BACKGROUND: The mechanism of kidney injury in hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is not completely understood. Renal C4d staining is a marker of classic complement activation and endothelial injury and has been described in preliminary reports of HSCT recipients with TA-TMA. Our objective was to evaluate complement in the pathogenesis of small vessel injury in children receiving HSCT. We hypothesized that kidney tissue from children with TA-TMA would more frequently show C4d deposition compared with HSCT recipients without histologic TA-TMA. METHODS: We reviewed kidney specimens (biopsy or autopsy) from children who had undergone HSCT at a single center. Using histologic criteria alone, subjects were divided into TA-TMA (n = 8) and non-TA-TMA (control) groups (n = 12). C4d staining was performed by immunohistochemistry and evaluated on arterioles, peritubular capillaries, glomeruli, and tubular basement membranes. RESULTS: Diffuse or focal renal arteriolar C4d staining was more common in subjects with histologic TA-TMA (75%) compared with controls (8%). Rare peritubular capillary C4d staining was present in 50% of TA-TMA samples and was absent in controls. Glomerular C4d staining was seen at a similar frequency in cases and controls, whereas tubular basement membrane staining was less frequently observed and only in subjects with TA-TMA. CONCLUSIONS: Arteriolar C4d deposition may be a pathologic marker of TA-TMA, implicating localized complement fixation in HSCT recipients with kidney disease secondary to small vessel injury. Further studies to better characterize the preferential arteriolar C4d staining may identify a renal compartment of injury, possibly explaining the dramatic hypertension seen in TA-TMA.
BACKGROUND: The mechanism of kidney injury in hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is not completely understood. Renal C4d staining is a marker of classic complement activation and endothelial injury and has been described in preliminary reports of HSCT recipients with TA-TMA. Our objective was to evaluate complement in the pathogenesis of small vessel injury in children receiving HSCT. We hypothesized that kidney tissue from children with TA-TMA would more frequently show C4d deposition compared with HSCT recipients without histologic TA-TMA. METHODS: We reviewed kidney specimens (biopsy or autopsy) from children who had undergone HSCT at a single center. Using histologic criteria alone, subjects were divided into TA-TMA (n = 8) and non-TA-TMA (control) groups (n = 12). C4d staining was performed by immunohistochemistry and evaluated on arterioles, peritubular capillaries, glomeruli, and tubular basement membranes. RESULTS: Diffuse or focal renal arteriolar C4d staining was more common in subjects with histologic TA-TMA (75%) compared with controls (8%). Rare peritubular capillary C4d staining was present in 50% of TA-TMA samples and was absent in controls. Glomerular C4d staining was seen at a similar frequency in cases and controls, whereas tubular basement membrane staining was less frequently observed and only in subjects with TA-TMA. CONCLUSIONS: Arteriolar C4d deposition may be a pathologic marker of TA-TMA, implicating localized complement fixation in HSCT recipients with kidney disease secondary to small vessel injury. Further studies to better characterize the preferential arteriolar C4d staining may identify a renal compartment of injury, possibly explaining the dramatic hypertension seen in TA-TMA.
Authors: Danielle Cohen; Aletta Buurma; Natascha N Goemaere; Guillermina Girardi; Saskia le Cessie; Sicco Scherjon; Kitty W M Bloemenkamp; Emile de Heer; Jan A Bruijn; Ingeborg M Bajema Journal: J Pathol Date: 2011-06-20 Impact factor: 7.996
Authors: Siribha Changsirikulchai; David Myerson; Katherine A Guthrie; George B McDonald; Charles E Alpers; Sangeeta R Hingorani Journal: Clin J Am Soc Nephrol Date: 2009-01-14 Impact factor: 8.237
Authors: Meredith P Schuh; Michael R Bennett; Adam Lane; Sonata Jodele; Benjamin L Laskin; Prasad Devarajan Journal: Pediatr Nephrol Date: 2018-12-19 Impact factor: 3.714
Authors: Jamie S Chua; Hans J Baelde; Malu Zandbergen; Suzanne Wilhelmus; Leendert A van Es; Johan W de Fijter; Jan A Bruijn; Ingeborg M Bajema; Danielle Cohen Journal: J Am Soc Nephrol Date: 2015-01-08 Impact factor: 10.121
Authors: Sonata Jodele; Benjamin L Laskin; Christopher E Dandoy; Kasiani C Myers; Javier El-Bietar; Stella M Davies; Jens Goebel; Bradley P Dixon Journal: Blood Rev Date: 2014-11-28 Impact factor: 8.250
Authors: Sonata Jodele; Stella M Davies; Adam Lane; Jane Khoury; Christopher Dandoy; Jens Goebel; Kasiani Myers; Michael Grimley; Jack Bleesing; Javier El-Bietar; Gregory Wallace; Ranjit S Chima; Zachary Paff; Benjamin L Laskin Journal: Blood Date: 2014-05-29 Impact factor: 22.113
Authors: Sonata Jodele; Tsuyoshi Fukuda; Kana Mizuno; Alexander A Vinks; Benjamin L Laskin; Jens Goebel; Bradley P Dixon; Ranjit S Chima; Russel Hirsch; Ashley Teusink; Danielle Lazear; Adam Lane; Kasiani C Myers; Christopher E Dandoy; Stella M Davies Journal: Biol Blood Marrow Transplant Date: 2015-10-09 Impact factor: 5.742
Authors: Sonata Jodele; Tsuyoshi Fukuda; Alexander Vinks; Kana Mizuno; Benjamin L Laskin; Jens Goebel; Bradley P Dixon; Ashley Teusink; Fred G Pluthero; Lily Lu; Christoph Licht; Stella M Davies Journal: Biol Blood Marrow Transplant Date: 2013-12-25 Impact factor: 5.742
Authors: Reem Elfeky; Giovanna Lucchini; Su-Han Lum; Giorgio Ottaviano; Natalia Builes; Zohreh Nademi; Alexandra Battersby; Terence Flood; Stephen Owens; Andrew J Cant; Helen Young; Sinéad Greener; Patrick Walsh; David Kavanagh; Srinivas Annavarapu; Kanchan Rao; Persis Amrolia; Robert Chiesa; Austen Worth; Claire Booth; Roderick Skinner; Bilyana Doncheva; Joseph Standing; Andrew R Gennery; Waseem Qasim; Mary Slatter; Paul Veys Journal: Blood Adv Date: 2020-06-09