Chronic Kidney Disease: Challenges in Translational Medicine.

Chronic kidney disease (CKD) has long been recognized as a state of progressive decline in renal function. Morbidity and mortality are well correlated to the stage of renal function decline. Approximately one million deaths are estimated to be related to CKD worldwide. They are mostly associated with cardiovascular disease as a result of concurrent hypertension, accelerated atherosclerosis, and volume overload. Even with the best current treatment, disease progression is the general rule with a small fraction who reach CKD stage 5 requiring kidney transplantation or dialysis. Transplant patients show substantial reductions in mortality and cardiovascular events, as well as improvements in quality of life. However, the capacity of health systems to deliver kidney transplantation varies worldwide with worse indicators in low-income countries. Consequently, exploring novel and better therapeutic options for CKD is mandatory. Cell-based therapy is a promising strategy for treating CKD in preclinical models, and several clinical trials involving kidney disease exhibit a favorable safety profile. This chapter aims to provide an overview of CKD and the recent results of clinical trials of cell therapy in kidney diseases.

Brilliant blue G, a P2X7 receptor antagonist, attenuates early phase of renal inflammation, interstitial fibrosis and is associated with renal cell proliferation in ureteral obstruction in rats.

BACKGROUND: Previous study showed that purinergic P2X7 receptors (P2X7R) reach the highest expression in the first week after unilateral ureteral obstruction (UUO) in mice, and are involved in the process of inflammation, apoptosis and fibrosis of renal tissue. We, herein, document the role of purinergic P2X7 receptors activation on the third day of UUO, as assessed by means of BBG as its selective inhibitor. METHODS: We investigated the effects of brilliant blue G (BBG), a P2X7R antagonist, in the third day of kidney tissue response to UUO in rats. For this purpose, male Wistar rats submitted to UUO or sham operated, received BBG or vehicle (V), comprising four groups: UUO-BBG, UUO-V, sham-BBG and sham-V. The kidneys were harvested on day 3 UUO and prepared for histology, immunohistochemistry (P2X7R, PCNA, CD-68, α-sma, TGF-ß1, Heat-shock protein-47, TUNEL assay), quantitative real-time PCR (IL-1ß, procollagens type I, III, and IV) for mRNA quantification. RESULTS: The group UUO-V presented an enhancement in tubular cell P2X7-R expression, increase influx of macrophages and myofibroblasts, HSP-47 and TGF- ß1 expression. Also, upregulation of procollagen types I, III, and IV, and IL-1ß mRNAs were seen. On the other hand, group UUO-BBG showed lower expression of procollagens and IL-1ß mRNAs, as well as less immunoreactivity of HSP-47, TGF-ß, macrophages, myofibroblasts, and tubular apoptosis. This group also presented increased epithelial cell proliferation. CONCLUSION: BBG, a known highly selective inhibitor of P2X7R, attenuated renal inflammation, collagen synthesis, renal cell apoptosis, and enhanced renal cell proliferation in the early phase of rat model of UUO.

Bone marrow-derived mononuclear cells promote improvement in glomerular function in rats with early diabetic nephropathy.

BACKGROUND/AIMS: Diabetic nephropathy is one of the main causes of end-stage renal disease. The present study investigated the effect of mononuclear cell (MC) therapy in rats subjected to diabetic nephropathy. METHODS: Male Wistar rats were divided into control (CTRL), diabetic (DM), CTRL+MC and DM+MC groups. Diabetes was induced by a single injection of streptozotocin (45 mg/kg, i.p.) and, 4 weeks later, 2×10(7) MCs were injected via the jugular vein. RESULTS: The rats in the DM and DM+MC groups showed increased glycemia, glomerular filtration rate and glomerular tuff area versus control groups. The glomerular filtration rate and glomerular tuff area were normalized in the DM+MC group. No alterations were observed in the fractional excretion of electrolytes and proteinuria between the DM and DM+MC groups. TGF-ß1 protein levels in the DM group were significantly increased versus control animals and normalized in the DM+MC group. An increase in ED1(+)/arginase I(+) macrophages and IL-10 renal expression was observed in the DM+MC group versus DM group. CONCLUSIONS: Bone marrow-derived MC therapy was able to prevent glomerular alterations and TGF-ß1 protein overexpression and modulated glomerular arginase I(+) macrophage infiltration in rats subjected to early diabetic nephropathy.

Alpha-tocopherol supplementation decreases electronegative low-density lipoprotein concentration [LDL(-)] in haemodialysis patients.

BACKGROUND: Oxidative stress is a significant contributor to cardiovascular diseases (CVD) in haemodialysis (HD) patients, predisposing to the generation of oxidized low-density lipoprotein (oxLDL) or electronegatively charged LDL subfraction. Antioxidant therapy such as alpha-tocopherol acts as a scavenger of lipid peroxyl radicals attenuating the oxidative stress, which decreases the formation of oxLDL. The present study was designed to investigate the influence of the alpha-tocopherol supplementation on the concentration of electronegative low-density lipoprotein [LDL(-)], a minimally oxidized LDL, which we have previously described to be high in HD patients. METHODS: Blood samples were collected before and after 120 days of supplementation by alpha-tocopherol (400 UI/day) in 19 stable HD patients (50 +/- 7.8 years; 9 males). The concentrations of LDL(-) in blood plasma [using an anti-LDL- human monoclonal antibody (mAb)] and the anti-LDL(-) IgG auto-antibodies were determined by ELISA. Calculation of body mass index (BMI) and measurements of waist circumference (WC), triceps skin folds (TSF) and arm muscle area (AMA) were performed. RESULTS: The plasma alpha-tocopherol levels increased from 7.9 microM (0.32-18.4) to 14.2 microM (1.22-23.8) after the supplementation (P = 0.02). The mean concentration of LDL(-) was reduced from 570.9 microg/mL (225.6-1241.0) to 169.1 microg/mL (63.6-621.1) (P < 0.001). The anti-LDL(-) IgG auto-antibodies did not change significantly after the supplementation. The alpha-tocopherol supplementation also reduced the total cholesterol and LDL-C levels in these patients, from 176 +/- 42.3 mg/dL to 120 +/- 35.7 mg/dL (P < 0.05) and 115.5 +/- 21.4 mg/dL to 98.5 +/- 23.01 mg/dL (P < 0.001), respectively. CONCLUSION: The oral administration of alpha-tocopherol in HD patients resulted in a significant decrease in the LDL(-), total cholesterol and LDL-C levels. This effect may favour a reduction in cardiovascular risk in these patients, but a larger study is required to confirm an effect in this clinical setting.