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Aims: Active vitamin D deficiency is associated with increased aortic-pulse wave velocity (Ao-PWV) in people with type 2 diabetes (T2DM) and chronic kidney disease (CKD). There are no randomised controlled trials investigating the effect of active vitamin D treatment on Ao-PWV in people with T2DM and CKD. Methods: A 48-week duration single-centre randomised double-blind parallel-group trial examined the impact of oral 1,25 dihydroxyvitamin D (calcitriol 0.25 mcg OD) as compared to placebo on a primary endpoint of Ao-PWV. People with T2DM and stable stage 3 CKD with intact parathyroid hormone (iPTH) level >30 pg/mL were eligible. Results: In total, 127 (70% male) people were randomised (calcitriol n = 64 or placebo n = 63). There was no change in Ao-PWV observed, mean ± standard deviation (SD), in the calcitriol group of 11.79 (±2.5) to 12.08 (3.0) m/s as compared to 10.90 (±2.4) to 11.39 (±2.6) m/s with placebo. The between-treatment group adjusted mean (95% confidence interval [(CI]] change was 0.23 (−0.58 to 1.05) m/s, P =.57. No effect of calcitriol was observed on central arterial pressures, albuminuria, serum calcium or phosphate levels. However, iPTH fell with calcitriol treatment (mean [95% CI] between-group difference of −27.8 (−42.3 to −13.2) pg/mL, P

Damage to the vasculature is the primary mechanism driving chronic diabetic microvascular complications such as diabetic nephropathy which manifests as albuminuria. Therefore, treatments that protect the diabetic vasculature have significant therapeutic potential. Soluble Neurite outgrowth inhibitor-B (sNogo-B) is a circulating N-terminus isoform of full-length Nogo-B which plays a key role in vascular remodelling following injury. However, there is currently no information on the role of sNogo-B in the context of diabetic nephropathy. We demonstrate that overexpression of sNogo-B in the circulation ameliorates diabetic kidney disease by reducing albuminuria, hyperfiltration, abnormal angiogenesis and protecting glomerular capillary structure. Systemic sNogo-B overexpression in diabetic mice also associates with dampening VEGF-A signalling and reducing eNOS, AKT and GSK3β phosphorylation. Furthermore, sNogo-B prevented the impairment of tube formation which occurred when human endothelial cells were exposed to sera from patients with diabetic kidney disease. Collectively, these studies provide the first evidence that sNogo-B protects the vasculature in diabetes and may represent a novel therapeutic target for diabetic vascular complications.

Alternatively activated macrophages (M2) have regenerative properties and shown promise as cell therapy in chronic kidney disease. However, M2 plasticity is one of the major hurdles to overcome. Our previous studies showed that genetically modified macrophages stabilized by neutrophil gelatinase-associated lipocalin (NGAL) were able to preserve their M2 phenotype. Nowadays, little is known about M2 macrophage effects in diabetic kidney disease (DKD). The aim of the study was to investigate the therapeutic effect of both bone marrow-derived M2 (BM-фM2) and ф-NGAL macrophages in the db/db mice. Seventeen-week-old mice with established DKD were divided into five treatment groups with their controls: D+BM-фM2; D+ф-BM; D+ф-NGAL; D+ф-RAW; D+SHAM and non-diabetic (ND) (db/- and C57bl/6J) animals. We infused 1 × 10 macrophages twice, at baseline and 2 weeks thereafter. BM-фM2 did not show any therapeutic effect whereas ф-NGAL significantly reduced albuminuria and renal fibrosis. The ф-NGAL therapy increased the anti-inflammatory IL-10 and reduced some pro-inflammatory cytokines, reduced the proportion of M1 glomerular macrophages and podocyte loss and was associated with a significant decrease of renal TGF-β1. Overall, our study provides evidence that ф-NGAL macrophage cell therapy has a therapeutic effect on DKD probably by modulation of the renal inflammatory response caused by the diabetic milieu., This work was supported by Spanish Government Instituto de Salud Carlos III (ISCIII) grant PI12/01427, PI15/00638 and PI12/ 00720, AMGEN grant under the auspices of The Red de Investigación Renal (European Regional Development Funds ISCIII Red Temática de Investigación Cooperativa en Salud Red de Investigación Renal; RD16/0009/0003) and SENEFRO (awarded to AS). SAF 2015‐ 67770 (awarded to GH). AS is supported by Miguel Servet Contracting System (CP08/00138).

Background and Aims: Active vitamin D [1,25(OH)2D3] deficiency is a potential modifiable risk factor for cardiovascular (CVD) and renal disease in patients with type 2 diabetes (T2DM) and stage 3/4 chronic kidney disease (CKD). Exact mechanisms are unclear. Arterial stiffness is an independent predictor of CVD. There is limited data on the effect of active vitamin D treatment on arterial haemodynamics in this patient population. Materials and Methods: We performed a 48 week duration single centre randomised double blind placebo controlled trial on the impact of calcitriol 0.25 mcg od in patients with T2DM and stage 3 CKD. Primary endpoint was change in Ao-PWV (index of arterial stiffness) measured by applanation tonometry (Sphygmocor system). Secondary endpoints included albuminuria (albumin excretion rate-AER) and changes in other indices of central haemodynamics. Results: 127 (male 70%) patients were randomised to calcitriol (n = 64) or placebo (n = 63). Baseline, mean ± SD, values were: age 64.2 ± 7.7, eGFR 43.2 ± 20.2 ml/min, SBP 146.2 ± 19.9 mmHg, Ao-PWV 11.6 ± 3.3 m/s, and AER median (IQR) 50.51 (11.5 to 188.6) mcg/min. There was no significant mean (95% CI) change in Ao-PWV as compared to placebo of 0.05 m/s (−0.68 to 0.78) vs 0.23 m/s (−0.46 to 0.93) with a between treatment mean (95% CI) difference for Ao-PWV of 0.19 (−0.81 to 1.19) m/s (p = 0.71). No significant effect of calcitriol treatment observed on augmentation index or albuminuria. Conclusion: In T2DM patients with stage 3 CKD, 48 week treatment with calcitriol as compared to placebo does not improve Ao-PWV, albuminuria or other indices of central haemodynamics.

Chronic kidney disease (CKD) has become a major health problem worldwide. This review describes the role of macrophages in CKD and highlights the importance of anti-inflammatory M2 macrophage activation in both renal fibrosis and wound healing processes. Furthermore, the mechanisms by which M2 macrophages induce renal repair and regeneration are still under debate and currently demand more attention. The M1/M2 macrophage balance is related to the renal microenvironment and could influence CKD progression. In fact, an inflammatory renal environment and M2 plasticity can be the major hurdles to establishing macrophage cell-based therapies in CKD. M2 macrophage cell-based therapy is promising if the M2 phenotype remains stable and is 'fixed' by in vitro manipulation. However, a greater understanding of phenotype polarization is still required. Moreover, better strategies and targets to induce reparative macrophages in vivo should guide future investigations in order to abate kidney diseases.

Aims/hypothesis We previously demonstrated hepatocyte growth factor (HGF) gene therapy was able to induce regression of glomerulosclerosis in diabetic nephropathy through local reparative mechanisms. The aim of this study was to test whether bone-marow-derived cells are also involved in this HGF-induced reparative process. Methods We have created chimeric db/db mice as a model of diabetes that produce enhanced green fluorescent protein (EGFP) in bone marrow cells. We performed treatment with HGF gene therapy either alone or in combination with granulocyte-colony stimulating factor, in order to induce mobilisation of haematopoietic stem cells in these diabetic and chimeric animals. Results We find HGF gene therapy enhances renal expression of stromal-cell-derived factor-1 and is subsequently associated with an increased number of bone-marrow-derived cells getting into the injured kidneys. These cells are mainly monocyte-derived macrophages, which may contribute to the renal tissue repair and regeneration consistently observed in our model. Finally, HGF gene therapy is associated with the presence of a small number of Bowman’s capsule parietal epithelial cells producing EGFP, suggesting they are fused with bone-marrow-derived cells and are contributing to podocyte repopulation. Conclusions/interpretation Altogether, our findings provide new evidence about the therapeutic role of HGF and open new opportunities for inducing renal regeneration in diabetic nephropathy.

Aims Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists and mammalian target of rapamycin (mTOR) inhibitors share mechanisms concerning cell growth and reduction of extracellular matrix accumulation. The purpose of this study was to evaluate the potential synergistic effect of this combination on diabetic kidney disease in rats. Main methods Diabetes was induced by streptozotocin in 42 male Sprague–Dawley rats. Sixteen weeks after diabetes induction, animals were divided into four groups: diabetic animals without intervention (D), diabetic animals with administration of sirolimus (D + SRL), diabetic animals with administration of rosiglitazone (D + RGT), and diabetic animals with administration of sirolimus and rosiglitazone (D + SRL + RGT). Key findings At a 30-day follow up, diabetic rats showed higher kidney weight, mean glomerular volume, mesangial expansion and albuminuria compared with non-diabetic rats. mTOR downstream proteins, p-T389-S6K and p-T37/46-4EBP1, were higher in diabetic than non-diabetic kidneys, whereas p-S473-AKT was not, suggesting that hyperglycemia mainly activated the mTORC1 pathway in vivo. Moreover, the catalytic subunit of protein phosphatase 2A (PP2Ac) was down-regulated in the diabetic kidney. Sirolimus inhibited the mTORC1 pathway, while the PPAR-γ agonist rosiglitazone enhanced PP2Ac and reduced p70S6K. Both drugs were associated with a reduction in albuminuria, renal enlargement and mesangial expansion, but without any improvement in glycemic control. Sirolimus and rosiglitazone in combination down-regulated the mTORC1 pathway and over-activated PP2Ac in diabetic kidney. This effect may account for the synergistic reduction of renal hypertrophy, albuminuria and renal TGF-β1 observed in diabetic rats treated with SRL + RGT. Significance The combination of sirolimus and rosiglitazone is renoprotective with respect to diabetic nephropathy.

Background. In clinical renal transplantation, an increase in proteinuria after conversion from calcineurin inhibitors to rapamycin has been reported. In contrast, there are studies showing a nephro-protective effect of rapamycin in proteinuric diseases characterized by progressive interstitial inflammatory fibrosis. Methods. Because of the contradictory reports concerning rapamycin on proteinuria, we examined proteinuria and podocyte damage markers on two renal disease models, with clearly different pathophysiological mechanisms: a glomerular toxico-immunological model induced by puromycin aminonucleoside, and a chronic hyperfiltration and inflammatory model by mass reduction, both treated with a fixed high rapamycin dose. Results. In puromycin groups, rapamycin provoked significant increases in proteinuria, together with a significant fall in podocin immunofluorescence, as well as clear additional damage to podocyte foot processes. Conversely, after mass reduction, rapamycin produced lower levels of proteinuria and amelioration of inflammatory and pro-fibrotic damage. In contrast to the puromycin model, higher glomerular podocin and nephrin expression and amelioration of glomerular ultrastructural damage were found. Conclusions. We conclude that rapamycin has dual opposing effects on subjacent renal lesion, with proteinuria and podocyte damage aggravation in the glomerular model and a nephro-protective effect in the chronic inflammatory tubulointerstitial model. Rapamycin produces slight alterations in podocyte structure when acting on healthy podocytes, but it clearly worsens those podocytes damaged by other concomitant injury.

PURPOSE OF REVIEW: To briefly show which are the mechanisms and cell types involved in kidney regeneration and describe some of the therapies currently under study in regenerative medicine for kidney transplantation. RECENT FINDINGS: The kidney contains cell progenitors that under specific circumstances have the ability to regenerate specific structures. Apart from the knowledge gained in the self-regenerative properties of the kidney, new concepts in regenerative medicine such as organ engineering and the use of mesenchymal stem cell-based therapies are currently the focus of attention in the field. SUMMARY: Overall, kidney regeneration is a reality and the knowledge on how to control it will be one of the main scopes in the present and future.

In solid organ transplantation, mesenchymal stem cell (MSC) therapy is strongly emerging among other cell therapies due to the positive results obtained in vitro and in vivo as an immunomodulatory agent and their potential regenerative role. We aimed at testing whether a single dose of MSCs, injected at 11 weeks after kidney transplantation for the prevention of chronic mechanisms, enhanced regeneration and provided protection against the inflammatory and fibrotic processes that finally lead to the characteristic features of chronic allograft nephropathy (CAN). Either bone marrow mononuclear cells (BMCs) injection or no-therapy (NT) were used as control treatments. A rat kidney transplantation model of CAN with 2.5 h of cold ischemia was used, and functional, histological, and molecular parameters were assessed at 12 and 24 weeks after transplantation. MSC and BMC cell therapy preserves renal function at 24 weeks and abrogates proteinuria, which is typical of this model (NT24w: 68.9 +/- 26.5mg/24 h, MSC24w: 16.6 +/- 2.3mg/24 h, BMC24w: 24.1 +/- 5.3mg/24 h, P < 0.03). Only MSC-treated animals showed a reduction in interstitial fibrosis and tubular atrophy (NT24w: 2.3 +/- 0.29, MSC24w: 0.4 +/- 0.2, P < 0.03), less T cells (NT: 39.6 +/- 9.5, MSC: 8.1 +/- 0.9, P < 0.03) and macrophages (NT: 20.9 +/- 4.7, MSC: 5.9 +/- 1.7, P < 0.05) infiltrating the parenchyma and lowered expression of inflammatory cytokines while increasing the expression of anti-inflammatory factors. MSCs appear to serve as a protection from injury development rather than regenerate the damaged tissue, as no differences were observed in Ki67 expression, and kidney injury molecule-1, Clusterin, NGAL, and hepatocyte growth factor expression were only up-regulated in nontreated animals. Considering the results, a single delayed MSC injection is effective for the long-term protection of kidney allografts.

[Background/Aims] Alternatively activated macrophages (AAM) have regenerative and anti-inflammatory characteristics. Here, we sought to evaluate whether AAM cell therapy reduces renal inflammation and fibrosis in the unilateral ureteral obstruction (UUO) mice model., [Methods] We stabilized macrophages by adenoviral vector NGAL (Neutrophil gelatinase-associated lipocalin-2) and infused them into UUO mice. To ascertain whether macrophages were capable of reaching the obstructed kidney, macrophages were stained and detected by in vivo cell tracking., [Results] We demonstrated that some infused macrophages reached the obstructed kidney and that infusion of macrophages overexpressing NGAL was associated with reduced kidney interstitial fibrosis and inflammation. This therapeutic effect was mainly associated with the phenotype and function preservation of the transferred macrophages isolated from the obstructed kidney, [Conclusions] Macrophage plasticity is a major hurdle for achieving macrophage therapy success in chronic nephropathies and could be overcome by transferring lipocalin-2., This research was supported by Spanish Government Instituto de Salud Carlos III (ISCIII) grant PI12/01427, PI15/00638 and PI12/00720 Confunded by FEDER funds/European Regional Development Fund (ERDF)-a way to Build Europe-//, AMGEN grant under the auspices of The Red de Investigación Renal (European Regional Development Funds ISCIII Red Temática de Investigación Cooperativa en Salud Red de Investigación Renal; RD16/0009/0003) and SENEFRO (awarded to AS). SAF 2015-67770 (awarded to GH). AS is supported by Miguel Servet contracting system (CP08/00138).