Yoko Nishijima

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.

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.

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.

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.

Circadian rhythm of plasma and urinary angiotensinogen in healthy volunteers and in patients with chronic kidney disease

The urinary angiotensinogen (AGT) excretion rate could be a novel biomarker for the intrarenal activity of the renin-angiotensin system. Little is known about the circadian rhythm of AGT levels in plasma or urine. In this short article, making use of data in plasma and urine of healthy volunteers and patients with chronic kidney diseases, we first report that we were unable to find evidence for a circadian rhythm of AGT under any condition. Next we critically discuss to what degree elevated urinary AGT levels might be considered an independent biomarker that is not simply the non-specific consequence of proteinuria.

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.

Urinary Angiotensinogen Could Be a Prognostic Marker of Renoprotective Effects of Alogliptin in Patients with Type 2 Diabetes

Background. The aims of this study were (1) to examine the renoprotective effects of alogliptin and (2) to establish urinary angiotensinogen (AGT) as a prognostic marker of renoprotective effects of alogliptin in patients with type 2 diabetes (T2D). Methods. In 43 patients with T2D (18 women, 66.1 ± 1.71 years), 25 mg/day of alogliptin was added to the traditional hypoglycemic agents and/or nondrug treatments. Urinary concentrations of albumin (Alb) and AGT, normalized by urinary concentrations of creatinine (Cr) (UAlbCR and UAGTCR, respectively), were measured before and after the 12-week alogliptin treatment. Results. Alogliptin treatment tended to decrease UAlbCR (99.6 ± 26.8 versus 114.6 ± 36.0 mg/g Cr, P = 0.198). Based on % change in UAlbCR, patients were divided into two groups, responders (<−25%) and nonresponders (≥−25%), and a logistic analysis of UAGTCR before treatment showed cutoff value of 20.8 µg/g Cr. When all patients were redivided into two groups, those with higher values of UAGTCR before the treatment (Group H, n = 20) and those with lower values (Group L), Group H showed significantly decreased UAlbCR in response to alogliptin (−14.6 ± 8.6 versus +22.8 ± 16.8%, P = 0.033). Conclusion. Urinary AGT could be a prognostic marker of renoprotective effects of alogliptin in patients with T2D.

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 (β = –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.

WT1 immunoenzyme staining using SurePath™ processed urine cytology helps to detect kidney disease

Damage and detachment of podocytes and loss into the urine have been implicated in the progression of kidney diseases. The purpose of this study was to investigate the potential role of urine cytology based on SurePath™ combined with immunoenzyme staining using Wilms’ tumour 1 (WT1) antibody as a podocyte marker in the discrimination of normality and non‐renal urinary tract disease from kidney disease.