In this issue of Blood, Ofori-Acquah et al investigate hemolysis, hemopexin deficiency, and kidney function in sickle cell disease (SCD) and report that (1) acute elevations in heme lead to kidney damage in hemopexin-deficient states, and (2) a compensatory rise in α-1 microglobulin (A1M) relative to hemopexin concentration is associated with acute kidney injury.1
Acute kidney injury causes capillary loss, dysregulated apoptosis, and sustained proinflammatory and profibrotic signaling in animal models and leads to the subsequent development and progression of chronic kidney disease in the general population.2 Acute kidney injury is observed in 5% to 17% of hospitalizations for vasoocclusive episodes in patients with SCD3,4 and is associated with a 4.6-fold greater risk for chronic kidney disease progression.4 The mechanisms for kidney injury are not well understood, and targeted therapies to prevent and ameliorate the damage are urgently needed. The findings by Ofori-Acquah et al highlight the central role of intravascular hemolysis and heme processing pathways in SCD-related kidney injury.
Cell-free hemoglobin is released during intravascular hemolysis and, if not efficiently scavenged by haptoglobin, undergoes autooxidation to ferric hemoglobin with release of free heme to the plasma. Hemopexin plays an essential role in sequestering plasma-free heme, thereby preventing direct heme-mediated oxidative damage or augmentation of inflammatory and immune response pathways, such as those mediated by toll-like receptor 4. Hemopexin delivers heme to hepatocytes through the lipoprotein receptor-related protein-1 receptor. Hepatocyte heme oxygenase-1 degrades heme, and the iron released in this process is recycled.5
Haptoglobin and hemopexin are both depleted in SCD, resulting in circulating concentrations of cell-free heme that range from 0 to 20 μM at steady state and increase up to 40 μM during a vasoocclusive episode.6,7 The kidneys may be continuously exposed to toxic cell-free hemoglobin and heme and damaged through direct oxidative injury, activation of inflammatory and immune response pathways, upregulation of endothelial cell adhesion molecules, and/or consumption of nitric oxide leading to vasculopathy.5 In patients with SCD, increased markers of hemolysis are associated with iron deposition in the renal cortex as revealed by magnetic resonance imaging, glomerular dysfunction (albuminuria), and proximal tubular injury, as indicated by increased urine levels of kidney injury molecule-1 (KIM-1).5,8
In this report, the investigators examined whether an acute elevation in plasma heme concentration leads to increased kidney heme processing and acute kidney injury in SCD. After an IV hemin challenge, excess heme was deposited primarily in the kidneys of SCD mice vs the liver of control mice. The SCD mice, but not the control mice, experienced significant rises in plasma creatinine, urine albumin, urine KIM-1, and histopathologic kidney tubular change, and a reduction in measured glomerular filtration after the hemin challenge. Heme-mediated kidney toxicity was further studied by transplanting hemoglobin SS bone marrow into hemopexin null and wild-type mice. The hemoglobin SS/hemopexin-null mice had the lowest measured glomerular filtration rate at baseline and the most severe reduction in the glomerular filtration rate after hemin challenge compared with hemoglobin SS/hemopexin wild-type mice or hemoglobin AA/hemopexin-null mice. Furthermore, infusion of hemopexin prior to a hemin challenge prevented significant changes in the glomerular filtration rate in the SCD mice.
This work builds upon the body of literature that heme promotes toxicity to the kidneys in hemopexin-deficient states. Increased lipid peroxidation and induction of heme oxygenase-1 have been observed in the kidneys of hemopexin knockout vs wild-type mice challenged with hemin.9 Increased iron deposition, tubular cell damage, and lipid peroxidation have been observed in the kidneys of hemopexin knockout vs wild-type mice after inducing intravascular hemolysis with phenylhydrazine.10
A new mechanism for how heme may be shuttled to the kidney and impair kidney function under hemolytic conditions is presented in this report (see figure). A1M is a 26-kDa protein that scavenges heme in the circulation and passes through the glomerular filtration barrier. In the current study, the authors demonstrate that A1M is increased 1.6-fold in SCD patients at steady state compared with healthy controls. In addition, a higher molar ratio of A1M:hemopexin correlates with elevated markers of hemolytic anemia and with increased levels of 2 tubular cell injury biomarkers, urine KIM-1 and urine neutrophil gelatinase-associated lipocalin, in SCD patients. Parallel with what was observed in SCD patients, a sevenfold increase in the A1M:hemopexin ratio was observed in SCD vs control mice. Consistent with transport of heme to the kidney by A1M in hemopexin-deficient states, the administration of A1M immediately prior to hemin infusion exacerbated the reduction in glomerular filtration rate by 39% in the SCD mice.
In the present study, Oforo-Acquah et al provide compelling evidence that acute rises in cell-free heme are primarily handled by the kidneys and contribute to kidney injury in SCD. The findings from this study strengthen the observation that kidney damage is mediated by intravascular hemolysis and provide novel insight that A1M may transport toxic cell-free heme to the kidneys in hemopexin-deficient states. Other non-SCD models of acute intravascular hemolysis, such as red blood cell transfusion or phenylhydrazine-induced hemolysis, have demonstrated that haptoglobin, the first line of defense against intravascular hemolysis, may be more effective than hemopexin in preventing acute kidney injury.5 Future studies evaluating the protective benefits of cell-free hemoglobin vs heme scavenging, or the combination of both, may provide additional insight into the mechanisms of kidney damage in SCD and guide strategies to mitigate acute kidney injury.
Conflict-of-interest disclosure: The author declares no competing financial interests.