Soluble fms-Like Tyrosine Kinase 1 Localization in Renal Biopsies of CKD

Abstract

sFlt‐1 is a splice variant of the vascular endothelial growth factor (VEGF) receptor lacking the transmembrane and cytoplasmic domains and acts as a powerful antagonist of VEGF, thereby inhibiting VEGF signaling in the vasculature. Its excess can diminish and alter fenestrated capillary beds and it is considered causal in preeclampsia, but its presence is a physiologically necessity for limiting capillary growth in the vitreous and other compartments within the eye. Plasma sflt1 levels are higher in patients with chronic kidney disease (CKD) and using multivariate regression analysis were exclusively associated with renal function (higher levels correlate with decreasing function) [PMID: 19608702]. The source of this plasma sFlt‐1 is unclear, but circulating monocytes have been considered a possible etiology. 47 renal biopsies were immunostained for sFlt‐1 and evaluated on a 0–4 grading scale of positive cells within inflammatory infiltrates: 4 drug‐induced interstitial nephritis; 12 allografts, 3 with polyomavirus nephritis; 10 diabetes mellitus; 6 lupus glomerulonephritis; 5 ANCA; 5 IgA/HSP nephropathy and 5 miscellaneous chronic kidney diseases. 42 had infiltratory infiltrates of which 31 had sflt positive cells: 3 biopsies had cells which constituted more that 50% of the inflammatory infiltrate (grade 4), 6 biopsies 25–50% (grade 3), 4 biopsies 10–25% (grade 2), 3 biopsies 10% (grade1) and 15 biopsies <10% (grade +/−). The positive cells were generally single but formed clusters that became diffuse. The associated capillary network (immunostaining for CD34) was reduced or had disappeared. This data was supported by RT‐PCR analysis of sFlt‐1 in a subset of frozen biopsy samples. CD68 stains indicated that the positive cells were histiocytes/transitioning myofibroblasts such as seen in [PMID: 28209809]. In general, there was a correlation (r2= 0.89) between degree of inflammation and sFlt‐1 positive cells, but some inflammatory foci were negative; and no correlation was seen between inflammation and fibrotic changes (perhaps indicating that the fibrotic changes might be an ongoing/evolving process). Cases of polyomavirus nephritis (2), drug‐associated interstitial nephritis (3), advanced diabetic kidneys (3) and HSP(1) were the most positive (9/47), but significant (10% or greater) sFlt‐1 positivity was seen in many biopsies (16/47). In conclusion, sFlt‐1 positive cells are generally part of the inflammatory infiltrates in CKD and may be extremely abundant. Their presence promotes an anti‐angiogenic state that could inhibit capillary repair, contribute to peritubular capillary loss and enhance fibrosis in CKD. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Peritubular Capillary Rarefaction: An Underappreciated Regulator of CKD Progression

“…sFlt-1 is a truncated form of VEGFR1 and a potent circulating antagonist for VEGF-A. Renal biopsy samples demonstrated that sFlt-1 is expressed in CD68+ histiocytes (a part of macrophage population) and PTC network around sFlt-1+ cells are diminished [84]. In patients receiving cardiac surgery, perioperative low VEGF-A and high sFlt-1 levels in the plasma significantly predicted future development of acute kidney injury (AKI) [85].…”

The soluble VEGF receptor sFlt-1 contributes to endothelial dysfunction in IgA nephropathy

“…Soluble fms-like tyrosine kinase-1 (sFlt-1), a vascular endothelial growth factor (VEGF) antagonist, has been suggested as a marker of endothelial dysfunction in preeclampsia [8,9]. Many studies demonstrated excess sFlt-1 was associated with endothelial dysfunction in patients with chronic kidney disease (CKD) [10,11]. Our previous study reported sFlt-1 level elevated in IgAN patients and also correlated with proteinuria, hypertension and vWF level [12].…”

Circulating Soluble Fms-like Tyrosine Kinase in Renal Diseases Other than Preeclampsia

“…The authors suggested that sFlt-1 positive macrophages recruited into the kidneys during injury may promote a localized antiangiogenic milieu, leading to capillary repair inhibition. 67 Aside from monocytes/macrophages, renal epithelial cells may also account for local sFlt-1 production. Immunostaining of renal samples from patients with noncardiac surgery AKI evidenced a significant increase in tubular sFlt-1 expression compared with control samples (non-AKI tissue).…”

“…Renal sFlt-1 expression has been found in biopsies of patients with CKD, including those with hypertension, diabetes, ANCA, and IgA nephropathy. 67…”

“…Interestingly, Zsengellér et al . 67 reported on sFlt-1 expression by infiltrating histiocytes/macrophages in the kidneys of patients with CKD. Of 52 analyzed renal biopsies, 37 were positive for sFlt-1, and sFlt-1 expression was positively associated with the degree of inflammation.…”