Nephrotic-range proteinuria in a patient with a renal allograft treated with sorafenib for metastatic renal-cell carcinoma

Jonkers, I.J.A.M.; Buren, Marjolijn van

doi:10.1007/s10157-009-0167-5

Cited by 17 publications

(9 citation statements)

References 14 publications

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“…25 Several cases of nephrotic proteinuria have been reported in patients who were treated with sorafenib or sunitinib. 26,27 Proteinuria induced by VEGF inhibition may involve multiple pathways. VEGF is constitutively produced by podocytes with a function of activating VEGF receptor 2 on glomerular capillary endothelial cells, and its inhibition may cause a loss of endothelial fenestrations and podocytes and reduced proliferation of endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Bevacizumab Increases Risk for Severe Proteinuria in Cancer Patients

Kim²,

Baer³

et al. 2010

Journal of the American Society of Nephrology

202

127

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Treatment with the chemotherapeutic agent bevacizumab, a humanized mAb that neutralizes vascular endothelial growth factor, can lead to proteinuria and renal damage. The risk factors and clinical outcomes of renal adverse events are not well understood. We performed a systematic review and meta-analysis of published randomized, controlled trials to assess the overall risk for severe proteinuria with bevacizumab. We analyzed data from 16 studies comprising 12,268 patients with a variety of tumors. The incidence of high-grade (grade 3 or 4) proteinuria with bevacizumab was 2.2% (95% confidence interval [CI] 1.2 to 4.3%). Compared with chemotherapy alone, bevacizumab combined with chemotherapy significantly increased the risk for high-grade proteinuria (relative risk 4.79; 95% CI 2.71 to 8.46) and nephrotic syndrome (relative risk 7.78; 95% CI 1.80 to 33.62); higher dosages of bevacizumab associated with increased risk for proteinuria. Regarding tumor type, renal cell carcinoma associated with the highest risk (cumulative incidence 10.2%). We did not detect a significant difference between platinum-and non-platinum-based concurrent chemotherapy with regard to risk for high-grade proteinuria (P ϭ 0.39). In conclusion, the addition of bevacizumab to chemotherapy significantly increases the risk for high-grade proteinuria and nephrotic syndrome.

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Section: Discussionmentioning

confidence: 99%

Bevacizumab Increases Risk for Severe Proteinuria in Cancer Patients

Kim²,

Baer³

et al. 2010

Journal of the American Society of Nephrology

202

127

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“…VEGF-A is constitutively expressed in human and rodent kidneys(113, 114) and rodent models of progressive renal failure show loss in glomerular and tubular VEGF-A coinciding with loss of capillaries and the subsequent development of glomerulosclerosis and interstitial fibrosis (115). In humans, pharmacologic inhibition of VEGF-A during cancer treatment can lead to proteinuria and worsening kidney function (116). Glomerular and peritubular capillary rarefaction is an important feature of disease progression in other conditions including diabetic nephropathy (117).…”

Section: Discussionmentioning

confidence: 99%

The Detrimental Effects of IFN-α on Vasculogenesis in Lupus Are Mediated by Repression of IL-1 Pathways: Potential Role in Atherogenesis and Renal Vascular Rarefaction

Thacker

Berthier

Mattinzoli

et al. 2010

The Journal of Immunology

123

113

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Systemic lupus erythematosus (SLE) is characterized by increased vascular risk due to premature atherosclerosis independent of traditional risk factors. We previously proposed that IFN-α plays a crucial role in premature vascular damage in SLE. IFN-α alters the balance between endothelial cell apoptosis and vascular repair mediated by endothelial progenitor cells (EPCs) and myeloid circulating angiogenic cells (CACs). In this study, we demonstrate that IFN-α promotes an antiangiogenic signature in SLE and control EPCs/CACs, characterized by transcriptional repression of IL-1α and β, IL-1R1, and vascular endothelial growth factor A, and upregulation of IL-1R antagonist and the decoy receptor IL-1R2. IL-1β promotes significant improvement in the functional capacity of lupus EPCs/CACs, therefore abrogating the deleterious effects of IFN-α. The beneficial effects from IL-1 are mediated, at least in part, by increases in EPC/CAC proliferation, by decreases in EPC/CAC apoptosis, and by preventing the skewing of CACs toward nonangiogenic pathways. IFN-α induces STAT2 and 6 phosphorylation in EPCs/CACs, and JAK inhibition abrogates the transcriptional antiangiogenic changes induced by IFN-α in these cells. Immunohistochemistry of renal biopsies from patients with lupus nephritis, but not anti-neutrophil cytoplasmic Ab-positive vasculitis, showed this pathway to be operational in vivo, with increased IL-1R antagonist, downregulation of vascular endothelial growth factor A, and glomerular and blood vessel decreased capillary density, compared with controls. Our study introduces a novel putative pathway by which type I IFNs may interfere with vascular repair in SLE through repression of IL-1–dependent pathways. This could promote atherosclerosis and loss of renal function in this disease.

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“…22 This hypothesis was verified showing that in EBVtransformed B LCL ERK1/2 is hypo-phosphorylated in SPRY2 variant carriers and normal in the only family member, who tested negative for the variant. Moreover, as mentioned above, pERK1/2 is a strong transcriptional activator of SPRY2, 20,23,24 whereas its block causes SPRY2 transcriptional silencing. This tight transcriptional feedback explains the strong reduction observed in SPRY2 transcript, without apparent reduction in the protein levels.…”

Section: Association Of Mapkmentioning

confidence: 82%

“…Support to this hypothesis is derived from the observation of sudden worsening of kidney function because of the IgA deposits in a patient treated with Sorafenib, 20 an inhibitor of the ERK pathway, as well as other kinases. Therefore, the LCL157 was treated in vitro for 7 days with sorafenib, followed by the assessment of SPRY2 transcript levels, IgA and ERK1/2 phosphorylation.…”

Section: Exome Sequencing and Bioinformatics Analysismentioning

confidence: 99%

A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy

Milillo¹,

Carpia²,

Costanzi

et al. 2015

Eur J Hum Genet

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IgA nephropathy (IgAN) represents the most common primary glomerulonephritis worldwide with a prevalence of 25-50% among patients with primary glomerulopathies. In~5-10% of the patients the disease segregates with an autosomal dominant (AD) pattern. Association studies identified loci on chromosomes 1q32, 6p21, 8p23, 17p13, 22q12, whereas classical linkage studies on AD families identified loci on chromosomes 2q36, 4q26-31, 6q22, 17q12-22. We have studied a large Sicilian family where IgAN segregates with an AD transmission. To identify the causal gene, the exomes of two affected and one unaffected individual have been sequenced. From the bioinformatics analysis a p.(Arg119Trp) variant in the SPRY2 gene was identified as the probable disease-causing mutation. Moreover, functional characterization of this variant showed that it is responsible for the inhibition of the MAPK/ERK1/2 pathway. The same effect was observed in two sporadic IgAN patients carriers of wild-type SPRY2, suggesting that downregulation of the MAPK/ERK1/2 pathway represents a common mechanism leading to IgAN.

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Nephrotic-range proteinuria in a patient with a renal allograft treated with sorafenib for metastatic renal-cell carcinoma

Cited by 17 publications

References 14 publications

Bevacizumab Increases Risk for Severe Proteinuria in Cancer Patients

Bevacizumab Increases Risk for Severe Proteinuria in Cancer Patients

The Detrimental Effects of IFN-α on Vasculogenesis in Lupus Are Mediated by Repression of IL-1 Pathways: Potential Role in Atherogenesis and Renal Vascular Rarefaction

A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy

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