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Renal iron accumulation occurs in lupus nephritis and iron chelation delays the onset of albuminuria.

ABSTRACT: Proteins involved in iron homeostasis have been identified as biomarkers for lupus nephritis, a serious complication of systemic lupus erythematosus (SLE). We tested the hypothesis that renal iron accumulation occurs and contributes to renal injury in SLE. Renal non-heme iron levels were increased in the (New Zealand Black x New Zealand White) F1 (NZB/W) mouse model of lupus nephritis compared with healthy New Zealand White (NZW) mice in an age- and strain-dependent manner. Biodistribution studies revealed increased transferrin-bound iron accumulation in the kidneys of albuminuric NZB/W mice, but no difference in the accumulation of non-transferrin bound iron or ferritin. Transferrin excretion was significantly increased in albuminuric NZB/W mice, indicating enhanced tubular exposure and potential for enhanced tubular uptake following filtration. Expression of transferrin receptor and 24p3R were reduced in tubules from NZB/W compared to NZW mice, while ferroportin expression was unchanged and ferritin expression increased, consistent with increased iron accumulation and compensatory downregulation of uptake pathways. Treatment of NZB/W mice with the iron chelator deferiprone significantly delayed the onset of albuminuria and reduced blood urea nitrogen concentrations. Together, these findings suggest that pathological changes in renal iron homeostasis occurs in lupus nephritis, contributing to the development of kidney injury.

SUBMITTER: Marks ES

PROVIDER: S-EPMC5634457 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Renal iron accumulation occurs in lupus nephritis and iron chelation delays the onset of albuminuria.

Marks Eileen S ES Bonnemaison Mathilde L ML Brusnahan Susan K SK Zhang Wenting W Fan Wei W Garrison Jered C JC Boesen Erika I EI

Scientific reports 20171009 1

Proteins involved in iron homeostasis have been identified as biomarkers for lupus nephritis, a serious complication of systemic lupus erythematosus (SLE). We tested the hypothesis that renal iron accumulation occurs and contributes to renal injury in SLE. Renal non-heme iron levels were increased in the (New Zealand Black x New Zealand White) F1 (NZB/W) mouse model of lupus nephritis compared with healthy New Zealand White (NZW) mice in an age- and strain-dependent manner. Biodistribution studi ...[more]

PMID: 28993663

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Project description:INTRODUCTION: Among various lupus renal vascular changes, thrombotic microangiopathy (TMA) presented with the most severe clinical manifestations and high mortality. The pathogenesis of TMA in systemic lupus erythematosus (SLE) was complicated. The aim of this study was to assess clinical manifestations, laboratory characteristics, pathological features and risk factors for clinical outcomes of lupus nephritis patients co-existing with renal TMA in a large cohort in China. METHODS: Clinical and renal histopathological data of 148 patients with biopsy-proven lupus nephritis were retrospectively analyzed. Serum complement factor H, A Disintegrin and Metalloprotease with Thrombospondin type I repeats 13 (ADAMTS-13) activity, antiphospholipid antibodies and C4d deposition on renal vessels were further detected and analyzed. RESULTS: In the 148 patients with lupus nephritis, 36 patients were diagnosed as co-existing with renal TMA based on pathological diagnosis. Among the 36 TMA patients, their clinical diagnoses of renal TMA were as followings: 2 patients combining with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 2 patients combining with anti-phospholipid syndrome, 2 patients with malignant hypertension, 1 patient with scleroderma and the other 29 patients presenting with isolated renal TMA. Compared with the non-renal TMA group, patients with renal TMA had significantly higher urine protein (7.09±4.64 vs. 4.75±3.13 g/24h, P=0.007) and serum creatinine (159, 86 to 215 vs. 81, 68 to 112 ?mol/l, P<0.001), higher scores of total activity indices (AI) (P<0.001), endocapillary hypercellularity (P<0.001), subendothelial hyaline deposits (P=0.003), interstitial inflammation (P=0.005), glomerular leukocyte infiltration (P=0.006), total chronicity indices (CI) (P=0.033), tubular atrophy (P=0.004) and interstitial fibrosis (P=0.018). Patients with renal TMA presented with poorer renal outcome (P=0.005) compared with the non-TMA group. Renal TMA (hazard ratio (HR): 2.772, 95% confidence interval: 1.009 to 7.617, P=0.048) was an independent risk factor for renal outcome in patients with lupus nephritis. The renal outcome was poorer for those with both C4d deposition and decreased serum complement factor H in the TMA group (P=0.007). CONCLUSIONS: There were various causes of renal TMA in lupus nephritis. Complement over-activation via both classical and alternative pathways might play an important role in the pathogenesis of renal TMA in lupus nephritis.

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Renal iron accumulation occurs in lupus nephritis and iron chelation delays the onset of albuminuria.

Publications

Renal iron accumulation occurs in lupus nephritis and iron chelation delays the onset of albuminuria.

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