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.

ESA Hyporesponsiveness Is Associated with Adverse Events in Maintenance Hemodialysis (MHD) Patients, But Not with Iron Storage.

OBJECTIVE: It has been reported that hyporesponsiveness to erythropoiesis-stimulating agent (ESA) is associated with adverse events in patients on maintenance hemodialysis (MHD). However, it has not been determined whether higher iron storage is associated with an improved response, including better survival, to ESA. DESIGN AND METHOD: We measured serum ferritin, hemoglobin (Hb), and transferrin saturation (TSAT) levels every three months for two years in 1,095 MHD patients. The weekly dose of ESA to Hb ratio was also calculated as an index of ESA responsiveness (ERI). RESULTS: A significant correlation (p<0.001, R = 0.89) between ferritin and Hb was only observed in the patients with ferritin levels <50 ng/mL. High-dose (≥50 mg/week) intravenous iron administration, female sex, low serum albumin, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were significant predictors of a high ERI value (>280); however, serum ferritin and TSAT levels did not predict a higher ERI. In the time-dependent Cox hazard model, the risk for a composite event in the patients with a high ERI (≥280) and a high ferritin level (≥100 ng/mL) was significantly greater (hazard ratio [HR], 2.09, P = 0.033) than that for patients with a high ERI and a low ferritin (<100 ng/mL) level. CONCLUSION: Hb was dependent upon ferritin levels in patients with ferritin levels <50 ng/mL but not in patients with ferritin levels ≥50 ng/mL. Patients with hyporesponsiveness to ESA had a greater risk of composite events, but ERI was unrelated to iron storage.

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.

Plasmapheresis in a patient with antiphospholipid syndrome before living-donor kidney transplantation: a case report.

BACKGROUND: Early graft thrombosis and bleeding complications remain important causes of early graft loss following kidney transplantation in patients with antiphospholipid syndrome. Anti-ß2-glycoprotein I IgG is a disease-specific antibody in patients with antiphospholipid syndrome. Although plasmapheresis is partially effective for antibody removal, the optimal treatment allowing successful transplantation in patients with antiphospholipid syndrome has not been established. This is the first report of a patient with antiphospholipid syndrome who successfully underwent living-donor kidney transplantation following prophylactic plasmapheresis for removal of anti-ß2-glycoprotein I IgG. CASE PRESENTATION: A 37-year-old Japanese female was scheduled to undergo a living-donor kidney transplant from her mother. At age 25 years, she experienced renal vein thrombosis, was diagnosed with antiphospholipid syndrome secondary to systemic lupus erythematosus, and was subsequently treated with prednisolone and warfarin. At age 37 years, she was diagnosed with end stage kidney disease, requiring maintenance hemodialysis because of recurrent renal vein thrombosis despite taking anticoagulation therapy. The pretreatment protocol consisted of prophylactic plasmapheresis plus full anticoagulation therapy to counteract the risks of early graft thrombosis. Anticardiolipin and anti-ß2-glycoprotein I IgGs were successfully removed by both double filtration plasmapheresis and plasma exchange. The allograft kidney began to function soon after transplantation. No obvious thrombotic complications were observed after transplantation, although anti-ß2-glycoprotein I IgG increased to the level observed before plasmapheresis. One year after transplantation, the patient's kidney function remains stable while receiving anticoagulation therapy as well as a maintenance immunosuppressive regimen. CONCLUSION: Prophylactic plasmapheresis plus full anticoagulation therapy may be an effective strategy in patients with antiphospholipid syndrome undergoing living-donor kidney transplantation.

Detailed localization of augmented angiotensinogen mRNA and protein in proximal tubule segments of diabetic kidneys in rats and humans.

In the intrarenal renin-angiotensin system, angiotensinogen levels are well known to be increased in diabetes, and these enhanced intrarenal angiotensinogen levels may initiate the development and accelerate the progression of diabetic nephropathy. However, the specific localization of the augmented angiotensinogen in proximal tubule segments in diabetes is still unknown. We investigated the detailed localization of angiotensinogen in 3 proximal tubule segments in the diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and the control Long-Evans Tokushima Otsuka (LETO) rats. We also prepared OLETF rats treated with angiotensin II type 1 receptor blocker, olmesartan or with a combination of vasodilator agents. Moreover, biopsied samples of human kidney cortex were used to confirm the results of animal studies. We examined the co-localization of angiotensinogen with segment-specific markers by double staining using fluorescence in situ hybridization and/or immunofluorescence. Angiotensinogen mRNA expression was barely detectable in segment 1. In segment 3, the area of angiotensinogen mRNA expression was augmented in the OLETF rats compared with the LETO rats. Angiotensinogen protein expression areas in segments 1 and 3 were also increased in the OLETF rats compared with the LETO rats. Chronic treatment with olmesartan ameliorated these areas of augmented angiotensinogen expression. Biopsied human kidney samples showed similar results. These data suggest that the augmented angiotensinogen mRNA levels in segment 3 and angiotensinogen protein levels in segments 1 and 3 may contribute to the progression of diabetic nephropathy.

Association between hemoglobin variability, serum ferritin levels, and adverse events/mortality in maintenance hemodialysis patients.

In recent times, therapy for renal anemia has changed dramatically in that iron administration has increased and doses of erythropoiesis-stimulating agents (ESAs) have decreased. Here we used a prospective, observational, multicenter design and measured the serum ferritin and hemoglobin levels every 3 months for 2 years in 1086 patients on maintenance hemodialysis therapy. The associations of adverse events with fluctuations in ferritin and hemoglobin levels and ESA and iron doses were measured using a Cox proportional hazards model for time-dependent variables. The risks of cerebrovascular and cardiovascular disease (CCVD), infection, and hospitalization were higher among patients who failed to maintain a target-range hemoglobin level and who exhibited high-amplitude fluctuations in hemoglobin compared with patients who maintained a target-range hemoglobin level. Patients with a higher compared with a lower ferritin level had an elevated risk of CCVD and infectious disease. Moreover, the risk of death was significantly higher among patients with high-amplitude ferritin fluctuations compared with those with a low ferritin level. The risks of CCVD, infection, and hospitalization were significantly higher among patients who were treated with high weekly doses of intravenous iron compared with no intravenous iron. Thus, there is a high risk of death and/or adverse events in patients with hemoglobin levels outside the target range, in those with high-amplitude hemoglobin fluctuations, in those with consistently high serum ferritin levels, and in those with high-amplitude ferritin fluctuations.

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.

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.

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.

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.

Excess fluid distribution affects tacrolimus absorption in peritoneal dialysis patients.

BACKGROUND: Excess fluid distribution is a common disorder in peritoneal dialysis (PD) patients. Tacrolimus malabsorption may also occur in PD patients, and may lead to acute allograft rejection after transplantation. The purpose of this study was to evaluate the relationship between tacrolimus pharmacokinetics and excess fluid distribution according to pre-transplant dialysis modality. METHODS: We retrospectively analyzed 41 adult living-donor kidney transplantations, including nine PD patients and 32 hemodialysis (HD) patients. We examined tacrolimus pharmacokinetics in the peri-operative period and determined the association between the tacrolimus absorption rate and body weight reduction. The absorption efficacy of tacrolimus was evaluated as the dose-normalized tacrolimus absorption rate. Tacrolimus concentrations in PD effluent were measured by high-performance liquid chromatography. RESULTS: The tacrolimus absorption rate on the day before kidney transplantation tended to be lower in PD patients than in HD patients; however, the rate improved after kidney transplantation and was similar in both groups of patients. The peak tacrolimus concentration time was later in PD patients than in HD patients. The body weight reduction after kidney transplantation was greater in PD patients than in HD patients, and was significantly associated with the change in tacrolimus absorption rate (p=0.04, r=0.32). Only 0.002% of the oral tacrolimus dose was removed by PD itself. CONCLUSION: Excess fluid distribution in PD patients appears to contribute to tacrolimus malabsorption rather than PD itself. We should consider the risk of tacrolimus malabsorption in patients with possible excess fluid distribution, particularly in PD patients.

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.

Aldosterone induces vascular insulin resistance by increasing insulin-like growth factor-1 receptor and hybrid receptor.

OBJECTIVE: We previously showed that aldosterone induces insulin resistance in rat vascular smooth muscle cells (VSMCs). Because insulin-like growth factor-1 receptor (IGF1R) affects insulin signaling, we hypothesized that aldosterone induces vascular insulin resistance and remodeling via upregulation of IGF1R and its hybrid insulin/insulin-like growth factor-1 receptor. METHODS AND RESULTS: Hybrid receptor expression was measured by immunoprecipitation. Hypertrophy of VSMCs was evaluated by (3)H-labeled leucine incorporation. Aldosterone (10 nmol/L) significantly increased protein and mRNA expression of IGF1R and hybrid receptor in VSMCs but did not affect insulin receptor expression. Mineralocorticoid receptor blockade with eplerenone inhibited aldosterone-induced increases in IGF1R and hybrid receptor. Aldosterone augmented insulin (100 nmol/L)-induced extracellular signal-regulated kinase 1/2 phosphorylation. Insulin-induced leucine incorporation and α-smooth muscle actin expression were also augmented by aldosterone in VSMCs. These aldosterone-induced changes were significantly attenuated by eplerenone or picropodophyllin, an IGF1R inhibitor. Chronic infusion of aldosterone (0.75 µg/hour) increased blood pressure and aggravated glucose metabolism in rats. Expression of hybrid receptor, azan-positive area, and oxidative stress in aorta was increased in aldosterone-infused rats. Spironolactone and tempol prevented these aldosterone-induced changes. CONCLUSIONS: Aldosterone induces vascular remodeling through IGF1R- and hybrid receptor-dependent vascular insulin resistance. Mineralocorticoid receptor blockade may attenuate angiopathy in hypertensive patients with hyperinsulinemia.