Ryohei Yamamoto

Cigarette smoking and progression of IgA nephropathy.

BACKGROUND Multiple community-based cohort studies of mainly middle-aged and elderly populations have shown that cigarette smoking is a risk factor for chronic kidney disease. However, little information is available about an effect of cigarette smoking on progression of primary kidney diseases, including immunoglobulin A (IgA) nephropathy. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS 971 of 1,001 patients with a diagnosis of IgA nephropathy in 3 major nephrology centers in Osaka, Japan, between 1992 and 2005 who enrolled in the Study of Outcome and Practice Pattern of IgA Nephropathy (STOP-IgAN). PREDICTORS Smoking status and number of cigarettes smoked at the time of diagnosis using kidney biopsy. Dose-dependent associations between cigarette smoking and outcomes were assessed in multivariate Cox proportional hazards models. Significantly different clinical characteristics between non-/past and current smokers were controlled for using propensity score-based adjustment, stratification, and matching. OUTCOMES 50% increase in serum creatinine level as primary outcome. A composite outcome of a 100% increase in serum creatinine level or end-stage renal disease (ESRD) and ESRD alone as secondary outcomes. RESULTS During the median 5.8 years (interquartile range, 2.6-10.2) of the observational period, 117 participants progressed to a 50% increase in serum creatinine level and 47 advanced to ESRD. Multivariate Cox proportional hazards models identified current smokers (HR, 2.03 [95% CI, 1.33-3.10] for primary outcome) and number of cigarettes at kidney biopsy (HR, 1.21 [95% CI, 1.06-1.39] per 10 cigarettes per day) as significant predictors of outcomes. Propensity score-based models confirmed these results. Tests for interaction showed that the association of current smoking with adverse outcomes was stronger in those with lower compared with higher estimated glomerular filtration rates. LIMITATION Baseline smoking status was not verified using biochemical tests. Smoking status during the observational period was unavailable. CONCLUSIONS Cigarette smoking, in a dose-dependent manner, was identified as a key prognostic factor in IgA nephropathy. Smoking cessation should be encouraged as part of the treatment for IgA nephropathy.

Impact of Age and Overt Proteinuria on Outcomes of Stage 3 to 5 Chronic Kidney Disease in a Referred Cohort

BACKGROUND AND OBJECTIVES Population-based studies have reported outcomes and risk factors for patients with chronic kidney disease (CKD), defined primarily by decreased estimated GFR (eGFR). They are characterized by old age, low proteinuria level, and stage 3 CKD. However, many patients referred to nephrologists are younger and have overt proteinuria and advanced CKD. This study evaluated the association between outcomes and those factors among referred CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We retrospectively reviewed 461 referred patients with stage 3 to 5 CKD from January 2003 to December 2007. Key outcomes were death and ESRD. Patients were followed from the time of first serum creatinine measurement to December 2009. RESULTS The median age of subjects was 67.0 years, and median follow-up was 3.2 years. Overt proteinuria was present in 57.0% of subjects. For stage 3, 4, and 5 CKD, cumulative mortality and probability of ESRD at 3 years was 9.5 and 6.5%, 11.2 and 27.8%, and 16.5 and 79.1%, respectively. Using proportional-hazards regression models, age was a determinant for death, whereas overt proteinuria was strongly associated with ESRD. Among stage 3 CKD patients older than 65 years without overt proteinuria, the incidence of death before renal replacement therapy (RRT) was 2.8/100 patient-years and none had ESRD. In patients with advanced CKD and overt proteinuria, the incidence of ESRD was substantially higher than that of death before RRT. CONCLUSIONS Stratification by age, proteinuria level, and CKD stage could predict the competing outcomes of death before RRT and ESRD among CKD patients.

Use of xanthine oxidase inhibitor febuxostat inhibits renal interstitial inflammation and fibrosis in unilateral ureteral obstructive nephropathy

BackgroundRenal interstitial fibrosis is the common pathway in progressive renal diseases, where oxidative stress promotes inflammation and macrophage infiltration. Febuxostat is a novel nonpurine xanthine oxidase (XO)-specific inhibitor for treating hyperuricemia. While some reports suggest a relationship between hyperuricemia and chronic kidney disease (CKD), the renoprotective mechanism of an XO inhibitor in CKD remains unknown. Recent reports have focused on XO as a source of oxidative stress.MethodsHere, we investigate the potential of febuxostat to reduce fibrogenic and inflammatory responses in an established interstitial fibrosis model—unilateral ureteric obstruction (UUO). Male Sprague–Dawley rats were divided into three groups: sham-operated group, vehicle-treated UUO group, and febuxostat-treated UUO group.ResultsTreatment with febuxostat diminished XO activity in obstructed kidneys, and suppressed nitrotyrosine, a marker of oxidative stress. Consequently, febuxostat inhibited early proinflammatory cytokine expression, followed by a reduction of interstitial macrophage infiltration. In addition, febuxostat suppressed transforming growth factor-β messenger RNA expression, thereby ameliorating smooth muscle alpha actin and type I collagen expression.ConclusionOur results provide evidence for the renoprotective action of febuxostat against the formation of interstitial fibrosis. A decrease in macrophage infiltration and interstitial fibrosis, along with a decrease of the oxidative stress marker, strongly suggests the existence of a causal relationship between them. Febuxostat may have therapeutic value in slowing or preventing interstitial fibrosis in patients with CKD.

Self-reported Sleep Duration and Prediction of Proteinuria: A Retrospective Cohort Study

BACKGROUND Although multiple studies have shown that sleep duration is a predictor of cardiovascular diseases and mortality, few studies have reported an association between sleep duration and chronic kidney disease. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS 6,834 employees of Osaka University aged 20-65 years who visited Osaka University Healthcare Center for their mandatory annual health examinations between April 2006 and March 2010 and did not have estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2), proteinuria, or treatment for self-reported kidney disease. PREDICTOR Self-reported questionnaires about life style, including sleep duration, and blood and urine testing at the first examinations during the study period. An association between sleep duration and outcome was assessed using multivariate Poisson regression models adjusting for clinically relevant factors. OUTCOME Time to the development of proteinuria defined as 1+ or higher by dipstick test. RESULTS Self-reported baseline sleep duration was 6.0 ± 0.9 hours, which reflected the mean sleep duration during a median of 2.5 (25th-75th percentile, 1.4-3.9) years of the observational period. Development of proteinuria was observed in 550 employees (8.0%). A multivariate Poisson regression model clarified that shorter sleep duration, especially 5 or fewer hours, was associated with the development of proteinuria in a stepwise fashion (vs 7 hours; incidence rate ratios of 1.07 [95% CI, 0.87-1.33; P = 0.5], 1.28 [95% CI, 1.00-1.62; P = 0.05], and 1.72 [95% CI, 1.16-2.53; P = 0.007] for 6, 5, and ≤4 hours, respectively), along with younger age, heavier current smoking, trace urinary protein by dipstick test, higher eGFR, higher serum hemoglobin A(1c) level, and current treatment for heart disease. A stepwise association between shorter sleep duration and the development of proteinuria also was verified in 4,061 employees who did not work the night shift. LIMITATIONS Self-reported sleep duration might be biased. Results in a single center should be confirmed in the larger cohort including different occupations. CONCLUSION Short sleep duration, especially 5 or fewer hours, was a predictor of proteinuria.

Cigarette smoking and chronic kidney diseases.

Observational studies have suggested that different chronic kidney diseases (CKDs) have differing relationships to smoking, but no randomized controlled trial has been conducted to examine this topic. In this article, we review available evidence concerning the relationship between smoking and each type of CKD in the general population as well as in patients with diabetes mellitus (DM), hypertension (HT), primary glomerulonephritis and kidney transplants. There is good evidence of a relationship between smoking and CKD in patients with IgA nephropathy and kidney transplant recipients, but not in patients with DM or HT. Interestingly, it has been reported that the effect of smoking on CKD progression varies depending on the CKD stage. This variation might indicate a cumulative effect of smoking, possibly through oxidative stress. A better understanding of the relationship between smoking and CKD would be useful for nephrologists.

Thiazide diuretics enhance nocturnal blood pressure fall and reduce proteinuria in immunoglobulin A nephropathy treated with angiotensin Ii modulators

Objective We examined whether thiazide diuretics could restore nocturnal blood pressure (BP) decline and reduce urinary protein excretion in patients with glomerulopathy treated with angiotensin II modulators (angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers). Methods Twenty-five Japanese outpatients (11 men, 14 women; mean age 43 ± 12 years) with biopsy-proven immunoglobulin (Ig)A nephropathy, preserved renal function (serum creatinine concentration ≤1.2 mg/dl), stable non-nephrotic proteinuria (0.5–3 g daily), and treatment with angiotensin II modulators were studied. The patients received a diuretic, trichlormethiazide (2 mg daily) for 4 weeks after a baseline period lasting for 4 weeks. Results Diuretic therapy significantly reduced conventional, 24-h, daytime and night-time blood pressures. Nocturnal blood pressure fall was significantly enhanced by diuretic therapy and a significant interaction existed between diuretic therapy and nocturnal fall in mean arterial pressure, which indicated that the degree of nocturnal blood pressure fall was affected by diuretic therapy. The urinary protein excretion rate was significantly reduced from 1.10 ± 0.62 to 0.63 ± 0.39 g/day by diuretic therapy. Diuretic/baseline ratio of urinary protein excretion rate was not correlated with diuretic/baseline ratio of conventional, 24-h and daytime mean arterial pressures, but with diuretic/baseline ratio of night-time mean arterial pressure (r = 0.54, P = 0.006). Conclusions Diuretics enhanced nocturnal BP decline and reduced urinary protein excretion in patients with IgA nephropathy treated with angiotensin II modulators. The combination of angiotensin II modulators and diuretics may have additional therapeutic advantages in relieving the renal and cardiovascular risks by reducing nocturnal high blood pressure.

Serum hepcidin-25 levels and anemia in non-dialysis chronic kidney disease patients: a cross-sectional study

BACKGROUND Hepcidin is a central regulator of iron homeostasis. Increased hepcidin concentrations could cause iron-restricted erythropoiesis in chronic kidney disease (CKD)-associated anemia. This cross-sectional observational study was conducted to evaluate the association between hepcidin and CKD-associated anemia in non-dialysis CKD patients. METHODS A total of 505 non-dialysis CKD patients not treated with parenteral iron were recruited, and serum hepcidin-25 levels were measured by liquid chromatography tandem mass spectrometry. Multiple linear regression analysis was used to examine the relationship between hepcidin and glomerular filtration rate (GFR) and the relationship between hemoglobin concentration and predictors including the hepcidin level. RESULTS The median hepcidin level among the 505 CKD patients was 15.4 ng/mL (interquartile range, 5.5-33.6 ng/mL). Although hepcidin level significantly increased according to the CKD stage, multivariate analysis did not reveal an association of GFR with the hepcidin level. Hepcidin level was a significant predictor of hemoglobin concentration after the adjustment for confounders, and a significant interaction between hepcidin and ferritin was found. After stratifying at the median ferritin level, 91 ng/mL, we found a negative association between hepcidin level and hemoglobin in the high-ferritin group. A trend toward a negative association between hepcidin level and mean corpuscular volume was observed in the high-ferritin group. CONCLUSIONS Serum hepcidin-25 levels were negatively associated with hemoglobin concentrations in non-dialysis CKD patients with sufficient iron stores. We found that ferritin modified the association between hepcidin level and hemoglobin concentration. In addition, our results confirmed that the serum hepcidin level is not associated with GFR.

Activation of trypsinogen in experimental models of acute pancreatitis in rats

Trypsinogen activation peptide (TAP) concentration and α2-macroglobulin-trypsin complex (α2M-T) activity were measured in two experimental models of acute pancreatitis in rats to evaluate the significance of activation of trypsinogen in acute pancreatitis. TAP concentration and α2M-T activity in serum rose significantly in trypsin-taurocholate-induced hemorrhagic acute pancreatitis, while in cerulein-induced edematous acute pancreatitis they did not rise in spite of a similar increase in immunoreactive trypsin. When rats in trypsin-taurocholate-induced pancreatitis were treated by protease inhibitor (FUT-175; nafamostat mesilate; FUT group), α2M-T activity in serum was significantly lower than that in nontreated controls (mean ± SEM, 20.8 ± 1.43 U/L in the FUT group vs 79.1 ± 24.5 in controls; p < 0.01). The survival rate at 24 h was significantly improved in the FUT group compared with the controls (70 vs 43%; p < 0.05). The increase in TAP concentration in the FUT group was similar to that in controls. The TAP concentration in pancreatic tissue at 24 h was significantly (p < 0.01) lower in the survival group (7.8 ± 0.8 ng/ml) than in the lethal group (25.9 ± 3.7 ng/ml). Activation of trypsinogen and its subsequent enzyme activity play an important role in the evolution of severe acute pancreatitis.

A novel classification for IgA nephropathy

IgA nephropathy is a common glomerulonephritis. About 30% of patients develop end-stage kidney disease within 20 years. A strategy for predicting prognosis from biopsy-based pathological evaluation has not been well established because of lack of reproducibility and inappropriate categorization. The new Oxford classification of IgA nephropathy provides a histopathological grading system with reproducibility for prediction of renal prognosis of IgA nephropathy independent of the clinical features. The classification must be validated in the different cohorts.

Chiral amino acid metabolomics for novel biomarker screening in the prognosis of chronic kidney disease

D-Amino acids, the enantiomers of L-amino acids, are increasingly recognized as novel biomarkers. Although the amounts of D-amino acids are usually very trace in human, some of them have sporadically been detected in blood from patients with kidney diseases. This study examined whether multiple chiral amino acids would be associated with kidney functions, comorbidities, and prognosis of chronic kidney disease (CKD) by enantioselective analyses of all chiral amino acids with a micro-two-dimensional high-performance liquid chromatograph (2D-HPLC)-based analytical platform. 16 out of 21 D-amino acids were detected in plasma from 108 CKD patients in a longitudinal cohort. The levels of D-Ser, D-Pro, and D-Asn were strongly associated with kidney function (estimated glomerular filtration ratio), the levels of D-Ala and D-Pro were associated with age, and the level of D-Asp and D-Pro were associated with the presence of diabetes mellitus. D-Ser and D-Asn were significantly associated with the progression of CKD in mutually-adjusted Cox regression analyses; the risk of composite end point (developing to ESKD or death before ESKD) was elevated from 2.7- to 3.8-fold in those with higher levels of plasma D-Ser and D-Asn. These findings identified chiral amino acids as potential biomarkers in kidney diseases.