Tadashi Sofue

Early Treatment With Olmesartan Prevents Juxtamedullary Glomerular Podocyte Injury and the Onset of Microalbuminuria in Type 2 Diabetic Rats

Background Studies were performed to determine if early treatment with an angiotensin II (Ang II) receptor blocker (ARB), olmesartan, prevents the onset of microalbuminuria by attenuating glomerular podocyte injury in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with type 2 diabetes mellitus. Methods OLETF rats were treated with either a vehicle, olmesartan (10 mg/kg/day) or a combination of nonspecific vasodilators (hydralazine 15 mg/kg/day, hydrochlorothiazide 6 mg/kg/day, and reserpine 0.3 mg/kg/day; HHR) from the age of 7–25 weeks. Results OLETF rats were hypertensive and had microalbuminuria from 9 weeks of age. At 15 weeks, OLETF rats had higher Ang II levels in the kidney, larger glomerular desmin-staining areas (an index of podocyte injury), and lower gene expression of nephrin in juxtamedullary glomeruli, than nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. At 25 weeks, OLETF rats showed overt albuminuria, and higher levels of Ang II in the kidney and larger glomerular desmin-staining areas in superficial and juxtamedullary glomeruli compared to LETO rats. Reductions in mRNA levels of nephrin were also observed in superficial and juxtamedullary glomeruli. Although olmesartan did not affect glucose metabolism, it decreased blood pressure and prevented the renal changes in OLETF rats. HHR treatment also reduced blood pressure, but did not affect the renal parameters. Conclusions This study demonstrated that podocyte injury occurs in juxtamedullary glomeruli prior to superficial glomeruli in type 2 diabetic rats with microalbuminuria. Early treatment with an ARB may prevent the onset of albuminuria through its protective effects on juxtamedullary glomerular podocytes.

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.

The cyclin-dependent kinase inhibitor p21 is essential for the beneficial effects of renal ischemic preconditioning on renal ischemia/reperfusion injury in mice.

The cyclin-dependent kinase inhibitor p21 plays important roles in chronic renal disorders; however, its roles in response to acute renal stress are unclear. Here we evaluated p21 in acute kidney injury and ischemic preconditioning using wild-type and p21 knockout mice that underwent renal ischemia followed by reperfusion. The decline in renal function and histological changes were worse in the knockout than in wild-type mice. Ischemia/reperfusion increased p21 expression in the kidney of wild-type mice compared with sham surgery, suggesting p21 may confer tolerance to ischemia/reperfusion injury. We next tested whether p21 is associated with the protective effect of ischemic preconditioning, an established method to reduce ischemia/reperfusion injury. Ischemic preconditioning attenuated ischemia/reperfusion injury in wild-type but not p21-knockout mice. This preconditioning decreased the number of proliferating tubular cells before but increased them at 24 h after ischemia/reperfusion in the kidneys of wild-type mice. In p21-knockout mice, ischemic preconditioning did not change the number of proliferating cells before but decreased them after ischemia/reperfusion. Ischemic preconditioning increased renal p21 expression and the number of cells in the G1 phase of the cell cycle before ischemia/reperfusion compared with sham surgery. Thus, renal p21 is essential for the beneficial effects of renal ischemic preconditioning. Transient cell cycle arrest induced by ischemic preconditioning by a p21-dependent pathway seems to be important for subsequent tubular cell proliferation after ischemia/reperfusion.

Efficacy and safety of febuxostat in the treatment of hyperuricemia in stable kidney transplant recipients

Background Post-transplant hyperuricemia (PTHU), defined as serum uric acid concentration ≥7.0 mg/dL or need for treatment with allopurinol or benzbromarone, reduces long-term allograft survival in kidney transplant recipients. Febuxostat, a new nonpurine selective xanthine oxidase inhibitor, is well tolerated in patients with moderate renal impairment. However, its efficacy and safety in kidney recipients with PTHU is unclear. We therefore assessed the efficacy and safety of febuxostat in stable kidney transplant recipients with PTHU. Methods Of 93 stable adult kidney transplant recipients, 51 were diagnosed with PTHU (PTHU group) and 42 were not (NPTHU group). Of the 51 patients with PTHU, 26 were treated with febuxostat (FX group) and 25 were not (NFX group), at the discretion of each attending physician. One-year changes in serum uric acid concentrations, rates of achievement of target uric acid (<6.0 mg/dL), estimated glomerular filtration rates in allografts, and adverse events were retrospectively analyzed in the FX, NFX, and NPTHU groups. Results The FX group showed significantly greater decreases in serum uric acid (−2.0±1.1 mg/dL versus 0.0±0.8 mg/dL per year, P<0.01) and tended to show a higher rate of achieving target uric acid levels (50% versus 24%; odds ratio 3.17 [95% confidence interval 0.96–10.5], P=0.08) than the NFX group. Although baseline allograft estimated glomerular filtration rates tended to be lower in the FX group than in the NFX group (40±14 mL/min/1.73 m2 versus 47±19 mL/min/1.73 m2), changes in allograft estimated glomerular filtration rate were similar (+1.0±4.9 mL/min/1.73 m2 versus −0.2±6.9 mL/min/1.73 m2 per year, P=0.50). None of the patients in the FX group experienced any severe adverse effects, such as pancytopenia or attacks of gout, throughout the entire study period. Nephrologists were more likely than urologists to start febuxostat in kidney transplant recipients with PTHU (69% versus 8%). Conclusion Treatment with febuxostat sufficiently lowered uric acid levels without severe adverse effects in stable kidney transplant recipients with PTHU.

Angiotensin II Shifts Insulin Signaling Into Vascular Remodeling From Glucose Metabolism in Vascular Smooth Muscle Cells

BACKGROUND To clarify the role of angiotensin II (Ang II) in insulin-induced arteriosclerosis, we examined the effects of Ang II on insulin-induced mitogen-activated protein (MAP) kinase activation and cellular hypertrophy in rat vascular smooth muscle cells (VSMCs). METHODS Phosphorylated MAP kinases were detected with western blot analysis. Cellular hypertrophy and glucose uptake were evaluated from incorporation of [(3)H]-labeled-leucine and -deoxy-D-glucose, respectively. Cell sizes were measured by Coulter counter. RESULTS While Ang II (100 nmol/l, 18 h) augmented cellular hypertrophy by insulin (10 nmol/l, 24 h), insulin alone did not affect hypertrophy without Ang II pretreatment. Insulin increased p38MAP kinase and c-Jun N-terminal kinase (JNK) phosphorylation; in the presence of Ang II, p38MAP kinase, and JNK were further activated by insulin. Treatment of a p38MAP kinase inhibitor, SB203580 (10 µmol/l), and a JNK inhibitor, SP600125 (20 µmol/l), abrogated the [(3)H]-leucine incorporation by insulin in the presence of Ang II. Both the Ang II receptor blocker, RNH-6270 (100 nmol/l), and an antioxidant, ebselen (40 µmol/l), inhibited vascular cell hypertrophy. Specific depletion of insulin receptor substrate-1 with small interfering RNA increased [(3)H]-leucine incorporation by insulin (10 nmol/l, 24 h); pretreatment with Ang II attenuated insulin (10 nmol/l, 30 min)-induced glucose uptake. CONCLUSIONS Ang II attenuates insulin-stimulated glucose uptake and enhances vascular cell hypertrophy via oxidative stress- and MAP kinase-mediated pathways in VSMCs. Ang II may also cause insulin signaling to diverge from glucose metabolism into vascular remodeling, affecting insulin-induced arteriosclerosis in hypertension.

Mineral and Bone Disorder Is Temporary in Patients Treated With Early Rapid Corticosteroid Reduction After Kidney Transplantation: A Single-Center Experience

BACKGROUND Mineral and bone disorder (MBD) is a major complication of chronic kidney disease and remains a major problem even after kidney transplantation. Although early steroid withdrawal protocols have beneficial effects on mineral and bone metabolism, they are also associated with significantly increased rates of acute allograft rejection (AR). Recently, patients have been treated with early rapid corticosteroid reduction protocols, but it is still unclear whether these protocols reduce the rate of MBD. The aim of this study was to evaluate the effects of early rapid corticosteroid reduction on MBD after kidney transplantation. METHODS We retrospectively evaluated 34 adult kidney transplant recipients who were treated with an early rapid corticosteroid reduction protocol. Glucocorticoid treatment was reduced to methylprednisolone 4 mg/d at 1 month after transplantation. RESULTS The AR rate at 3 years after transplantation was 15%. Bone mineral density was slightly decreased in the femur at 4 months after transplantation but returned to the preoperative level by 24 months after transplantation. There was no significant decrease in the bone mineral density of the lumbar spine during the first year after transplantation. Urinary deoxypyridinoline levels and plasma osteocalcin levels returned to the normal range during the follow-up period. Bone mineral density tended to be lower in female patients than male patients and in patients who underwent long-term pretransplant dialysis than those who did not undergo long-term pretransplant dialysis. CONCLUSION The present study found that MBD was temporary in kidney transplant recipients who were treated with an early rapid corticosteroid reduction protocol and that these patients did not have an increased AR rate.

Short-Term Prognosis of Living-Donor Kidney Transplantation From Hypertensive Donors With High-Normal Albuminuria

Background High-normal albuminuria (HNA) is an independent predictor of cardiovascular risk in the general population. Although hypertensive donor (HTD) candidates with HNA were considered acceptable donors by the Amsterdam Forum 2004, the transplant prognosis of HTDs with HNA has not been determined. Therefore, we investigated the transplant prognosis of HTDs with HNA. Methods We retrospectively analyzed 52 adult living-donor kidney transplants performed at Kagawa University Hospital. HNA was defined as albuminuria of 15 to 30 mg/g Cr. Changes in kidney function of donors and recipients were assessed up to 2 years after transplantation. Results Overall, 38 donors were normotensive and 14 were hypertensive. Nine of 14 HTDs exhibited HNA before donation. More HTDs with HNA had arteriosclerotic vasculopathy or glomerulosclerosis than did normotensive donors (NTDs). Hypertension and the degree of albuminuria did not affect the donors’ posttransplantation kidney function. The risk of discompensatory changes in kidney function after donation was significantly higher in HTDs with HNA than in NTDs (odds ratio, 10.5; 95% confidence interval, 1.51–72.9; P=0.02). In multivariate analysis, the coexistence of hypertension and HNA was not significantly associated with discompensatory changes after donation (adjusted odds ratio, 6.04; 95% confidence interval, 0.19–192; P=0.31). Recipients of HTDs with HNA had similar allograft survival rates but lower allograft function compared with recipients of NTDs. Conclusions Although further studies are needed to confirm our results, the short-term prognosis of living-donor kidney transplantation was similar between HTDs with HNA and NTDs.

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

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.

Angiotensin II receptor blocker is a renoprotective remedy for metabolic syndrome.

Obesity leads to a high risk of developing various diseases, such as type II diabetes, hypertension, dyslipidemia and ischemic heart disease. Metabolic syndrome is characterized by visceral obesity, glucose intolerance, dyslipidemia and hypertension. Insulin resistance and activation of the sympathetic nerve system were often observed in individuals with metabolic syndrome. Although the absence of leptin or its receptor causes severe obesity and hyperphagia in humans and in rodents,1 leptin itself has not yet been used as a practical medicine for metabolic syndrome. As the prevalence of metabolic syndrome has been increasing along with the development of modern conveniences throughout the world, establishment of an effective prevention against metabolic syndrome is greatly anticipated.

Association Between Post-transplantation Immunoglobulin A Deposition and Reduced Allograft Function

BACKGROUND Post-transplantation de novo and recurrent immunoglobulin A (IgA) deposition (IgAD) in the allograft is commonly observed. However, the association between post-transplantation IgAD and reduced allograft function has not been determined. We therefore investigated the association between reduced allograft function and post-transplantation IgAD using serial allograft biopsies. METHODS IgAD was retrospectively analyzed in 45 adults who underwent kidney transplantation for chronic glomerulonephritis, including IgA nephropathy, at Kagawa University Hospital. Allograft biopsy samples were obtained from per protocol biopsies obtained 1 and 3 years after transplantation, as well as from episode biopsies. Factors contributing to post-transplantation IgAD were assessed by calculating adjusted odds ratios (AORs) using logistic regression analysis. RESULTS Of the 45 recipients, 18 had post-transplantation allograft IgAD. The estimated glomerular filtration rates (eGFR) 1, 2, and 3 years after transplantation were lower in the recipients with than without IgAD. Urinalysis was normal in 61% of recipients with IgAD. Reduced allograft function (eGFR <40 mL/min/1.73 m(2)) 1 year after transplantation was significantly associated with post-transplantation IgAD (AOR = 34.4 [95% CI = 2.35-502], P = .01). Conversely, blood concentrations of mycophenolic acid and latent IgAD from donor kidneys were not significantly associated with post-transplantation IgAD. CONCLUSION Reduced allograft function may be associated with post-transplantation IgAD in the allograft.