Medullary angiitis and pauci-immune crescentic glomerulonephritis Jeffrey Klein, MD, William Rodriguez, MD, Michael Kuperman, MD, and Harold Szerlip, MD
Although almost all pathological diagnoses made from a native kidney biopsy come from careful examination of the renal cortex, certain diseases 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 antibodyassociated vasculitis. Medullary angiitis identified in the setting of negative immunofluorescence is most suggestive of pauci-immune crescentic glomerulonephritis, as presented in this case.
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he gold standard for evaluation and proper classification of kidney disease is microscopic examination of renal tissue. 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 findings, namely in the glomeruli. However, certain disease entities remain elusive without close inspection of the medulla. Medullary angiitis is an uncommon finding on renal biopsies with rare descriptions in the literature (2, 3). These findings 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 finding is needed, as medullary angiitis can be ignored or misdiagnosed as acute interstitial nephritis (4). This case describes the association between medullary angiitis and systemic vasculitis with a discussion of the underlying etiology. CASE DESCRIPTION A 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. These findings remained stable until his creatinine increased from 1.5 to 2.2 mg/dL with 2+ hematuria over a 1-month period. The patient admitted to frequent use of nonsteroidal antiinflammatory 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. Three weeks later, the creatinine was 3.5 mg/dL with 5.2 g of protein in a 24-hour urine collection. Proc (Bayl Univ Med Cent) 2017;30(3):351–352
A kidney biopsy disclosed 12 glomeruli. None were globally sclerosed; one had a cellular crescent, two had fibrocellular crescents, and three had fibrous crescents. The glomeruli had normal size and cellularity. There was severe acute tubular injury consisting of tubular cell necrosis with sloughing and apical blebbing. The medulla had extensive interstitial hemorrhage and leukocytoclasia of neutrophils (Figure 1). Tubular atrophy and interstitial fibrosis involved 40% to 50% of the cortex. Immunofluorescence was negative. Electron microscopy revealed normal glomerular basement membrane thickness without deposits. Approximately 80% of the glomerular basement membrane surface had podocyte foot process effacement. Based on the kidney biopsy findings, the patient was diagnosed with pauci-immune glomerulonephritis with medullary angiitis. ANCA was positive with a titer of 1:320. Antigen testing was positive for myeloperoxidase. The induction regimen included intravenous cyclophosphamide 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 microalbuminuria and stable kidney function. DISCUSSION Medullary 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 findings 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 fibrinoid necrosis of 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: [email protected]). 351
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pears to be regulated by endothelialspecific angiopoietins (Ang). Ang-2 can be used to measure the extent of endothelial cell detachment, with a strong correlation between active AAV with renal involvement as measured by Birmingham Vasculitis Activity Score and Ang-2 levels (16). These 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 associated with Wegener’s granulomatosis. Hum Pathol 1983;14(6):551–557. Figure 1. (a) Segmental fibrocellular crescent (Periodic acid–Schiff, 200×). (b) Interstitial hemorrhage within the 4. Hendricks AR, Harris AA, Walker PD, medulla (hematoxylin and eosin [H&E], 40×). (c) Interstitial hemorrhage, neutrophils, and karyorrhectic debris (H&E, Larsen CP. Renal medullary angiitis: a 200×). (d) Extravasated red blood cells and neutrophils (H&E, 400×). 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 the vasa recta. Of the 18 cases without papillary necrosis, only pauci-immune rapidly progressive glomerulonephritis in Wessex, UK: a 103 had both medullary interstitial changes and classic glomerular year retrospective study. Nephrol Dial Transplant 2000;15(10):1593–1599. lesions. 6. Holle JU, Gross WL. Treatment of ANCA-associated vasculitides (AAV). The histologic diagnosis may prove invaluable, as medullary Autoimmun Rev 2013;12(4):483–486. angiitis may be the only hint of severe systemic disease. Bonsib 7. Sinico RA, Di Toma L, Radice A. Renal involvement in anti-neutrophil cytoplasmic autoantibody associated vasculitis. Autoimmun Rev et al noted necrotizing medullary lesions in 8 of 56 renal pa2013;12(4):477–482. thology specimens with known AAV (2). Unlike the original 8. D’Amico G, Sinico RA, Ferrario F. Renal vasculitis. Nephrol Dial Transdescriptions by Watanabe, some glomerular lesions did not corplant 1996;11(Suppl 9):69–74. relate with the severity of the medullary lesions. Further, cortical 9. Falk RJ, Jennette JC. ANCA small-vessel vasculitis. J Am Soc Nephrol sampling may be insufficient or nondiagnostic, so medullary 1997;8(2):314–322. angiitis may be the only finding to suggest systemic vasculitis 10. Jennette JC, Wilkman AS, Falk RJ. Anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and vasculitis. Am J Pathol and thus lead to proper therapy (9–11). 1989;135(5):921–930. Medullary angiitis is associated with ANCA positivity, IgA 11. Walker PD, Cavallo T, Bonsib SM, Ad Hoc Committee on Renal Biopsy nephropathy, and drug-induced interstitial nephritis (2). HenGuidelines of the Renal Pathology Society. Practice guidelines for the renal dricks et al reviewed 38 patients with medullary angiitis, and 19 biopsy. Mod Pathol 2004;17(12):1555–1563. of the 30 patients (67%) were identified as having AAV (4). The 12. Rutgers A, Slot M, van Paassen P, van Breda Vriesman P, Heeringa P, Tervaert JW. Coexistence of anti-glomerular basement membrane antibodremaining 11 patients had IgA nephropathy (20%) and 17% ies and myeloperoxidase-ANCAs in crescentic glomerulonephritis. Am J had various infections treated with associated antibiotics (4). Kidney Dis 2005;46(2):253–262. Similar to crescentic glomerulonephritis, the finding of medul13. Woywodt A, Streiber F, de Groot K, Regelsberger H, Haller H, Haubitz lary angiitis on renal biopsy should provoke further serologic M. Circulating endothelial cells as markers for ANCA-associated smalltesting (12). If no immunologic factor is identified (ANCA or vessel vasculitis. Lancet 2003;361(9353):206–210. 14. Erdbruegger U, Grossheim M, Hertel B, Wyss K, Kirsch T, Woywodt A, IgA), then drug-induced etiologies should be considered (9). Haller H, Haubitz M. Diagnostic role of endothelial microparticles in While NSAID use with minimal change disease was a differenvasculitis. Rheumatology (Oxford) 2008;47(12):1820–1825. tial consideration, it has not been implicated in AAV. 15. Hu N, Westra J, Kallenberg CG. Dysregulated neutrophil-endothelial Diminished renal perfusion with relative medullary hypoxia interaction in antineutrophil cytoplasmic autoantibody (ANCA)-associhas been proposed for medulla-specific peritubular capillary ated vasculitides: implications for pathogenesis and disease intervention. Autoimmun Rev 2011;10(9):536–543. involvement (4). More recent investigation into endothelial 16. Kumpers P, Hellpap J, David S, Horn R, Leitolf H, Haller H, Haubitz cell dysregulation has revealed complex microvascular interplay M. Circulating angiopoietin-2 is a marker and potential mediator of (13). The neutrophils stimulated by ANCA lead to endothelial endothelial cell detachment in ANCA-associated vasculitis with renal cell activation and vessel destruction (14, 15). This process apinvolvement. Nephrol Dial Transplant 2009;24(6):1845–1850.
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Baylor University Medical Center Proceedings
Volume 30, Number 3
Although almost all pathological diagnoses made from a native kidney biopsy come from careful examination of the renal cortex, certain diseases 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 antibodyassociated vasculitis. Medullary angiitis identified in the setting of negative immunofluorescence is most suggestive of pauci-immune crescentic glomerulonephritis, as presented in this case.
T
he gold standard for evaluation and proper classification of kidney disease is microscopic examination of renal tissue. 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 findings, namely in the glomeruli. However, certain disease entities remain elusive without close inspection of the medulla. Medullary angiitis is an uncommon finding on renal biopsies with rare descriptions in the literature (2, 3). These findings 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 finding is needed, as medullary angiitis can be ignored or misdiagnosed as acute interstitial nephritis (4). This case describes the association between medullary angiitis and systemic vasculitis with a discussion of the underlying etiology. CASE DESCRIPTION A 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. These findings remained stable until his creatinine increased from 1.5 to 2.2 mg/dL with 2+ hematuria over a 1-month period. The patient admitted to frequent use of nonsteroidal antiinflammatory 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. Three weeks later, the creatinine was 3.5 mg/dL with 5.2 g of protein in a 24-hour urine collection. Proc (Bayl Univ Med Cent) 2017;30(3):351–352
A kidney biopsy disclosed 12 glomeruli. None were globally sclerosed; one had a cellular crescent, two had fibrocellular crescents, and three had fibrous crescents. The glomeruli had normal size and cellularity. There was severe acute tubular injury consisting of tubular cell necrosis with sloughing and apical blebbing. The medulla had extensive interstitial hemorrhage and leukocytoclasia of neutrophils (Figure 1). Tubular atrophy and interstitial fibrosis involved 40% to 50% of the cortex. Immunofluorescence was negative. Electron microscopy revealed normal glomerular basement membrane thickness without deposits. Approximately 80% of the glomerular basement membrane surface had podocyte foot process effacement. Based on the kidney biopsy findings, the patient was diagnosed with pauci-immune glomerulonephritis with medullary angiitis. ANCA was positive with a titer of 1:320. Antigen testing was positive for myeloperoxidase. The induction regimen included intravenous cyclophosphamide 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 microalbuminuria and stable kidney function. DISCUSSION Medullary 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 findings 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 fibrinoid necrosis of 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: [email protected]). 351
a
b
pears to be regulated by endothelialspecific angiopoietins (Ang). Ang-2 can be used to measure the extent of endothelial cell detachment, with a strong correlation between active AAV with renal involvement as measured by Birmingham Vasculitis Activity Score and Ang-2 levels (16). These 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 associated with Wegener’s granulomatosis. Hum Pathol 1983;14(6):551–557. Figure 1. (a) Segmental fibrocellular crescent (Periodic acid–Schiff, 200×). (b) Interstitial hemorrhage within the 4. Hendricks AR, Harris AA, Walker PD, medulla (hematoxylin and eosin [H&E], 40×). (c) Interstitial hemorrhage, neutrophils, and karyorrhectic debris (H&E, Larsen CP. Renal medullary angiitis: a 200×). (d) Extravasated red blood cells and neutrophils (H&E, 400×). 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 the vasa recta. Of the 18 cases without papillary necrosis, only pauci-immune rapidly progressive glomerulonephritis in Wessex, UK: a 103 had both medullary interstitial changes and classic glomerular year retrospective study. Nephrol Dial Transplant 2000;15(10):1593–1599. lesions. 6. Holle JU, Gross WL. Treatment of ANCA-associated vasculitides (AAV). The histologic diagnosis may prove invaluable, as medullary Autoimmun Rev 2013;12(4):483–486. angiitis may be the only hint of severe systemic disease. Bonsib 7. Sinico RA, Di Toma L, Radice A. Renal involvement in anti-neutrophil cytoplasmic autoantibody associated vasculitis. Autoimmun Rev et al noted necrotizing medullary lesions in 8 of 56 renal pa2013;12(4):477–482. thology specimens with known AAV (2). Unlike the original 8. D’Amico G, Sinico RA, Ferrario F. Renal vasculitis. Nephrol Dial Transdescriptions by Watanabe, some glomerular lesions did not corplant 1996;11(Suppl 9):69–74. relate with the severity of the medullary lesions. Further, cortical 9. Falk RJ, Jennette JC. ANCA small-vessel vasculitis. J Am Soc Nephrol sampling may be insufficient or nondiagnostic, so medullary 1997;8(2):314–322. angiitis may be the only finding to suggest systemic vasculitis 10. Jennette JC, Wilkman AS, Falk RJ. Anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and vasculitis. Am J Pathol and thus lead to proper therapy (9–11). 1989;135(5):921–930. Medullary angiitis is associated with ANCA positivity, IgA 11. Walker PD, Cavallo T, Bonsib SM, Ad Hoc Committee on Renal Biopsy nephropathy, and drug-induced interstitial nephritis (2). HenGuidelines of the Renal Pathology Society. Practice guidelines for the renal dricks et al reviewed 38 patients with medullary angiitis, and 19 biopsy. Mod Pathol 2004;17(12):1555–1563. of the 30 patients (67%) were identified as having AAV (4). The 12. Rutgers A, Slot M, van Paassen P, van Breda Vriesman P, Heeringa P, Tervaert JW. Coexistence of anti-glomerular basement membrane antibodremaining 11 patients had IgA nephropathy (20%) and 17% ies and myeloperoxidase-ANCAs in crescentic glomerulonephritis. Am J had various infections treated with associated antibiotics (4). Kidney Dis 2005;46(2):253–262. Similar to crescentic glomerulonephritis, the finding of medul13. Woywodt A, Streiber F, de Groot K, Regelsberger H, Haller H, Haubitz lary angiitis on renal biopsy should provoke further serologic M. Circulating endothelial cells as markers for ANCA-associated smalltesting (12). If no immunologic factor is identified (ANCA or vessel vasculitis. Lancet 2003;361(9353):206–210. 14. Erdbruegger U, Grossheim M, Hertel B, Wyss K, Kirsch T, Woywodt A, IgA), then drug-induced etiologies should be considered (9). Haller H, Haubitz M. Diagnostic role of endothelial microparticles in While NSAID use with minimal change disease was a differenvasculitis. Rheumatology (Oxford) 2008;47(12):1820–1825. tial consideration, it has not been implicated in AAV. 15. Hu N, Westra J, Kallenberg CG. Dysregulated neutrophil-endothelial Diminished renal perfusion with relative medullary hypoxia interaction in antineutrophil cytoplasmic autoantibody (ANCA)-associhas been proposed for medulla-specific peritubular capillary ated vasculitides: implications for pathogenesis and disease intervention. Autoimmun Rev 2011;10(9):536–543. involvement (4). More recent investigation into endothelial 16. Kumpers P, Hellpap J, David S, Horn R, Leitolf H, Haller H, Haubitz cell dysregulation has revealed complex microvascular interplay M. Circulating angiopoietin-2 is a marker and potential mediator of (13). The neutrophils stimulated by ANCA lead to endothelial endothelial cell detachment in ANCA-associated vasculitis with renal cell activation and vessel destruction (14, 15). This process apinvolvement. Nephrol Dial Transplant 2009;24(6):1845–1850.
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Baylor University Medical Center Proceedings
Volume 30, Number 3
