Galectin-9 deficiency exacerbates lipopolysaccharide-induced hypothermia and kidney injury.

BACKGROUND: Galectin-9 (Gal-9) is a multifunctional lectin that moderates inflammation and organ damage. In this study, we tested whether Gal-9 has a protective role in the pathogenesis of endotoxemic acute kidney injury. METHODS: We examined the levels of Gal-9 in control mice after lipopolysaccharide (LPS) administration. We developed Gal-9 knockout (KO) mice that lack Gal-9 systemically and evaluated the role of Gal-9 in LPS-induced proinflammatory cytokines, vascular permeability, and renal injury. RESULTS: Gal-9 levels were increased in the plasma, kidney, and spleen within 4 h after LPS administration to wild-type mice. Gal-9 deficiency did not affect the LPS-induced increase in plasma tumor necrosis factor-α levels at 1 h or vascular permeability at 6 h. Lower urine volume and reduced creatinine clearance were observed in Gal-9-KO mice compared with wild-type mice after LPS administration. Gal-9-KO mice had limited improvement in urine volume after fluid resuscitation compared with wild-type mice. LPS reduced the body temperature 12 h after its administration. Hypothermia had disappeared in wild-type mice by 24 h, whereas it was sustained until 24 h in Gal-9-KO mice. Importantly, maintaining body temperature in Gal-9-KO mice improved the response of urine flow to fluid resuscitation. CONCLUSION: Deficiency in Gal-9 worsened LPS-induced hypothermia and kidney injury in mice. The accelerated hypothermia induced by Gal-9 deficiency contributed to the blunted response to fluid resuscitation.

The effects of a participatory structured group educational program on the development of CKD: a population-based study.

BACKGROUND: The type of lifestyle guidance that is effective for preventing development of chronic kidney disease (CKD) is unknown. Here, we aim to investigate the effects of a participatory structured group education (SGE) program on the development of CKD in a population-based study. METHODS: We retrospectively analyzed 1060 adult special health check-up examinees with CKD. Examinees with an estimated glomerular filtration rate (eGFR) from 50 to 60 mL/min/1.73 m2 and/or proteinuria 1+ were encouraged to attend an SGE program. The SGE program included participatory small group discussions on the attendees' remaining risk factors. The primary outcome of this study was the change in eGFR per year. RESULTS: The changes in eGFR in examinees who attended the SGE program (n = 209, + 2.9 mL/min/1.73 m2 [95% confidence interval (CI) + 1.9 to + 3.9]) significantly improved compared with control (n = 383, + 1.2 mL/min/1.73 m2 [95% CI + 0.5 to + 1.9], p = 0.006). Attending an SGE program was independently and positively related to the changes in eGFR at 1 year after attendance, after adjusting for classical covariates (ß = 1.55 [95% CI 0.37-2.73], p = 0.01). Attending an SGE program was effective for the examinees with a lower eGFR compared with those with only proteinuria. CONCLUSIONS: Our SGE program showed the beneficial effects of preventing the development of CKD, independent of classical factors. The type of SGE program that is more effective for preventing development of CKD should be investigated in a long-term analysis.

Tubular Cell Senescence in the Donated Kidney Predicts Allograft Function, but Not Donor Remnant Kidney Function, in Living Donor Kidney Transplantation.

BACKGROUND: It is uncertain whether kidneys from marginal donors are suitable for live kidney transplantation. In deceased donor kidneys, tubular cell senescence affects allograft function. However, the degree of cell senescence in a living donor kidney with marginal factors has not been reported. In this study, we assessed the association of tubular cell senescence with allograft and remnant kidney function by a prospective observational clinical study. METHODS: Thirty-eight living donor kidney transplantations were analyzed prospectively. Tissue sections obtained from preimplantation kidney biopsies were immunostained for p16INK4a to indicate cell senescence. Various kidney biomarkers were analyzed in urine and blood samples. RESULTS: Of the 38 donors, 21 had marginal factors. Severe tubular senescence was found in living donors with overlapping marginal criteria. Tubular senescence in living donor kidneys was significantly related to donor age and lower recipient kidney function at 1 year after transplantation independently of donor age (ß = -0.281; p = 0.050) but did not affect remnant kidney function after donation. Pretransplantation donor pre-estimated glomerular filtration rate and hypertension did not show a significant area under the curve (AUC) for prediction of high tubular senescence. High plasma levels of soluble αKlotho were associated with a higher predictive value for low tubular cell senescence with an AUC of 0.78 (95% CI 0.62-0.93; p < 0.01). CONCLUSIONS: The nuclear p16-staining rate in donated kidney tubules is a predictor for allograft kidney function but not donor remnant kidney function. Detection of tubular cell senescence may facilitate selection of appropriate living donor candidates.

Latent IgA deposition from donor kidneys does not affect transplant prognosis, irrespective of mesangial expansion.

INTRODUCTION: Latent mesangial immunoglobulin A (IgA) deposition in the donated kidney has been investigated in the context of kidney transplantation. However, few studies have examined the impact of mesangial expansion accompanied with IgA deposition. Therefore, we investigated the effects of latent IgA deposition and mesangial expansion on transplant prognosis following living-donor kidney transplantation. METHODS: We retrospectively analyzed 68 consecutive adult living-donor kidney transplantations performed at Kagawa University Hospital. Biopsies were performed at pre-implantation and at one year after transplantation. RESULTS: Twenty kidneys exhibited latent IgA deposition in pre-implantation biopsies, including 14 with mesangial expansion. Latent IgA deposition was not associated with renal function or donor urinalysis after donation, irrespective of mesangial expansion. Latent IgA deposition was not significantly associated with graft survival rate, allograft function, abnormal urinalysis, or the recurrence of IgA nephropathy, irrespective of mesangial expansion. At one year after transplantation, IgA deposition had disappeared in 14/20 allografts. Estimated glomerular function rate >40 mL/min/1.73 m(2) was significantly associated with the disappearance of IgA deposition. CONCLUSIONS: The present study showed that latent IgA deposition from the donor kidney, irrespective of mesangial expansion, does not affect transplant prognosis following living-donor kidney transplantation.

Pre-existing arteriosclerotic intimal thickening in living-donor kidneys reflects allograft function.

BACKGROUND: Donor shortage is a serious problem worldwide and it is now debated whether kidneys from marginal donors are suitable for renal transplantation. Recent studies have shown that the findings of preimplantation kidney biopsy are useful to evaluate vasculopathy in the donated kidney, and may predict transplant outcomes in deceased- donor kidney transplantation. However, few studies have focused on the pathological findings of preimplantation biopsy in living-donor kidney transplantation. Therefore, we investigated whether arteriosclerotic vasculopathy in living-donor kidneys at the time of transplantation predicts the recipient's kidney function (allograft function) later in life. METHODS: We retrospectively analyzed 75 consecutive adult living-donor kidney transplants performed at Kagawa University Hospital. Renal arteriosclerotic vasculopathy was defined according to the presence of fibrous intimal thickening in the interlobular artery. RESULTS: Forty-one kidneys exhibited mild arteriosclerotic vasculopathy on preimplantation kidney biopsies. The decreases in estimated glomerular filtration rate after donation were similar in donors with or without renal arteriosclerotic vasculopathy. Pre-existing arteriosclerotic vasculopathy did not affect graft survival rate, patient survival rate or the incidence of complications. Recipients of kidneys with arteriosclerotic vasculopathy had lower allograft function at 1 and 3 years after transplantation than the recipients of arteriosclerosis-free kidneys with or without donor hypertension. In multivariate analysis, fibrous intimal thickening on preimplantation biopsy was predictive of reduced allograft function at 1 year after transplantation. CONCLUSIONS: The present study demonstrated that mild arteriosclerotic vasculopathy in the donated kidney is an important pathological factor that reflects future impaired function of renal allografts from marginal donors.

Galectin-9 ameliorates clinical severity of MRL/lpr lupus-prone mice by inducing plasma cell apoptosis independently of Tim-3.

Galectin-9 ameliorates various murine autoimmune disease models by regulating T cells and macrophages, although it is not known what role it may have in B cells. The present experiment shows that galectin-9 ameliorates a variety of clinical symptoms, such as proteinuria, arthritis, and hematocrit in MRL/lpr lupus-prone mice. As previously reported, galectin-9 reduces the frequency of Th1, Th17, and activated CD8(+) T cells. Although anti-dsDNA antibody was increased in MRL/lpr lupus-prone mice, galectin-9 suppressed anti-dsDNA antibody production, at least partly, by decreasing the number of plasma cells. Galectin-9 seemed to decrease the number of plasma cells by inducing plasma cell apoptosis, and not by suppressing BAFF production. Although about 20% of CD19(-/low) CD138(+) plasma cells expressed Tim-3 in MRL/lpr lupus-prone mice, Tim-3 may not be directly involved in the galectin-9-induced apoptosis, because anti-Tim-3 blocking antibody did not block galectin-9-induced apoptosis. This is the first report of plasma cell apoptosis being induced by galectin-9. Collectively, it is likely that galectin-9 attenuates the clinical severity of MRL lupus-prone mice by regulating T cell function and inducing plasma cell apoptosis.