey N, Walker S, Roderick P. Incidence and outcome of pauci-immune rapidly progressive glomerulonephritis in Wessex, UK: a 10-year retrospective study. Nephrol Dial Transplant 2000;15(10):1593–1599.

6. Holle JU, Gross WL. Treatment of ANCA-associated vasculitides (AAV). Autoimmun Rev 2013;12(4):483–486.

7. Sinico RA, Di Toma L, Radice A. Renal involvement in anti-neutro-phil cytoplasmic autoantibody associated vasculitis. Autoimmun Rev 2013;12(4):477–482.

8. D’Amico G, Sinico RA, Ferrario F. Renal vasculitis. Nephrol Dial Trans-plant 1996;11(Suppl 9):69–74.

9. Falk RJ, Jennette JC. ANCA small-vessel vasculitis. J Am Soc Nephrol 1997;8(2):314–322.

10. Jennette JC, Wilkman AS, Falk RJ. Anti-neutrophil cytoplasmic au-toantibody-associated glomerulonephritis and vasculitis. Am J Pathol 1989;135(5):921–930.

11. Walker PD, Cavallo T, Bonsib SM, Ad Hoc Committee on Renal Biopsy Guidelines of the Renal Pathology Society. Practice guidelines for the renal biopsy. Mod Pathol 2004;17(12):1555–1563.

12. Rutgers A, Slot M, van Paassen P, van Breda Vriesman P, Heeringa P, Tervaert JW. Coexistence of anti-glomerular basement membrane antibod-ies and myeloperoxidase-ANCAs in crescentic glomerulonephritis. Am J Kidney Dis 2005;46(2):253–262.

13. Woywodt A, Streiber F, de Groot K, Regelsberger H, Haller H, Haubitz M. Circulating endothelial cells as markers for ANCA-associated small-vessel vasculitis. Lancet 2003;361(9353):206–210.

14. Erdbruegger U, Grossheim M, Hertel B, Wyss K, Kirsch T, Woywodt A, Haller H, Haubitz M. Diagnostic role of endothelial microparticles in vasculitis. Rheumatology (Oxford) 2008;47(12):1820–1825.

15. Hu N, Westra J, Kallenberg CG. Dysregulated neutrophil-endothelial interaction in antineutrophil cytoplasmic autoantibody (ANCA)-associ-ated vasculitides: implications for pathogenesis and disease intervention. Autoimmun Rev 2011;10(9):536–543.

16. Kumpers P, Hellpap J, David S, Horn R, Leitolf H, Haller H, Haubitz M. Circulating angiopoietin-2 is a marker and potential mediator of endothelial cell detachment in ANCA-associated vasculitis with renal involvement. Nephrol Dial Transplant 2009;24(6):1845–1850.

Figure 1. (a) Segmental fibrocellular crescent (Periodic acid–Schiff, 200×). (b) Interstitial hemorrhage within the

medulla (hematoxylin and eosin [H&E], 40×). (c) Interstitial hemorrhage, neutrophils, and karyorrhectic debris (H&E,

200×). (d) Extravasated red blood cells and neutrophils (H&E, 400×).

a b

dc