Utility of serum ß2-microglobulin for prediction of kidney outcome among patients with biopsy-proven diabetic nephropathy.

AIM: To examine whether serum ß2-microglobulin (ß2-MG) could improve the prediction performance for kidney failure with replacement therapy (KFRT) among patients with diabetic nephropathy (DN). METHODS: Patients with biopsy-proven DN at Nara Medical University Hospital were included. The exposure of interest was log-transformed serum ß2-MG levels measured at kidney biopsy. The outcome variable was KFRT. Multivariable Cox regression models and competing-risk regression models, with all-cause mortality as a competing event, were performed. Model fit by adding serum ß2-MG levels was calculated using the Akaike information criterion (AIC). The net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indexes were used to evaluate the improvement of predictive performance for 5-year cumulative incidence of KFRT by serum ß2-MG levels. RESULTS: Among 408 patients, 99 developed KFRT during a median follow-up period of 6.7 years. A higher serum ß2-MG level (1-unit increase in log-transformed serum ß2-MG level) was associated with a higher incidence of KFRT, even after adjustments for previously known clinical and histological risk factors (hazard ratio [95% confidence interval {CI}]: 3.30 [1.57-6.94] and subdistribution hazard ratio [95% CI]: 3.07 [1.55-6.06]). The addition of log-transformed serum ß2-MG level reduced AIC and improved the prediction of KFRT (NRI and IDI: 0.32 [0.09-0.54] and 0.03 [0.01-0.56], respectively). CONCLUSIONS: Among patients with biopsy-proven DN, serum ß2-MG was an independent predictor of KFRT and improved prediction performance. In addition to serum creatinine, serum ß2-MG should probably be measured for DN.

Differential impact of glomerular and tubule-interstitial histological changes on kidney outcome between non-proteinuric and proteinuric diabetic nephropathy.

BACKGROUND: Studies on kidney function and histological findings in diabetic nephropathy (DN) with low urinary protein (UP) are few. We examined the differential impact of histological changes on kidney outcomes between non-proteinuric and proteinuric DN. METHODS: Patients diagnosed with DN by renal biopsy during 1981-2014 were divided into non-proteinuric (UP ≤ 0.5 g/day) and proteinuric (UP > 0.5 g/day) DN. The Cox proportional hazard model was used to examine the association of glomerular lesions (GLs) and interstitial fibrosis and tubular atrophy (IFTA) with end-stage kidney disease (ESKD) development after adjusting for relevant confounders. RESULTS: The non-proteinuric and proteinuric DN groups included 197 and 199 patients, respectively. During the 10.7-year median follow-up period, 16 and 83 patients developed ESKD in the non-proteinuric and proteinuric DN groups, respectively. In the multivariable Cox hazard model, hazard ratios (HRs) [95% confidence intervals (CIs)] of GL and IFTA for ESKD in proteinuric DN were 2.94 [1.67-5.36] and 3.82 [2.06-7.53], respectively. Meanwhile, HRs [95% CIs] of GL and IFTA in non-proteinuric DN were < 0.01 [0-2.48] and 4.98 [1.33-18.0], respectively. IFTA was consistently associated with higher incidences of ESKD regardless of proteinuria levels (P for interaction = 0.49). The prognostic impact of GLs on ESKD was significantly decreased as proteinuria levels decreased (P for interaction < 0.01). CONCLUSIONS: IFTA is consistently a useful predictor of kidney prognosis in both non-proteinuric and proteinuric DN, while GLs are a significant predictor of kidney prognosis only in proteinuric DN.

Trace proteinuria detected via dipstick test is associated with kidney function decline and new-onset overt proteinuria: the Japan Specific Health Checkups (J-SHC) Study.

BACKGROUND: Microalbuminuria is associated with mortality, cardiovascular disease, and end-stage kidney disease. The association between trace proteinuria (detected via dipstick test) and kidney outcomes is unclear. METHODS: This nationwide longitudinal study used data from the Japan Specific Health Checkups Study conducted during 2008-2014. The frequency of trace proteinuria (detected via dipstick test) during first two visits was used as an exposure variable (TrUP 0/2, no trace proteinuria; TrUP 1/2, detected once; TrUP 2/2, detected twice), and kidney outcomes were evaluated. The association between the frequency of trace proteinuria and incidence of 1.5-fold increase in serum creatinine levels and overt proteinuria was analyzed using Cox regression analysis. Trajectories of estimated glomerular filtration rate (eGFR) were compared using a mixed-effect model. RESULTS: Among 306,317 participants, 3188 and 17,461 developed a 1.5-fold increase in serum creatinine levels and new-onset overt proteinuria, respectively, during the median follow-up period of 36.2 months. The adjusted hazard ratio (HR) and 95% confidence interval (CI) for 1.5-fold increase in serum creatinine level in the TrUP 1/2 and TrUP 2/2 groups, compared to TrUP 0/2 group, were 1.23 (1.07-1.42) and 1.39 (1.01-1.92), respectively, and the adjusted HR (95% CI) for overt proteinuria were 2.94 (2.83-3.06) and 5.14 (4.80-5.51), respectively. The eGFR decline rates in the TrUP 1/2 and TrUP 2/2 groups were higher than that in the TrUP 0/2 group (p for interaction < 0.001). CONCLUSIONS: Trace proteinuria (detected via dipstick test) was associated with subsequent kidney function decline and overt proteinuria in the general population.

Association of pulse pressure with incident end-stage kidney disease according to histopathological kidney findings in patients with diabetic nephropathy.

Diabetic patients as well as the elderly are known to have high pulse pressure (PP), but there are few studies on how microangiopathy and macroangiopathy are involved in its mechanism. In this study, we examined the association between PP and atherosclerotic lesions by vessel size in kidney biopsy tissue and examined how PP is associated with kidney prognosis. This retrospective observational study included 408 patients with biopsy-proven diabetic nephropathy at Nara Medical University Hospital. Exposure of interest was PP measured at kidney biopsy. Outcome variable was kidney failure with replacement therapy (KFRT). Cox proportional hazards and competing risk regression models with all-cause mortality as a competing event were used to examine these associations. A total of 408 patients were divided into tertiles based on PP (mmHg): Tertile 1 (reference), <51; Tertile 2, 51-64; and Tertile 3, >64. Among the 408 patients, 99 developed KFRT during a median follow-up period of 6.7 years. Higher PP was independently associated with higher incidences of KFRT (hazard ratio [95% confidence interval] for Tertile 3 vs. Tertile 1; 2.07 [1.05-4.09]. In histological lesions, PP was strongly associated with glomerular lesions, tubulointerstitial lesions, and arteriolar hyalinosis (all ps for trend <0.001), but not with intimal thickening (p for trend = 0.714). PP was significantly associated with diabetic glomerular/tubulointerstitial lesions and arteriolar hyalinosis but not with intimal thickening at the time of kidney biopsy and was also significantly associated with subsequent KFRT in patients with diabetic nephropathy.

Serum High-Density Lipoprotein Cholesterol Levels and the Risk of Kidney Function Decline: The Japan Specific Health Checkups (J­SHC) Study.

AIMS: Both low and high serum levels of high-density lipoprotein cholesterol (HDL-C) were reported to be associated with adverse kidney outcomes. However, this association has not been well investigated in the general Japanese population. METHODS: This nationwide longitudinal study used data from the Japan Specific Health Checkups Study conducted between 2008-2014. The association between serum HDL-C levels and 40% decline in estimated glomerular filtration rate (eGFR) was analyzed using Cox regression analysis. Trajectories of eGFR were compared using mixed-effects model. RESULTS: Among 768,495 participants, 6,249 developed 40% decline in eGFR during the median follow-up period of 34.6 (interquartile range: 14.8-48.4) months. Using serum HDL-C levels of 40-59 mg/dL as a reference, the adjusted hazard ratios (95% confidence intervals) for the kidney outcome of serum HDL-C levels of ＜40, 60-79 and ≥ 80 mg/dL were 1.26 (1.14-1.39), 0.91 (0.86-0.96), and 0.86 (0.78-0.93), respectively. Restricted cubic spline analysis showed that HDL-C levels of less than approximately 60 mg/dL were associated with an increased risk of kidney outcomes. Subgroup analysis showed that baseline eGFR and proteinuria modified the effects of serum HDL-C levels on kidney outcomes. The mixed-effects model showed that the lower category of HDL-C level was associated with a higher eGFR decline rate (p for interaction ＜0.001). CONCLUSIONS: Low HDL-C levels were associated with kidney function decline; however, high HDL-C levels were not associated with adverse kidney outcomes in the general Japanese population.

Association of body indices with mortality in older population: Japan Specific Health Checkups (J-SHC) Study.

BACKGROUND: Obesity indices reflect not only fat mass but also muscle mass and nutritional status in older people. Therefore, they may not accurately reflect prognosis. This study aimed to investigate associations between a body shape index (ABSI), body mass index (BMI), and mortality in the general older population. METHODS: This nationwide observational longitudinal study included individuals aged between 65 and 74 years who underwent annual health checkups between 2008 and 2014. Exposures of interest were ABSI and BMI, and the primary outcome was all-cause mortality. Association between the ABSI and BMI quartile (Q1-4) and mortality was assessed using Cox regression analysis. A restricted cubic spline was also used to investigate nonlinear associations. The missing values were imputed using multiple imputation by chained equations. RESULTS: Among 315,215 participants, 5074 died during a median follow-up period of 42.5 (interquartile range: 26.2-59.3) months. Compared with ABSI Q1, ABSI Q3 and Q4 were associated with increased risk of mortality, with the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of 1.13 (1.05-1.22) and 1.23 (1.13-1.35), respectively. Compared with BMI Q3, BMI Q1 and Q2 were associated with an increased risk of mortality, with aHRs and 95% CIs of 1.51 (1.39-1.65) and 1.12 (1.03-1.22), respectively. The impacts of these indices were greater in male than in female. The heatmap of the aHR for mortality by continuous ABSI and BMI showed that higher ABSI was consistently associated with higher mortality risk regardless of BMI, and that the combination of low BMI and high ABSI was strongly associated with increased mortality risk. CONCLUSIONS: High ABSI and low BMI are additively associated with the risk of all-cause mortality in the general older population in Japan. Combination of ABSI and BMI is useful for evaluating mortality risk in older people.

Association of triglycerides to high-density lipoprotein cholesterol ratio with incident cardiovascular disease but not end-stage kidney disease among patients with biopsy-proven diabetic nephropathy.

Increased triglycerides (TG) and decreased high-density lipoprotein cholesterol (HDL-C) are dyslipidemias characteristic of diabetes. Here, we aimed to examine associations of TG/HDL-C ratio with cardiovascular disease (CVD) and kidney dysfunction among patients with diabetic nephropathy. This retrospective observational study consists of patients with biopsy-proven diabetic nephropathy at Nara Medical University Hospital. Exposure of interest was TG/HDL-C ratio measured at kidney biopsy. Outcome variables were kidney histological findings, incident CVD and end-stage kidney disease (ESKD). Multivariable logistic regression models and Cox proportional hazard models were used to examined these associations. A total of 353 subjects were divided into quartiles based on TG/HDL-C ratio: Quartile 1 (reference), <1.96; Quartile 2, 1.96-3.10; Quartile 3, 3.11-4.55; and Quartile 4, ≥4.56. TG/HDL-C ratio was not a predictor of any histological findings in fully adjusted models. During median follow-up periods of 6.2 and 7.3 years, 152 and 90 subjects developed CVD and ESKD, respectively. Higher TG/HDL-C ratio was independently associated with higher incidences of CVD even after adjustments for potential confounders (hazard ratio [95% confidence interval] for Quartile 3 vs. reference; 1.73 [1.08-2.79] and Quartile 4 vs. reference; 1.86 [1.10-3.17]). Although there was a weak association between TG/HDL-C ratio and ESKD in the univariable model, the association was not significant in fully adjusted models. In conclusion, among patients with biopsy-proven diabetic nephropathy, higher TG/HDL-C ratio was independently associated with higher incidences of CVD but not with kidney outcomes, suggesting different impact of TG/HDL-C ratio on cardiorenal outcomes.

Microscopic hematuria is a risk factor for end-stage kidney disease in patients with biopsy-proven diabetic nephropathy.

INTRODUCTION: There are fewer reports about whether the presence of hematuria affects the progression of chronic kidney disease in patients with diabetic nephropathy. We analyzed whether microscopic hematuria in diabetic nephropathy is a risk factor for end-stage kidney disease (ESKD). RESEARCH DESIGN AND METHODS: The present study was a retrospective cohort study of patients with biopsy-proven diabetic nephropathy. We recruited 397 patients with diabetic nephropathy, which was confirmed by renal biopsy between June 1981 and December 2014 and followed them until October 2018 or death. Patients with microscopic hematuria before renal biopsy were defined as the hematuria group (n=91), and the remainder as the no-hematuria group (n=306). The main outcome was the occurrence of ESKD, which was defined by the requirement of permanent renal replacement therapies. RESULTS: The systolic and diastolic blood pressure, serum creatinine and proteinuria were significantly higher, and the estimated glomerular filtration rate was significantly lower in the hematuria group compared with the no-hematuria group. Pathological evaluations revealed that glomerular, tubulointerstitial and vascular lesions in the hematuria group were significantly more severe. During a median of 10.1 years, 44 and 52 patients developed ESKD in the hematuria group and the no-hematuria group, respectively. Survival analyses showed that the incidence of ESKD was significantly higher in the hematuria group compared with the no-hematuria group (log-rank, p<0.0001). The multivariable Cox proportional hazards models revealed a significant association between hematuria and the incidence of ESKD after adjusting for clinically relevant factors, including proteinuria and renal pathology (adjusted HR 1.64, 95% CI 1.03 to 2.60). The subgroups of men, proteinuria ≥0.5 g/day, and systolic blood pressure ≥132 mm Hg showed a stronger association between hematuria and ESKD than their opposing subgroups. CONCLUSIONS: Microscopic hematuria is a risk factor for ESKD in diabetic nephropathy, independent of proteinuria and renal pathology.