The glomerulopathy of sickle cell disease Kenneth I. Ataga, 1 * Vimal K. Derebail, 2 and David R. Archer 3 Sickle cell disease (SCD) produces many structural and functional abnormalities in the kidney, including glomerular abnormalities. Albuminuria is the most common manifestation of glomerular damage, with a prevalence between 26 and 68% in adult patients. The pathophysiology of albuminuria in SCD is likely multifactorial, with contributions from hyperfiltration, glomerular hypertension, ischemia-reperfusion injury, oxidative stress, decreased nitric oxide (NO) bioavailability, and endothelial dysfunction. Although its natural history in SCD remains inadequately defined, albuminuria is associated with increased echocardiography- derived tricuspid regurgitant jet velocity, systemic blood pressure, and hypertension, as well as history of stroke, suggesting a shared vasculopathic pathophysiology. While most patients with albuminuria are treated with angiotensin converting enzyme inhibitors/angiotensin receptor blockers, there are no published long-term data on the efficacy of these agents. With the improved patient survival following kidney transplantation, SCD patients with end-stage renal disease should be considered for this treatment modality. Given the high prevalence of albuminuria and its association with multiple SCD-related clinical complications, additional studies are needed to answer several clinically important questions in a bid to adequately elucidate its pathophysiology, natural history, and treatment. Am. J. Hematol. 89:907–914, 2014. V C 2014 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.  Introduction Sickle cell disease (SCD), one of the most common monogenic disorders worldwide, results in many structural and functional abnormalities in the kidney, including abnormalities of tubular function, hematuria, and glomerular abnormalities [1]. The kidney is particularly sensitive to the effects of hypoxia because of its high rate of oxygen consumption [2]. Due to the presence of acidosis, hypertonicity and hypoxia in the environ- ment of the renal medulla, this portion of the kidney is very susceptible to changes in oxygen delivery. As blood traverses the slow-moving circuit of the medullary vasa recta, the hyperosmolar milieu may enhance dehydration of red blood cells (RBCs), allowing polymerization of sickle hemo- globin (HbS) and resulting in vaso-occlusion and medullary microinfarction [3,4]. Indeed, microangiopathic studies show the loss of vasa recta in older patients with SCD, with those that remain being abnormally dilated or blunted [5]. This review will focus on albuminuria, the most common clinical manifestation of glomerular damage in SCD.  Renal Pathology in SCD In young SCD patients with normal renal function, the kidneys are enlarged, with a smooth capsular surface [6]. With advancing age and the development of chronic renal failure, the kidneys become scarred and shrunken, with the capsular surface ranging from coarsely granular to grossly distorted and scarred [6]. Unlike in normal individuals, glomerular size increases with age in SCD [6]. These enlarged, markedly hypercel- lular glomeruli exhibit lobulation of the glomerular tuft on histological examination. In the early stages of sickle cell nephropathy, renal biopsy shows glomerular hypertrophy, hemosiderin deposits, and focal areas of hemorrhage or necrosis [7,8]. In later stages, interstitial inflammation, edema, fibrosis, tubular atrophy, and papillary infarcts are commonly observed, with these changes mostly due to vascular dropout [7,8]. A multi- center retrospective survey of 18 SCD patients (HbSS—16; HbSC—1; 1 HbSb 1 thalassemia—1) who underwent renal biopsies for isolated protei- nuria or in association with acute or progressive impairment of renal function showed focal segmental glomerulosclerosis (FSGS) in seven cases, membranoproliferative glomerulonephritis (MPGN) in five cases, thrombotic microangiopathic glomerulopathy in three cases, and glomerular hypertrophy with or without mesangial hypercellularity (early sickle cell disease glomerulopathy) in three cases, suggesting a wide spectrum of glo- merular lesions in SCD [9]. Regardless of the observed morphologic lesion, glomeruli were enlarged and the capillaries were distended by sickled RBCs. Of the seven FSGS cases, exclusive not otherwise specified (NOS) lesions were seen in three cases, NOS lesions associated with tip lesions in two cases and two cases showed concomitant tip lesions and perihilar lesions [9]. A collapsing pattern of FSGS has also been reported [10]. 1 Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC; 2 Division of Nephrology and Hypertension, University of North Carolina, Chapel Hill, NC; 3 Department of Pediatrics, Emory University, Atlanta, GA Conflict of interest: KIA is a consultant for Pfizer and Celgene, and has served on scientific advisory boards for Adventrx, HemaQuest, Sangart, Selexys, and Biogen Idec This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduc- tion in any medium, provided the original work is properly cited and is not used for commercial purposes. *Correspondence to: Kenneth I. Ataga, MBBS; Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Physicians’ Office Bldg., 3rd Floor, CB# 7305, 170 Manning Drive, Chapel Hill, NC 27599-7305. E-mail: kataga@med.unc.edu Contract grant sponsor: NIH; Contract grant number: R01 HL111659 (to KIA, VKD, DRA). Received for publication: 14 May 2014; Accepted: 14 May 2014 Am. J. Hematol. 89:907–914, 2014. Published online: 20 May 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23762 V C 2014 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc. doi:10.1002/ajh.23762 American Journal of Hematology, Vol. 89, No. 9, September 2014 907 CRITICAL REVIEW A JH A JH