Changes in Prevalence and Health Checkup Coverage Rate of Chronic Kidney Disease (CKD) after Introduction of Prefecture-Wide CKD Initiative: Results of the Kagawa Association of CKD Initiatives.

The National Health Insurance (NHI) special health checkup system in Japan targets the NHI population aged 40-74 years. Since 2015, the Kagawa NHI special health checkup was initiated in a prefecture-wide chronic kidney disease (CKD) initiative, including renal examination as an essential item in NHI health checkups. Here, we aimed to investigate the effects of the prefecture-wide CKD initiative. We conducted a retrospective cohort survey using the Kagawa National Health Insurance database created by the Kagawa National Health Insurance Organization. Results of the NHI health checkup (2015-2019) and prefecture-wide outcomes (2013-2019) were analyzed. The prevalence of CKD among examinees who underwent the NHI health checkup increased from 17.7% in 2015 to 23.2% in 2019. The percentage of examinees who completed a medical visit was 29.4% in 2015. After initiation of the initiative, the NHI health checkup coverage rate increased significantly, from a mean (standard deviation) of 40.8% (0.4%) to 43.2% (1.1%) (p = 0.04). After the start of the CKD initiative, we found an increase in the prevalence of CKD and the NHI health checkup coverage rate.

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.

Effects of Olmesartan and Azilsartan on Albuminuria and the Intrarenal Renin-Angiotensin System.

PURPOSE: Olmesartan and azilsartan decrease blood pressure more effectively than other angiotensin receptor blockers (ARBs). ARBs additionally decrease the urinary albumin to creatinine ratio (UACR), a urinary albumin marker, and urinary angiotensinogen (u-AGT), an intrarenal renin-angiotensin system activity marker. We examined the effects of these ARBs on blood pressure, UACR, and u-AGT in patients with uncontrolled hypertension. METHODS: Patients with uncontrolled hypertension treated with conventional ARBs, excluding olmesartan and azilsartan, for over 8 weeks were enrolled. We randomly switched patients from their prior ARBs to either olmesartan or azilsartan, and followed them for 24 weeks. RESULTS: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and central systolic blood pressure (cSBP) significantly decreased at 24 weeks. UACR and u-AGT also decreased at 24 weeks in both groups. There were no significant differences in SBP, DBP, cSBP, UACR, or u-AGT between the groups. Therefore, we combined both groups for further analyses. After combining, SBP (160.5 ± 16.4 to 139.6 ± 15.6 mm Hg, P < 0.0001), DBP (88.4 ± 13.7 to 80.7 ± 13.2 mm Hg, P = 0.008), cSBP (167.4 ± 20.8 to 146.6 ± 24.6 mm Hg, P < 0.0001), UACR (13.8 to 9.0 mg/g Cre, P = 0.0096), and u-AGT (4.13 to 2.32 µg/g Cre, P = 0.0074) significantly decreased at 24 weeks. Patients with microalbuminuria (UACR ≥ 30 mg/g Cre) had significantly greater ΔUACR (-39.4 vs 0.27, P = 0.0024) and Δu-AGT (-11.9 vs -0.61, P = 0.0235) than patients without microalbuminuria. The changes in u-AGT were significantly associated with changes in UACR (r = 0.411, P = 0.046); however, there was no significant relationship between the changes in u-AGT and those in SBP or DBP. CONCLUSION: Olmesartan and azilsartan decreased blood pressure, UACR, and u-AGT more than the other ARBs, and exerted depressor and renoprotective effects.

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.

Urinary Angiotensinogen Could Be a Prognostic Marker of the Renoprotection of Olmesartan in Metabolic Syndrome Patients.

This study was performed to demonstrate urinary angiotensinogen as a potential prognostic marker of the albuminuria reduction effects of olmesartan in patients with metabolic syndrome. In 24 patients (eight women, 57.88 ± 2.00 years), 5-40 mg/day of olmesartan were given. Urinary concentrations of albumin and angiotensinogen (normalized by urinary concentrations of creatinine) and plasma renin activity were measured before and after the 12- and 24-week marks of olmesartan treatment. Olmesartan treatment increased plasma renin activity and decreased urinary albumin and urinary angiotensinogen significantly (p < 0.05). Based on the % change in urinary albumin, patients were divided into two groups, responders (<-50%) and non-responders (≥-50%), and a logistic analysis of urinary angiotensinogen before treatment showed the area under the curve as 0.694. When the cutoff value of urinary angiotensinogen before the treatment of 13.9 µg/g Cr was used, the maximum Youden index (0.500, specificity: 11/12 = 91.7% and sensitivity: 7/12 = 58.3%) was obtained. When all patients were re-divided into two groups, those with higher values of urinary angiotensinogen before the treatment (Group H, n = 16) and those with lower values, Group H showed significantly decreased urinary albumin (p < 0.05). Therefore, urinary angiotensinogen could be a prognostic marker of the albuminuria reduction effects of olmesartan in patients with metabolic syndrome.

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.

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.

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 m(2) versus 47±19 mL/min/1.73 m(2)), changes in allograft estimated glomerular filtration rate were similar (+1.0±4.9 mL/min/1.73 m(2) versus -0.2±6.9 mL/min/1.73 m(2) 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.

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.

Important aspects of urine sampling for angiotensinogen measurement: time and preservation conditions in healthy individuals.

Intrarenal renin-angiotensin system (RAS) plays an important role for the pathogenesis of renal injuries. Experimental studies have demonstrated that angiotensinogen levels in renal tissues reflect the activity of intrarenal RAS. However, dynamics of urinary angiotensinogen have not been investigated in detail. Therefore, we examined the preservation conditions of the measured values of urinary angiotensinogen concentrations and an ultradian rhythm of urinary angiotensinogen excretion in humans. Urine samples were collected from 24 healthy volunteers. The urinary concentrations of angiotensinogen were measured by using ELISA. Two different urine preservation conditions were examined. One cycle of freeze-and-thaw did not change the measured values of urinary angiotensinogen concentrations. Moreover, to keep urine samples at room temperature for 12 hours did not change the measured values of urinary angiotensinogen concentrations. Thus, preservation conditions do not change the measured values of urinary angiotensinogen concentrations. Regarding an ultradian rhythm, blood pressure and the urinary concentrations of angiotensinogen were measured at 09:00, 13:00, and 16:00. The averaged levels of blood pressure were similar over the time. The average of urinary angiotensinogen/creatinine (Cr) ratios was 8.73 ± 1.15 ng/mg Cr at 09:00, 9.53 ± 1.58 ng/mg Cr at 13:00, and 8.58 ± 1.26 ng/mg Cr at 16:00. The urinary angiotensinogen excretion in healthy volunteers does not have an ultradian change during the daytime (P = 0.482). This may be another indication that the intrarenal RAS is independent of the systemic RAS. We have to pay attention to these findings in handling urine samples for measurements of angiotensinogen.

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.

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.