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.

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.

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 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.