2.LEONARDI, P. & RUOL, A. Renal Hemosiderosis in the Hemolytic Anemias: Diagnosis by Means
Disease or insult / Findings
Human studies
Red blood cell aplasia / ↑Urinary haemosiderin(method not specified); ↑CMJ iron (MRI); not haemolysing1
Chronic haemolytic anaemia / Urinary haemosiderin↑(Prussian reaction of Perls); kidney iron ↑ (Turnbull iron reaction); hepatic iron↔1,2
Antibody haemolytic anaemia / Kidney iron↑(Prussian blue staining); histological kidney damage3
HO1 deficiency / Proximal tubule iron↑(Prussian blue staining); histological kidney damage; HO1 caused haemolytic anaemia4
HIV–HUS / Urinaryiron↑(ferrozine staining); glomerular and tubular damage; transferrin, haemopexin, haptoglobin, lactotransferrin, NGAL↑5
Thalassemia major,mechanical haemolysis, pernicious anaemia / Urinaryiron ↑(benzidine method of Crosby and Furth and reaction with dipyridyl); pernicious anaemia is a type of megaloblastic anaemia6
Sickle cell disease / Urinaryiron ↑(benzidine method of Crosby and Furth and reaction with dipyridyl); proximal tubule iron MRI↑(MRI); histological kidney damage6-8
PNH / Urinary haemosiderin↑(Prussian reaction of Perls, benzidine method of Crosby and Furth and reaction with dipyridyl); kidney iron↑ (Turnbull iron reaction, MRI Prussian blue staining); proteinuria2,6,9-12
Hereditary spherocytosis / Urinary haemosiderin↑(Prussian reaction of Perls); kidney iron↑(Turnbull iron reaction)2
Haemolysis after cardiac surgery / Kidney iron↑(Prussian blue staining); histological kidney damage(electron microscopy); AKI13
Rhabdomyolysis / Myoglobin in urine↑(immunoassay); myoglobinuria predicted kidney failure after rhabdomyolysis14-16
-thalassaemia / Kidney iron↑ (MRI)17
Patients who complied badly with chelation therapy had higher serum ferritin levels and kidney dysfunction than did patients who complied well
Animal studies
Haemolytic anaemia in mice / Kidney iron↑ (Prussian blue staining)18
Glycerol-induced myoglobinuric AKI (rhabdomyolysis) / Urinaryiron↑(bleomycin assay); kidney iron↑(bleomycin assay, immunoperoxidase method to detect myoglobin); glomerular and tubular damage(histologic, malondialdehyde, PAS); renal cortical haemopexin mRNA↑;
AKIin rat by plasma creatinine and plasma nitrogen urea, partly in vitro
Deferoxamine infusion attenuated kidney dysfunction and oxidative stress19-25
Haem protein infusion in rat / Large haem-filled endolysosomes in proximal tubule; haem casts in distal nephron; proximal tubule damage(histologic)26
HO1 deficiencyleading tohaemolytic anaemia / Proximal tubule iron↑(Prussian blue staining); histological kidney damage; CD163, ferritin light chain, ferritin heavy chain, ferroportin mRNA↑; haemopexin protein↑27
In vitro studies
Cells exposed to haem / DNA damage in distal tubule (MCDK) cellsbut not proximal tubule (LLC-PK1) cells20
Proximal tubule cells exposed to myoglobin / Cell damage (LDH); HK-2 cells and extracted proximal tubule cells used28
Proximal tubule cells exposed to haemoglobin / Cell damage (MTT assay); human proximal tubule cells used29
Abbreviations: ↑, increased; ↔, unchanged; AKI,acute kidney injury; AKF,acute kidney failure; CMJ, corticomedullary junction; HK-2, human kidney 2; HO1, haem oxygenase 1; HUS, haemolytic uremic syndrome; LDH,lactate dehydrogenase; LLC–PK1,pig kidney epithelial cells;MDCK, Madin–Darby canine kidney; MTT, PAS,pernicious anaemia staining; PNH,paroxysmal nocturnal haemoglubinuria.
1.Rakow-Penner, R., Glader, B., Yu, H. & Vasanawala, S. Adrenal and renal corticomedullary junction iron deposition in red cell aplasia. Pediatr. Radiol.40, 1955–1957 (2010).
2.LEONARDI, P. & RUOL, A. Renal hemosiderosis in the hemolytic anemias: diagnosis by means of needle biopsy. Blood16, 1029–1038 (1960).
3.Fervenza, F.C. etal. Induction of Heme Oxygenase1 and Ferritin in the Kidney in Warm Antibody Hemolytic Anemia. Am. J. Kidney Dis.52, 972–977 (2008).
4.Yachie, A. etal. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase1 deficiency. J. Clin. Invest.103, 129–135 (1999).
5.Soler-García, Á.A., Johnson, D., Hathout, Y. & Ray, P.E. Iron-related proteins: Candidate urine biomarkers in childhood HIV-associated renal diseases. Clin. J. Am. Soc. Nephrol.4, 763–771 (2009).
6.Sears, D.A., Anderson, P.R., Foy, A.L., Williams, H.L. & Crosby, W.H. Urinary iron excretion and renal metabolism of hemoglobin in hemolytic diseases. Blood28, 708–725 (1966).
7.Schein, A., Enriquez, C., Coates, T.D. & Wood, J.C. Magnetic resonance detection of kidney iron deposition in sickle cell disease: A marker of chronic hemolysis. J. Magn. Reson. Imaging28, 698–704 (2008).
8.Buckalew Jr, V.M. & Someren, A. Renal manifestations of sickle cell disease. Arch. Intern. Med.133, 660–669 (1974).
9.Hsiao, P.J., Wang, S.C., Wen, M.C., Diang, L.K. & Lin, S.H. Fanconi Syndrome and CKD in a Patient With Paroxysmal Nocturnal Hemoglobinuria and Hemosiderosis. Am. J. Kidney Dis.55, e1e5 (2010).
10.Suzukawa, K. etal. Demonstration of the deposition of hemosiderin in the kidneys of patients with paroxysmal nocturnal hemoglobinuria by magnetic resonance imaging. Intern. Med.32, 686–690 (1993).
11.Nath, K.A. etal. Heme protein-induced chronic renal inflammation: Suppressive effect of induced heme oxygenase11. Kidney Int.59, 106–117 (2001).
12.Ballarín, J. etal. Acute renal failure associated to paroxysmal nocturnal haemoglobinuria leads to intratubular haemosiderin accumulation and CD163 expression. Nephrol. Dial. Transplant.26, 3408–3411 (2011).
13.Qian, Q., Nath, K.A., Wu, Y., Daoud, T.M. & Sethi, S. Hemolysis and acute kidney failure. Am. J. Kidney Dis.56, 780–784 (2010).
14.Holt, S.G. & Moore, K.P. Pathogenesis and treatment of renal dysfunction in rhabdomyolysis. Intensive Care Med.27, 803–811 (2001).
15.Al-Ismaili, Z., Piccioni, M. & Zappitelli, M. Rhabdomyolysis: Pathogenesis of renal injury and management. Pediatr. Nephrol.26, 1781–1788 (2011).
16.Khan, A.A. & Quigley, J.G. Control of intracellular heme levels: Heme transporters and heme oxygenases. Biochim. Biophys. Acta 1813, 668–682 (2011).
17.Hashemieh, M., Azarkeivan, A., Akhlaghpoor, S., Shirkavand, A. & Sheibani, K. T2-star (T2*) magnetic resonance imaging for assessment of kidney iron overload in thalassemic patients. Arch. Iran. Med.15, 91–94 (2012).
18.Veuthey, T., D’Anna, M.C. & Roque, M.E. Role of the kidney in iron homeostasis: Renal expression of Prohepcidin, Ferroportin, and DMT1 in anemic mice. Am. J. Physiol. Renal Physiol.295, F1213F1221 (2008).
19.Baliga, R., Zhang, Z., Baliga, M. & Shah, S.V. Evidence for cytochrome P450 as a source of catalytic iron in myoglobinuric acute renal failure. Kidney Int.49, 362–369 (1996).
20.Nath, K.A. etal. Intracellular targets in heme protein-induced renal injury. Kidney Int.53, 100–111 (1998).
21.Zager, R.A., Foerder, C. & Bredl, C. The influence of mannitol on myoglobinuric acute renal failure: functional, biochemical, and morphological assessments. J. Am. Soc. Nephrol.2, 848–855 (1991).
22.Wei, Q., Hill, W.D., Su, Y., Huang, S. & Dong, Z. Heme oxygenase1 induction contributes to renoprotection by GCSF during rhabdomyolysis-associated acute kidney injury. Am. J. Physiol. Renal Physiol.301, F162F170 (2011).
23.Paller, M.S. Hemoglobin- and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity. Am. J. Physiol.255, (1988).
24.Boutaud, O. etal. Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation and attenuates rhabdomyolysis-induced renal failure. Proc. Nat. Acad. Sci.USA107, 2699–2704 (2010).
25.Zager, R.A., Johnson, A.C.M. & Becker, K. Renal cortical hemopexin accumulation in response to acute kidney injury. Am. J. Physiol. Renal Physiol. 303, F1460F1472 (2012).
26.Zager, R.A. Rhabdomyolysis and myohemoglobinuric acute renal failure. Kidney Int. 49, 314–326 (1996).
27.Kovtunovych, G., Eckhaus, M.A., Ghosh, M.C., Ollivierre-Wilson, H. & Rouault, T.A. Dysfunction of the heme recycling system in heme oxygenase 1deficient mice: Effects on macrophage viability and tissue iron distribution. Blood116, 6054–6062 (2010).
28.Zager, R.A. & Burkhart, K. Myoglobin toxicity in proximal human kidney cells: Roles of Fe, Ca2+, H2O2, and terminal mitochondrial electron transport. Kidney Int.51, 728–738 (1997).
29.Sheerin, N.S., Sacks, S.H. & Fogazzi, G.B. Invitro erythrophagocytosis by renal tubular cells and tubular toxicity by haemoglobin and iron. Nephrol. Dial. Transplant.14, 1391–1397 (1999).
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