Modified Glomerular Filtration Rate-Estimating Equations Developed in Asiatic Population for Chinese Patients with Type 2 Diabetes

Objectives. To evaluate eight modified equations developed in Asiatic populations in type 2 diabetic patients in China. Methods. A total of 209 Chinese patients with type 2 diabetes were recruited. Using the technetium—99m diethylenetriaminepentaacetic acid—glomerular filtration rate (GFR) to act as the reference, comparisons of their efficiency to estimate GFR in the subjects were made between various equations. Results. Median of difference of the Chinese equation 1 was the lowest (median of difference, 0.51 mL/min/1.73 m2). Median percent of absolute difference of the Chinese equation 2 was less than those of the other equations (26.97 versus ranged from 32.54 to 37.61 mL/min/1.73 m2, [P<0.001 for all]). Precision of the simplified reexpressed MDRD equation was the best (92.9 mL/min/1.73 m2). Accuracies of the Chinese equation 2 were greater (P<0.05 for all). There was also an improvement in chronic kidney disease (CKD) stage misclassification of the Chinese equation 2 (55.0 versus ranged from 61.2 to 64.6%, [P<0.001 for all]). However, the 30% accuracies of all the equations were less than 70%. Conclusions. Our study highlighted a limitation in the use of the above equations in the majority of Chinese diabetic subjects. A better equation is needed in order to give an accurate estimation of GFR in type 2 diabetic patients in China

Low alpha-defensin gene copy number increases the risk for IgA nephropathy and renal dysfunction

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Although a major source of genetic variation, copy number variations (CNVs) and their involvement in disease development have not been well studied. Here, we performed association analysis of the DEFA1A3 CNV locus in two independent IgAN cohorts of Southern Chinese Han (total1189 cases and 1187 controls). We discovered three independent copy number associations within the locus: DEFA1A3 (P=3.99×10-9, OR=0.88), DEFA3 (P=6.55×10-5, OR=0.82) and a noncoding deletion variant (211bp) (P=3.50×10-16, OR=0.75) (OR per copy, fixed-effects meta-analysis). While showing strong association with increased risk for IgAN (P=9.56×10-20), low total copy numbers of the three variants also showed significant association with renal dysfunction in patients with IgAN (P=0.03, HR=3.69, after controlling for the effects of known prognostic factors) as well as high serum IgA1 (P=0.02) and a high proportion of galactose-deficient IgA1 (P=0.03). For replication, we confirmed the associations of DEFA1A3 (P=4.42×10-4, OR=0.82) and DEFA3 copy numbers (P=4.30×10-3, OR=0.74) with IgAN in a Caucasian cohort (531 cases and 198 controls) and found the 211bp variant to be much rarer in Caucasians. Interestingly, we also observed an association of the 211bp copy number with membranous nephropathy (P=1.11×10-7, OR=0.74 in 493 Chinese cases and 500 matched controls), but not with diabetic kidney disease (in 806 Chinese cases and 786 matched controls). By explaining 4.96% of disease risk and influencing the renal dysfunction in IgAN, the DEFA1A3 CNV locus is a potential candidate for therapeutic target and prognostic marker development

A new modified CKD-EPI equation for Chinese patients with type 2 diabetes.

OBJECTIVE: To improve the performance of glomerular filtration rate (GFR) estimating equation in Chinese type 2 diabetic patients by modification of the CKD-EPI equation. DESIGN AND PATIENTS: A total of 1196 subjects were enrolled. Measured GFR was calibrated to the dual plasma sample 99mTc-DTPA-GFR. GFRs estimated by the re-expressed 4-variable MDRD equation, the CKD-EPI equation and the Asian modified CKD-EPI equation were compared in 351 diabetic/non-diabetic pairs. And a new modified CKD-EPI equation was reconstructed in a total of 589 type 2 diabetic patients. RESULTS: In terms of both precision and accuracy, GFR estimating equations all achieved better results in the non-diabetic cohort comparing with those in the type 2 diabetic cohort (30% accuracy, P≤0.01 for all comparisons). In the validation data set, the new modified equation showed less bias (median difference, 2.3 ml/min/1.73 m2 for the new modified equation vs. ranged from -3.8 to -7.9 ml/min/1.73 m2 for the other 3 equations [P<0.001 for all comparisons]), as was precision (IQR of the difference, 24.5 ml/min/1.73 m2 vs. ranged from 27.3 to 30.7 ml/min/1.73 m2), leading to a greater accuracy (30% accuracy, 71.4% vs. 55.2% for the re-expressed 4 variable MDRD equation and 61.0% for the Asian modified CKD-EPI equation [P = 0.001 and P = 0.02]). CONCLUSION: A new modified CKD-EPI equation for type 2 diabetic patients was developed and validated. The new modified equation improves the performance of GFR estimation

Serum IgA1 from IgA nephropathy patients induces apoptosis in podocytes through direct and indirect pathways

Purpose: To investigate apoptosis of podocytes induced by IgA1 isolated from IgA nephropathy (IgAN) patients through direct and indirect pathways. Methods: Jacalin affinity chromatography and Sephacryl S-200 molecular sieve chromatography were used to isolate IgA1 from blood of IgAN patients made as aggregated IgA1 (aIgA1). Podocytes were incubated with aIgA1 or special treated medium from mesangial cells after co-incubation with aIgA1 from IgAN patients. Apoptosis of podocytes was assessed by TUNEL staining and flow cytometry. Real-time PCR was used to detect the mRNA expression of Bcl-2, Bax, Fas and Fas-L. Results: AIgA1 from IgAN patients induced more apoptosis of podocytes by both time and concentration-dependent patterns than control (30.5&#177;5.4% vs 20.5&#177;4.5, respectively, P < 0.05). The percentage of apoptotic podocytes exposed to treated medium was higher than control (28.5&#177;5.9 % vs 20.5&#177;4.5%, respectively, P < 0.05). The level of normalized Fas mRNA expression in podocytes exposed to aIgA1 was 2.4-fold higher than control (P < 0.05), while the level in podocytes exposed with treated medium was 1.89-fold higher than control (P < 0.05), and the level of normalized Bcl-2 mRNA expression in this group was 72% lower than control (P < 0.05) Conclusion: IgA1 from IgAN patients may induce apoptosis of podocytes through direct and indirect pathways. IgA1 may accelerate progression of IgAN by inducing apoptosis of podocytes

Diabetic Kidney Disease versus Primary Glomerular Disease: A Propensity Score-Matched Analysis of Association between Ambulatory Blood-Pressure Monitoring and Target-Organ Damage

Diabetic kidney disease (DKD) and primary glomerular disease (PGD) are the main causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). This study was conducted to compare the characteristics of ambulatory blood-pressure monitoring (ABPM) and its relationship with target-organ damage (TOD) in patients with DKD and PGD matched by propensity score. The assessment of TOD included macroalbuminuria, left ventricular hypertrophy (LVH) and macrovascular disease. Propensity-score weighting (PSW) was used in stratified analysis. Results: Patients with DKD had a higher prevalence of abnormal blood-pressure patterns such as reversed dipper pattern, nocturnal hypertension, and sustained hypertension and had a higher prevalence of TOD than did patients with PGD. Logistic regression indicated that patients with DKD were more related to TOD than to PGD. The stratified analysis indicated that DKD patients with white-coat hypertension, masked hypertension and sustained hypertension had closer relationships with TOD compared with PGD patients. Conclusion: Patients with type 2 diabetic kidney disease had more abnormal blood-pressure patterns and were more closely related to target organ damage than were patients with primary glomerular disease

Different effects of morning and nocturnal hypertension on target organ damage in chronic kidney disease

Both morning hypertension (MH) and nocturnal hypertension (NH) are associated with severe target organ damage in patients with chronic kidney disease (CKD). However, the isolated or combined effects of MH and NH on target organ damage are less well‐defined. A cross‐sectional study was conducted among 2386 non‐dialysis CKD patients with ambulatory blood pressure monitoring. The authors categorized patients into four groups based on the presence or absence of MH and NH. Multivariate logistic analyses were used to evaluate the correlation between hypertension subtypes and target organ damage, including left ventricular hypertrophy (LVH), abnormal carotid intima‐media thickness (CIMT), low estimated glomerular filtration rate (eGFR), and albuminuria. The percentages of isolated MH, isolated NH, and combined MH and NH were 2.3%, 24.0%, and 49.3%, respectively. Compared to patients without MH and NH, isolated MH was only related to low eGFR (2.26 [95% confidence interval: 1.00–5.09]) and albuminuria (2.17 [95% CI: 1.03–4.54]). Meanwhile, combined MH and NH group compared to the group without MH and NH had a higher risk of LVH (2.87 [95% CI: 2.01–4.09]), abnormal CIMT (2.01 [95% CI: 1.47–2.75]), low eGFR (3.18 [95% CI: 2.23–4.54]), and albuminuria (1.79 [95% CI: 1.33–2.40]), even in patients without daytime hypertension. The risk of cardiovascular and renal damage was also observed in the isolated NH group. In conclusion, morning hypertension is associated with kidney dysfunction and has combined effects with nocturnal hypertension on cardiovascular damage in chronic kidney disease patients

Activation of the Nrf2-ARE Pathway Attenuates Hyperglycemia-Mediated Injuries in Mouse Podocytes

Background: Damage to podocytes caused by excessive reactive oxygen species (ROS) contributes to onset and progression of diabetic kidney disease (DKD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a redox-sensing transcription factor that can induce the expression of antioxidant enzymes. We explored whether activation of Nrf2 pathway attenuated hyperglycemia-induced injuries in mouse podocytes. Methods: Tert-Butylhydroquinone (tBHQ) and small interfering RNAs (siRNAs) were used to regulate Nrf2 expression. Apoptosis and intracellular superoxide anion production were measured by flow cytometry. The activity of the Nrf2 antioxidant pathway was measured by an antioxidant response element (ARE)-driven luciferase reporter gene assay, and Nrf2 expression was assessed by real-time PCR and western blot analyses. Results: Podocytes incubated with high-glucose (HG) medium had higher intracellular superoxide anion and hydrogen peroxide production, higher apoptosis rate, higher bovine serum albumin (BSA) permeability and lower synaptopodin expression compared with podocytes exposed normal glucose (NG) (pppConclusions: Our findings suggest that protection against activation of the Nrf2-ARE pathway in podocytes exposed to hyperglycemia. Thus, regulation of the Nrf2-ARE pathway could be a therapeutic option to combat oxidative stress and inhibit the development of DKD

Nighttime Systolic Blood-Pressure Load Is Correlated with Target-Organ Damage Independent of Ambulatory Blood-Pressure Level in Patients with Non-Diabetic Chronic Kidney Disease.

The impacts of blood pressure (BP) load on target-organ damage in patients with chronic kidney disease (CKD) are largely unclear. We examined whether BP load is correlated with target-organ damage (TOD) in Chinese CKD patients independent of BP level.We recruited 1219 CKD patients admitted to our hospital division in this cross-sectional study. The TOD were measured by estimated glomerular filtration rate (eGFR), proteinuria, left ventricular mass index (LVMI) and carotid intima-media thickness (cIMT) in this study. Univariate and multivariate linear analyses were used to evaluate the relationship between systolic blood pressure (SBP) load, diastolic blood pressure (DBP) load and these renal, cardiovascular parameters.In multivariable-adjusted models, BP load and ambulatory BP levels both independently correlated with LVMI, eGFR and proteinuria in all groups of CKD patients (p<0.05), 24-h SBP correlated with cIMT only in non-diabetic CKD patients without hypertension (p<0.05), while nighttime SBP load was associated with cIMT only in non-diabetic CKD patients (p<0.05). Furthermore, nighttime SBP load additionally increased coefficient of determination (R(2)) and correlated with LVMI, proteinuria in non-diabetic CKD patients without hypertension (R(2) = 0.034, P<0.001 and R(2) = 0.012, P = 0.006 respectively) and LVMI, cIMT, eGFR in non-diabetic CKD patients with hypertension (R(2)>0.008, P<0.05) in multivariable-adjusted model which already including the 24-h BP. BP load did not refine this correlation based on the 24-h BP level in diabetic CKD patients.Night-time SBP load was correlated with TOD in patients with non-diabetic chronic kidney disease independent of BP level