Disease or injury / Findings
Human studies
Proteinuria / Proximal tubuleand distal damage(GST); GST- and GST- allow timing and site determination of injury in proteinuria, CKD1
Nephrotic syndrome / ↑Urinary iron (ferene-S); ↑kidney iron(EDX); proximal tubule damage (morphological); [Fe]lys correlated with damage and proteinuria; ↑urinary transferrin, CKD2
HIVAN / ↑Urinary iron(ferrozine staining); ↑kidney iron( Prussian bluestaining); glomerular and tubular damage; ↑transferrin, haemopexin, haptoglobin, lactotransferrin, NGAL
Glomerulonephritis / ↑Urinary iron(bleomycin assay)4
Treatment with deferiprone decreased proteinuria5
Membranoproliferative nephritis leading tonephrotic syndrome / ↑Urinary iron(immunoradiometric ferritin assay); ↑transferrin, anaemia6
MGN / ↑Urinary iron (Keberle method, ferene-S); ↑ urinary transferrin, which correlated with urinary Fe; anaemia7,8
FGN / ↑Urinary iron(Keberle method); ↑urinary transferrin, which correlated with urinary Fe7
FGS / ↑Urinary iron(ferene-S); ↑transferrin8
Diabetic nephropathy / ↑Urinary iron(bleomycin assay, flameless atomic absorption technique spectrophotometry); ↑albumin, proteinuria; ↑transferrin, which correlated with urinary Fe in nephrotic syndrome; urinary Fe was also higher in individuals with diabetes without diabetic nephropathy and correlated with proteinuria4,9
Treatment with deferiprone decreased proteinuria and stabilized kidney function5
MCGN / ↑Urinary iron(ferene-S); ↑transferrin8
PAN MGN[Should this be MGN, as listed in the abbreviations?] / ↑Urinary iron(ferene-S); ↑transferrin?8
IgA nephropathy / ↑Kidney iron (Berlin blue staining, Prussian bluestaining); ATN; kidney Feconcentrationassociated with CKD progression;ATN at sites with intraluminal red blood cell casts10–12
CD163 expression, HO1 expression and oxidative stress correlated positively with percentage of tubules with erythrocyte casts and tubular necrosis12
CD163-expressing macrophages surrounded tubules filled with erythrocytes and were loaded with haemosiderin deposits12
Animal studies*
Adriamycinleading tonephrotic syndrome / ↑Urinary iron (flameless atomic absorption technique spectrophotometry); ↑kidney iron (flameless atomic absorption technique spectrophotometry, Prussian blue staining), ↑[Fe]mitochondria (flameless atomic absorption technique spectrophotometry, electron microscopy); kidney damage; [Fe]distal tubule» [Fe]proximal tubule[Fe]mitochondria correlated with proteinuria. [Fe]distal tubule in lysosomes and mitochondria. [Fe]proximal tubule in cytoplasm and along brush border 13,14
PANproteinuria / ↑Urinary iron (flameless atomic absorption technique spectrophotometry); ↑kidney iron(EDX, flameless atomic absorption technique spectrophotometry, Prussian bluestaining, nonhaem iron by acid hydrolysis, bleomycin assay); proximal tubule damage (morphological), distal tubule damage; ↑lysosomal [Fe]proximal tubule,was theonly independent predictor of damage; deferoxamine prevented increase in bleomycin-detectable iron in glomeruli13,15,16
NSN / ↔Urinary iron (flameless atomic absorption technique spectrophotometry), ↑urinary iron(bleomycin assay); ↑kidney iron( flameless atomic absorption technique spectrophotometry, Prussian bluestaining); kidney damage; [Fe]distal tubule» [Fe]proximal tubule; thyroparathyroidectomy protected the kidney from functional deterioration, reduced proteinuria and prevented iron accumulation;low iron diet and deferoxamine infusion prevented iron accumulation, prevented the development of tubulointerstitial disease and renal functional deterioration13,17,18
PHN mouse model / ↑Total urinary iron; ↑kidney nonhaem iron (nonhaem iron by acid hydrolysis); iron-deficient diet prevented increase in UIE and tubular nonhaem iron content19
IgA nephropathy / Histological and DNA damage and oxidative stress in mouse kidney20
Glomerular sclerosis and proteinuria / Iron-deficient diet reduced proteinuria, glomerulosclerosis and indicated reduction of hypertension21
Nephron reduction (CKD model) / ↑Kidney iron(Prussian bluestaining in mice, Berlin blue staining in rats);22,23 proximal tubule damage in rats and mice (histology)22,23; ROS production in the kidney;23↑UIE(AAS);23 deferoxamine treatment exacerbated disease;63 dietary iron restriction attenuated proteinuria, UIE, glomerulosclerosis, tubulointerstitial damage and development of hypertension23
HIVAN rat model / ↑Urinary iron(ferrozine staining); ↑kidney iron(Prussian bluestaining); glomerular and tubule damage; ↑urinary NGAL3
In vitro studies
Proximal tubule cell exposed to ferric citrate / ↑Iron content (electron microscopy); cell damage (electron microscopy); LLC-PK1 and MDCK cells65
Proximal tubule cells exposed to holotransferrin
Proximal tubule cell exposed to FeSO4 and FeCl3 / Cell damage(MTT assay in; MDCK and human proximal tubule cells);24,25in human proximal tubule cells, holotransferrin was damaging at pH6 but not at pH 7.425
*In rat unless otherwise specified.Abbreviations: ↓, decrease; ↑, increase; ↔, unchanged; AAS, atomic absorption spectrometry; ATN, acute tubular necrosis; CKD, chronic kidney disease; EDX, energy-dispersive X-ray spectroscopy; FGN,focalglomerulonephritis; FGS,focal glomerulosclerosis; GN,glomerulonephritis; GST, glutathione S-transferase;HIVAN, HIV-associated nephropathy;HO1, haem oxygenase 1; K, kidney; LLC–PK1,pig kidney epithelial cells; lys, lysosomal; MDCK, Madin–Darby canine kidney;MCGN,minimal change glomerulonephritis; MGN,membranous glomerulonephritis; MPGN,membranoproliferative glomerulonephritis; NGAL, neutrophil gelatinase-associated lipocalin;NSN,nephrotic serum nephritis; PAN MGN,penicillamine-induced membranous glomerulonephritis;PAN proteinuria,puromycin aminonucleoside-induced proteinuria; PHN, passive Heymann nephritis model; ROS, reactive oxygen species;UIE, urinary iron excretion.
1. Branten,A.J.W., Mulder,T.P.J., Peters,W.H.M., Assmann,K.J.M. Wetzels,J.F.M. Urinary excretion of glutathione S transferases alpha and pi in patients with proteinuria: Reflection of the site of tubular injury. Nephron85, 120–126 (2000).
2.Nankivell,B.J., Boadle,R.A. Harris,D.C.H. Iron accumulation in human chronic renal disease. Am. J. Kidney Dis.20, 580–584 (1992).
3.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).
4.Shah,S.V., Baliga,R., Rajapurkar,M. Fonseca,V.A. Oxidants in chronic kidney disease. J. Am. Soc. Nephrol.18, 16–28 (2007).
5.Rajapurkar,M.M., Hegde,U., Bhattacharya,A., Alam,M.G. Shah,S.V. Effect of Deferiprone, an Oral Iron Chelator, in Diabetic and Non-diabetic Glomerular Disease. Toxicol. Mech. Methods23, 1–22 (2012).
6.Ellis,D. Anemia in the course of the nephrotic syndrome secondary to transferrin depletion. J. Pediatr.90, 953–955 (1977).
7.Prinsen,B.H.C.M. etal. Transferrin synthesis is increased in nephrotic patients insufficiently to replace urinary losses. J. Am. Soc. Nephrol.12, 1017–1025 (2001).
8.Brown,E.A., Sampson,B., Muller,B.R. Curtis,J.R. Urinary iron loss in the nephrotic syndrome - an unusual cause of iron deficiency with a note on urinary copper losses. Postgrad. Med. J.60, 125–128 (1984).
9.Howard,R.L., Buddington,B. Alfrey,A.C. Urinary albumin, transferrin and iron excretion in diabetic patients. Kidney Int.40, 923–926 (1991).
10.Wang,H. etal. Iron deposition in renal biopsy specimens from patients with kidney diseases. Am. J. Kidney Dis.38, 1038–1044 (2001).
11.Gutiérrez,E. etal. Factors that determine an incomplete recovery of renal function in macrohematuria-induced acute renal failure of IgA nephropathy. Clin. J. Am. Soc. Nephrol. 2, 51–57 (2007).
12.Gutierrez,E. etal. Oxidative Stress, Macrophage Infiltration and CD163 Expression Are Determinants of Long-Term Renal Outcome in Macrohematuria-Induced Acute Kidney Injury of IgA Nephropathy. Nephron Clin. Pract. 121, C42C53 (2012).
13.Alfrey,A.C. & Hammond,W.S. Renal iron handling in the nephrotic syndrome. Kidney Int.37, 1409–1413 (1990).
14.Harris,D.C.H. & Tay,Y.C. Mitochondrial function in rat renal cortex in response to proteinuria and iron. Clin. Exp. Pharmacol. Physiol.24, 916–922 (1997).
15.Harris,D.C.H., Tay,C. Nankivell,B.J. Lysosomal iron accumulation and tubular damage in rat puromycin nephrosis and ageing. Clin. Exp. Pharmacol. Physiol.21, 73–81 (1994).
16.Ueda,N., Baliga,R. Shah,S.V. Role of ‘catalytic’ iron in an animal model of minimal change nephrotic syndrome. Kidney Int.49, 370–373 (1996).
17.Alfrey,A.C., Froment,D.H. Hammond,W.S. Role of iron in the tubulo-interstitial injury in nephrotoxic serum nephritis. Kidney International36, 753–759 (1989).
18.Alfrey,A.C. Toxicity of tubule fluid iron in the nephrotic syndrome. Am. J.Physiol.263, F637F641 (1992).
19.Baliga,R., Ueda,N. Shah,S.V. Kidney iron status in passive Heymann nephritis and the effect of an iron-deficient diet. J. Am. Soc. Nephrol. 7, 1183–1188 (1996).
20.Ohashi,N., Urushihara,M. Kobori,H. Activated intrarenal reactive oxygen species and renin angiotensin system in IgA nephropathy. Minerva Urol. Nefrol.61, 55–66 (2009).
21.Remuzzi,A., Puntorieri,S., Brugnetti,B., Bertani,T. Remuzzi,G. Renoprotective effect of low iron diet and its consequence on glomerular hemodynamics. Kidney Int.39, 647–652 (1991).
22.Viau,A. etal. Lipocalin 2 is essential for chronic kidney disease progression in mice and humans. J. Clin .Invest.120, 4065–4076 (2010).
23.Naito,Y. etal. Effect of iron restriction on renal damage and mineralocorticoid receptor signaling in a rat model of chronic kidney disease. J. Hypertens.30, 2192–2201 (2012).
24.Sponsel,H.T. etal. Effect of iron on renal tubular epithelial cells. Kidney Int.50, 436–444 (1996).
25.Chen,L., Boadle,R.A. Harris,D.C.H. Toxicity of holotransferrin but not albumin in proximal tubule cells in primary culture. J. Am. Soc. Nephrol.9, 77–84 (1998).
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