Impact of Physiological Characteristics on Chylomicron Pathway-Mediated Absorption of Nanocrystals in the Pediatric Population.

Nanocrystals exhibit significant advantages in improving the oral bioavailability of poorly soluble drugs. However, the complicated absorption properties of nanocrystals and the differences in physiological characteristics between children and adults limit pediatric applications of nanocrystals. To elucidate the absorption differences and the underlying mechanisms between children and adults, the pharmacokinetics and tissue distribution of aprepitant crystals with different particle sizes (NC200, NC500, and MC2.5) in rats and mice at different ages were studied, and their absorption mechanisms were investigated in Caco-2 cells, mice, and rats. It was found that childhood animals demonstrated higher bioavailability compared with adolescent and adult animals, which was related to higher bile salt concentration and accelerated drug dissolution in the intestine of childhood animals. The majority of nanocrystals were dissolved and formed micelles under the influence of bile salts. Compared with intact nanocrystals, the bile salt micelle-associated aprepitant was absorbed through the chylomicron pathway, wherein Apo B assisted in the reassembling of the aprepitant micelles after endocytosis. Higher bile salt concentration and Apo B expression in the intestines of childhood animals are both responsible for the higher chylomicron transport pathways. Elucidation of the chylomicron pathway in the varied absorption of nanocrystals among children, adolescents, and adults provides strong theoretical guidance for promoting the rational and safe use of nanocrystals in pediatric populations.

High sodium intake and fluid overhydration predict cardiac structural and functional impairments in chronic kidney disease.

Background: High sodium intake and fluid overhydration are common factors of and strongly associated with adverse outcomes in chronic kidney disease (CKD) patients. Yet, their effects on cardiac dysfunction remain unclear. Aims: The study aimed to explore the impact of salt and volume overload on cardiac alterations in non-dialysis CKD. Methods: In all, 409 patients with CKD stages 1-4 (G1-G4) were enrolled. Daily salt intake (DSI) was estimated by 24-h urinary sodium excretion. Volume status was evaluated by the ratio of extracellular water (ECW) to total body water (TBW) measured by body composition monitor. Recruited patients were categorized into four groups according to DSI (6 g/day) and median ECW/TBW (0.439). Echocardiographic and body composition parameters and clinical indicators were compared. Associations between echocardiographic findings and basic characteristics were performed by Spearman's correlations. Univariate and multivariate binary logistic regression analysis were used to determine the associations between DSI and ECW/TBW in the study groups and the incidence of left ventricular hypertrophy (LVH) and elevated left ventricular filling pressure (ELVFP). In addition, the subgroup effects of DSI and ECW/TBW on cardiac abnormalities were estimated using Cox regression. Results: Of the enrolled patients with CKD, the median urinary protein was 0.94 (0.28-3.14) g/d and estimated glomerular filtration rate (eGFR) was 92.05 (IQR: 64.52-110.99) mL/min/1.73 m2. The distributions of CKD stages G1-G4 in the four groups was significantly different (p = 0.020). Furthermore, compared to group 1 (low DSI and low ECW/TBW), group 4 (high DSI and high ECW/TBW) showed a 2.396-fold (95%CI: 1.171-4.902; p = 0.017) excess risk of LVH and/or ELVFP incidence after adjusting for important CKD and cardiovascular disease risk factors. Moreover, combined with eGFR, DSI and ECW/TBW could identify patients with higher cardiac dysfunction risk estimates with an AUC of 0.704 (sensitivity: 75.2%, specificity: 61.0%). The specificity increased to 85.7% in those with nephrotic proteinuria (AUC = 0.713). The magnitude of these associations was consistent across subgroups analyses. Conclusion: The combination of high DSI (>6 g/d) and high ECW/TBW (>0.439) independently predicted a greater risk of LVH or ELVFP incidence in non-dialysis CKD patients. Moreover, the inclusion of eGFR and proteinuria improved the risk stratification ability of DSI and ECW/TBW in cardiac impairments in CKD.

25(OH)D level and vascular lesion scores in kidney histopathology as risk-stratification tool for predicting renal progression in people with type 2 diabetes.

AIM: To evaluate the potential of the combined individual vascular histopathological lesion and serum 25-hydroxy vitamin D [25(OH)D] level as predictors of outcomes in patients with diabetes and chronic kidney disease. METHODS: A total of 190 patients with type 2 diabetes and kidney disease stages 1-4 were retrospectively included. Kaplan-Meier analysis and the log-rank test were performed to assess renal survival differences. And the time-dependent receiver operating characteristic analyses were used to characterize the predictive accuracy. Hazard ratios for vascular lesion scores and 25(OH)D levels with renal outcomes were estimated using Cox proportional hazards regression models with follow-up time. RESULTS: Over a median follow-up of 23.78 (12.61, 37.14) months, 71 patients (37.4 %) experienced the renal outcomes. Enrolled patients with more severe vascular lesions had worse kidney function, heavier proteinuria, lower serum 25(OH)D levels, and higher prevalence of composite kidney outcomes. Baseline serum 25(OH)D was a significant independent risk factor for vascular lesion scores. The effect of serum 25(OH)D level on kidney prognosis was more pronounced in males and those with more exacerbated vascular lesions (score 2). The severity of vascular lesions and serum 25(OH)D levels were associated with unfavorable kidney outcomes. Accordingly, further time-dependent receiver operating characteristic curves confirmed that combined 25(OH)D level and vascular lesion score had a stable and reliable performance in renal outcomes prediction at short and long-term follow-up times. CONCLUSIONS: 25(OH)D level and vascular lesion scores in kidney histopathology could serve as a useful risk-stratification tool for predicting renal progression in patients with type 2 diabetes.

Utilization of the corticomedullary difference in magnetic resonance imaging-derived apparent diffusion coefficient for noninvasive assessment of chronic kidney disease in type 2 diabetes.

BACKGROUNDS: Accumulating data demonstrated that the cortico-medullary difference in apparent diffusion coefficient (ΔADC) of diffusion-weighted magnetic resonance imaging (DWI) was a better correlation with kidney fibrosis, tubular atrophy progression, and a predictor of kidney function evolution in chronic kidney disease (CKD). OBJECTIVES: We aimed to assess the value of ΔADC in evaluating disease severity, differential diagnosis, and the prognostic risk stratification for patients with type 2 diabetes (T2D) and CKD. METHODS: Total 119 patients with T2D and CKD who underwent renal MRI were prospectively enrolled. Of them, 89 patients had performed kidney biopsy for pathological examination, including 38 patients with biopsy-proven diabetic kidney disease (DKD) and 51 patients with biopsy-proven non-diabetic kidney disease (NDKD) and Mix (DKD + NDKD). Clinicopathological characteristics were compared according to different ΔADC levels. Moreover, univariate and multivariate-linear regression analyses were performed to explore whether ΔADC was independently associated with estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR). The diagnostic performance of ΔADC for discriminating DKD from NDKD + Mix was evaluated by receiver operating characteristic (ROC) analysis. In addition, an individual's 2- or 5-year risk probability of progressing to end-stage kidney disease (ESKD) was calculated by the kidney failure risk equation (KFRE). The effect of ΔADC on prognostic risk stratification was assessed. Additionally, net reclassification improvement (NRI) was used to evaluate the model performance. RESULTS: All enrolled patients had a median ΔADC level of 86 (IQR 28, 155) × 10-6 mm2/s. ΔADC significantly decreased across the increasing staging of CKD (P < 0.001). Moreover, those with pathological-confirmed DKD has a significantly lower level of ΔADC than those with NDKD and Mix (P < 0.001). It showed that ΔADC was independently associated with eGFR (ß = 1.058, 95% CI = [1.002,1.118], P = 0.042) and UACR (ß = -3.862, 95% CI = [-7.360, -0.365], P = 0.031) at multivariate linear regression analyses. Besides, ΔADC achieved an AUC of 0.707 (71% sensitivity and 75% specificity) and AUC of 0.823 (94% sensitivity and 67% specificity) for discriminating DKD from NDKD + Mix and higher ESKD risk categories (≥50% at 5 years; ≥10% at 2 years) from lower risk categories (<50% at 5 years; <10% at 2 years). Accordingly, the optimal cutoff value of ΔADC for higher ESKD risk categories was 66 × 10-6 mm2/s, and the group with the low-cutoff level of ΔADC group was associated with 1.232 -fold (95% CI 1.086, 1.398) likelihood of higher ESKD risk categories as compared to the high-cutoff level of ΔADC group in the fully-adjusted model. Reclassification analyses confirmed that the final adjusted model improved NRI. CONCLUSIONS: ΔADC was strongly associated with eGFR and UACR in patients with T2D and CKD. More importantly, baseline ΔADC was predictive of higher ESKD risk, independently of significant clinical confounding. Specifically, ΔADC <78 × 10-6 mm2/s and <66 × 10-6 mm2/s would help to identify T2D patients with the diagnosis of DKD and higher ESKD risk categories, respectively.

Association of Mitochondrial Pyruvate Carrier with the Clinical and Histological Features in Lupus Nephritis.

Background: Mounting evidence suggests that mitochondrial dysfunction contributes to lupus nephritis (LN) pathogenesis. Mitochondrial pyruvate carrier 1 (MPC1) and mitochondrial pyruvate carrier 2 (MPC2) mediating pyruvate transport from the cytoplasm to the mitochondrial matrix, determines the cell survival and cellular energy supply. Here, we aimed to investigate the association of mitochondrial pyruvate carrier expression with the clinical and histological features in LN. Methods: Patients with biopsy-proven proliferative LN (class III and class IV, n=18) and membranous LN (class V, n=18) were included. Expression of MPC1 and MPC2 were examined by immunohistochemistry. MPC protein levels in the two groups were evaluated by the Student's t-test. Correlation analysis between MPC levels and clinicopathological features was performed by Spearman's rank correlation. Results: Both MPC1 and MPC2 were exclusively expressed in renal tubules of enrolled LN. Significantly lower MPC1 and MPC2 were observed in patients with proliferative LN compared to membranous LN. In addition, the MPC1 and MPC2 were negatively correlated with SLEDAI-2K score, renal function, and renal pathology activity index. Conclusion: Both MPC1 and MPC2 were localized in renal tubules, and decreased MPC content was more pronounced in proliferative LN than membranous LN. MPC levels were significantly correlated with renal functions and renal pathology activity.

Serum 25-hydroxyvitamin D as a predictive biomarker of clinical outcomes in patients with primary membranous nephropathy.

Background: Primary membranous nephropathy (PMN) is an immune-related disease with increased morbidity and the most common cause of adult nephrotic syndrome (NS). The serum 25-hydroxyvitamin D [25(OH)D)], a biomarker of vitamin D (VD) status, tends to decline in patients with kidney disease. However, the relationship between 25(OH)D and PMN is still unclear. Therefore, this study aims to clarify the association between 25(OH)D and disease severity and therapy response of PMN. Methods: A total of 490 participants diagnosed with PMN by biopsy from January 2017 to April 2022 were recruited at the First Affiliated Hospital of Nanjing Medical University. The correlations between baseline 25(OH)D and manifestations of nephrotic syndrome (NS) or seropositivity of anti-PLA2R Ab were confirmed by univariate and multivariate logistic analyses. Spearman's correlations were used to examine the associations between baseline 25(OH)D and other clinical parameters. In the follow-up cohort, Kaplan-Meier analysis was used to assess remission outcomes among groups with low, medium, and high levels of 25(OH)D. Furthermore, the independent risk factors for non-remission (NR) were explored by COX regression analysis. Results: At baseline, 25(OH)D was negatively related to 24-h urinary protein and serum anti-PLA2R Ab. The lower level of baseline 25(OH)D was associated with an increased risk for the incidence of NS in PMN (model 2, OR 6.8, 95% CI 4.4, 10.7, P < 0.001) and seropositivity of anti-PLA2R Ab (model 2, OR 2.4, 95% CI 1.6, 3.7, P < 0.001). Furthermore, the lower level of 25(OH)D during follow-up was demonstrated as an independent risk factor for NR even after adjusting age, gender, MBP, 24 h UP, serum anti-PLA2R Ab, serum albumin, and serum C3 [25(OH)D (39.2-62.3 nmol/L): HR 4.90, 95% CI 1.02, 23.53 P = 0.047; 25(OH)D < 39.2 nmol/L: HR 17.52, 95% CI 4.04, 76.03 P < 0.001); vs. 25(OH)D ≥ 62.3 nmol/L]. The Kaplan-Meier survival analysis also demonstrated that the higher level of follow-up 25(OH)D had a higher possibility of remission than the lower one (log-rank test, P < 0.001). Conclusion: Baseline 25(OH)D was significantly correlated with nephrotic proteinuria and seropositivity of anti-PLA2R Ab in PMN. As an independent risk factor for NR, a low level of 25(OH)D during follow-up might serve as a prognostic tool for sensitively identifying cases with a high probability of poor treatment response.

Triglyceride-glucose index is associated with the risk of chronic kidney disease progression in type 2 diabetes.

OBJECTIVE: The study aimed to investigate the association of TyG index with chronic kidney disease (CKD) progression in type 2 diabetes mellitus (T2DM). METHODS: A total of 179 T2DM patients with CKD were retrospectively included. CKD progression was defined as a doubling of baseline serum creatinine or onset of end-stage kidney disease (ESKD). Internal validation was performed by the Kidney Failure Risk Equation (KFRE) model and Net reclassification improvement (NRI). RESULTS: The optimal cut-off value of the TyG index was 9.17. The cumulative incidence of kidney outcomes was significantly higher in the high-TyG group (v.s low-TyG group, P = 0.019). In addition, the high-TyG index was associated with a greater risk of CKD progression (HR 1.794, 95% CI 1.026-3.137, P = 0.040). And reclassification analyses confirmed the final adjusted model improved NRI (61.90% v.s model 2, 43.80% v.s model 1). The further RCS curves presented an inverted S-shaped relationship between the TyG index and the risk of CKD progression. Internal validation verified that a higher TyG index was associated with 2.10-fold increased odds of 2-year ESKD risk >10% (95% CI 1.82-8.21). Moreover, subgroup analysis suggested that the association was more pronounced in those at relatively early CKD stages (higher than stage 2) and with no medication history of oral hypoglycemic agents. CONCLUSION: An elevated TyG index was associated with a higher risk of CKD progression in T2DM patients. Our findings suggested that timely targeting insulin sensitivity at the early stages of T2DM might be associated with declined future risk of CKD development.

The thickness of glomerular basement membrane predicts complete remission in primary membranous nephropathy.

Objective: Glomerular basement membrane (GBM) thickening is a typical and essential histopathological characteristic for the diagnosis of primary membranous nephropathy (PMN). The present study aimed to explore the relationship between GBM thickness and treatment response in PMN patients.Methods: A total of 128 patients with nephrotic syndrome concurrent with PMN were studied. The highest GBM thickness was measured from at least five glomerular capillary loops using an electron microscope, and the mean value was obtained. Patients were categorized into three groups according to the tertiles of GBM thickness as follows: Group 1 (GBM thickness ≤ 1100 nm, n = 48), Group 2 (1100 nm < GBM thickness ≤ 1300 nm, n = 40), Group 3 (GBM thickness >1300 nm, n = 40). Clinicopathological features and treatment response were compared among the three groups. The associations of GBM thickness with complete remission (CR) were assessed by Cox proportional hazard analyses and a cubic spline curve.Results: During a median follow-up period of 25.80 months, 69 (53.9%) patients achieved CR. Kaplan-Meier analysis showed that the non-CR probability was significantly higher in the highest tertile of GBM thickness (p˂0.001). Univariate Cox proportional hazard analysis indicated that GBM thickness was associated with CR (HR per SD 0.617, 95% CI [0.471-0.809], p˂0.001). After adjusting for age, duration of PMN, estimated glomerular filtration rate (eGFR), urinary protein excretion, grade of C3 deposition, and titer of serum anti-phospholipase A2 receptor (PLA2R) antibody, GBM thickness remained an independent predictor of CR (HR per SD 0.580, 95% CI [0.436-0.772], p˂0.001). Further multivariable-adjusted restricted cubic spline analysis confirmed a significant reverse linear association between GBM thickness and CR (p for nonlinear = 0.1261).Conclusions: GBM thickness is an independent risk factor of CR. PMN patients with an increased level of GBM thickening at diagnosis have a lower probability of achieving CR.

Efficacy and safety of rituximab for primary nephrotic syndrome with acute kidney injury: A two-center prospective cohort study.

The purpose of this study was to investigate the efficacy and safety of a low-dose Rituximab (RTX) regimen driven by peripheral blood B lymphocyte count in the treatment of adult patients with nephrotic syndrome (NS) complicated with acute kidney disease (AKI). We conducted a prospective single-arm study to evaluate the effect of B cells-driven RTX regimen. Patients with NS (MCD, FSGS, MN, IgAN) complicated with AKI fulfilling the inclusion criteria were eligible for this study. Patients were followed up at intervals of 2 months. Student's t-test and Chi-squared test were used to analyze normally distributed continuous variables and non-normally distributed continuous variables, respectively. From August 2018 to January 2022, 23 patients met the inclusion criteria and agreed to participate in the study. 3, 9, and 11 patients were AKI stage 1, 2, and 3, respectively. From baseline to the latest follow-up, 20 patients had complete and partial recovery of renal function. Accompanied by depletion of B cells, significant reduction of urinary protein excretion, serum total cholesterol, and the number of relapses were observed during the 12 months after the first RTX infusion as compared with during the 12 months before RTX injection. The number of patients who maintained steroids and immunosuppressive medications also remarkably decreased. This study indicates that the targets-driven treatment of low-dose RTX can achieve a high remission rate and alleviate the loss of kidney function in treating NS with AKI. The long-term efficacy, side effects, and therapeutic economics of RTX are reasonable.

The association of RNA-binding protein Human antigen R with kidney clinicopathologic features and renal outcomes in patients with diabetic nephropathy.

AIMS: RNA-binding protein Human antigen R (HuR) is closely related to diabetic nephropathy (DN) pathogenesis. However, the capacity of histological HuR level as a biomarker for DN progression remains unclear. METHODS: A total of 147 patients with type 2 diabetes mellitus who had biopsy-proven DN were enrolled. Renal outcomes were defined by doubling serum creatinine level or progression to end-stage renal disease (ESRD). A nomogram was built to predict renal outcomes based on Cox proportional hazards regression. RESULTS: The median follow-up period was 31 months, during which 71 (48.30 %) patients confronted DN progression. Pearson's correlation indicated that histological HuR increased along with DN pathological class rising (r = 0.776, p < 0.001). Notably, multivariate Cox regression analysis showed that elevated HuR was associated with a greater risk of DN progression (HR 2.431, 95 %CI: 1.275-4.634, p = 0.007) beyond 6 months after renal biopsy. Patients in the higher HuR expression group had lower cumulative renal survival rates beyond the first 6 months. Simultaneously, a well-performed nomogram including HuR classification, was developed to predict the individual progression risk (C-index 0.828). CONCLUSIONS: Our findings demonstrated that the histologic HuR expression was an independent risk factor for kidney progression beyond 6 months after renal biopsy in DN.

Clinicopathological features and individualized treatment of kidney involvement in B-cell lymphoproliferative disorder.

Background: Due to the various clinical and pathological manifestations of kidney involvement in lymphoproliferative disorder (LPD), the whole spectrum of kidney disease in LPD is still unclear, and data on kidney prognosis is scarce. Methods: We retrospectively reviewed the renal pathology profiles from January 2010 to December 2021, and 28 patients with B-cell LPD combined with intact renal biopsy data were included. Results: There were 20 men and eight women aging 41 to 79 years at the time of renal biopsy (median age 62 years). According to hematological diagnosis, patients were classified into four groups: chronic lymphocytic leukemia (CLL) (group1, n=7), Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) (group 2, n=8; WM, n=6; LPL, n=2), Other non-Hodgkin's lymphomas (NHL) (group3, n=7; diffuse large B-cell lymphoma (DLBCL), n=2; mucosa-associated lymphoid tissue (MALT) lymphoma, n=4; Low grade B-cell lymphoma, n=1), and monoclonal gammopathy of undetermined significance/monoclonal gammopathy of renal significance (MGUS/MGRS) (group 4, n=6). Median serum creatinine (Scr) level was 129 (range,59-956) umol/L. Eight patients (29%) were presented with acute kidney injury (AKI), and five patients (18%) required hemodialysis upon admission. Twenty-three patients (82%) presented with proteinuria (median protein excretion, 2.14 g/d), 11(39%) of whom had the nephrotic syndrome. Interstitial malignant infiltration was the most frequent renal lesion (n=6). Eight patients underwent immunohistochemistry of renal tissues, of which three patients (CLL, n=1; LPL, n=1; WM, n=1) had confirmed lymphoma infiltrates, and the infiltrating cells in the remaining five patients (CLL, n=1; MALT lymphoma, n=2; MGUS, n=2) were considered unrelated to lymphoma. The most common glomerular diseases were renal amyloidosis (n=4) and membranous nephropathy (n=4). Only 20 patients were treated, 13 of whom were treated with rituximab separately or in combination. The median follow-up time was 11 months. Of these, six had achieved hematological response, complete response in five cases. Eight had achieved renal response. At the end-of-study visit, four patients died and two progressed to end stage kidney disease (ESKD). Conclusion: In conclusion, the clinicopathological spectrum of renal involvement in BLPD is diverse. Renal biopsy and immunohistochemistry are required for early diagnosis and prognostic assessment.

Effectiveness and safety of Belimumab combined with standard therapy in severe active lupus nephritis requiring kidney replacement therapy: A case report and literature review.

Lupus Nephritis (LN) is the most common manifestation of severe organ damage for systemic lupus erythematosus (SLE) patients. Severe active LN could result in acute kidney injury (AKI), which could even require Kidney Replacement Therapy (KRT). Therefore, there needs to be a more proactive and safe induction therapy to quickly and effectively control renal immune inflammation, maintain kidney function or reverse kidney damage. While multiple clinical studies have proven the efficacy and safety of Belimumab in treating SLE and LN, these studies have not included cases of severe LN requiring KRT. We observed the effectiveness and safety of Belimumab in treating four severe active LN patients undergoing KRT. With Belimumab administered at a dosage of 10mg/kg, all four patients were able to discontinue KRT with no adverse events (AEs) to date ultimately. These cases provided an excellent basis for the application of Belimumab combined with standard therapy to LN patients with a medium to severe kidney injury.

Association of Serum 25 (OH) Vitamin D With Chronic Kidney Disease Progression in Type 2 Diabetes.

Objectives: Growing evidence demonstrated that vitamin D levels had been linked to type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in light of various extraskeletal effects. Therefore, the present study aimed to evaluate the association of 25-hydroxyvitamin D [25(OH)D] level with the clinicopathological features and CKD progression in T2DM. Methods: A total of 182 patients with T2DM with CKD stages 1 through 4 (G1-G4) were retrospectively included. Identification of the serum 25(OH)D level associated with CKD progression was executed by Kaplan-Meier survival analysis and Cox proportional hazards models. We further performed sensitivity analyses with a time-weighted average (TWA) of the serum 25(OH)D level in 75 participants to reinforce the findings. Results: The median serum 25(OH)D level was 26 (IQR, 14; 39) nmol/L in the study participants. Median follow-up time was 42 months, during which 70 (38%) patients confronted CKD progression. Cumulative kidney outcomes were significantly higher in the lowest tertile of the serum 25(OH)D level in Kaplan-Meier analyses (P < 0.001). Consistently, the analyses of Cox proportional hazards regression models indicated a significantly greater risk for CKD progression in the lowest tertile of the serum 25(OH)D level compared with the highest tertile of the serum 25(OH)D level (P = 0.03). These relationships remained robust with further sensitivity analysis of data with TWA of the serum 25(OH)D level, showing an independent association between lower TWA of the serum 25(OH)D level and an unfavorable renal outcome in patients with T2DM with CKD. Conclusions: Our findings demonstrated that patients with T2DM with a decreased 25(OH)D level had deteriorated renal function. Both lower levels of baseline and TWA of serum 25(OH)D were associated with an increased risk of CKD progression in patients with T2DM, which suggested that the long-term maintenance of optimal vitamin D levels from early in life might be associated with reduced future risk of CKD development in T2DM.

Impact of Overhydration on Left Ventricular Hypertrophy in Patients With Chronic Kidney Disease.

Objective: Volume overload is a frequent feature related to left ventricular hypertrophy (LVH) in dialysis patients, but its influence on patients with chronic kidney disease (CKD) not on dialysis has not been accurately uncovered. This article was to examine the relationship between overhydration (OH) and LVH in patients with CKD not yet on dialysis. Methods: A total of 302 patients with CKD stages 1-4 were included. Participants were divided into different subgroups according to occurring LVH or not, and OH tertiles. Clinical and laboratory parameters were compared among groups. Spearman correlation analyses were adopted to explore the relationships of echocardiographic findings with the clinical and laboratory characteristics. Binary logistic regression models were performed to estimate the odds ratios (ORs) for the associations between OH and LVH. Restricted cubic splines were implemented to assess the possible non-linear relationship between OH and LVH. LVH was defined as left ventricular mass index (LVMI) >115 g/m2 in men and >95 g/m2 in women. Results: Of the enrolled patients with CKD, the mean age was 45.03 ± 15.14 years old, 165 (54.6%) cases were men, and 65 (21.5%) cases had LVH. Spearman correlation analyses revealed that OH was positively correlated with LVMI (r = 0.263, P < 0.001). After adjustment for age, gender, diabetes, body mass index (BMI), systolic blood pressure (SBP), hemoglobin, serum albumin, estimated glomerular filtration rate (eGFR), and logarithmic transformation of urinary sodium and urinary protein, multivariate logistic regression analyses demonstrated that both the middle and highest tertile of OH was associated with increased odds of LVH [OR: 3.082 (1.170-8.114), P = 0.023; OR: 4.481 (1.332-15.078), P = 0.015, respectively], in comparison to the lowest tierce. Restricted cubic spline analyses were employed to investigate the relationship between OH and LVH, which unfolded a significant non-linear association (P for non-linear = 0.0363). Furthermore, patients were divided into two groups according to CKD stages. The multivariate logistic regression analyses uncovered that increased odds of LVH were observed in the middle and the highest tertile of OH [OR: 3.908 (0.975-15.670), P = 0.054; OR: 6.347 (1.257-32.054), P = 0.025, respectively] in patients with stages 1-2. Conclusion: These findings suggest that a higher level of OH was associated with a higher occurrence of LVH in patients with CKD not on dialysis, especially in patients with CKD stages 1-2.

Association of urinary calcium and phosphorus excretion with renal disease progression in type 2 diabetes.

OBJECTIVES: Diabetes is associated with a high incidence of microvascular disease, including nephropathy. The current study aimed to investigate the association of urinary calcium and phosphorus excretion with chronic kidney disease (CKD) progression in type 2 diabetes mellitus. METHODS: A total of 159 T2DM patients with chronic kidney disease (CKD stage G1-G4) were retrospectively included. Patients were categorized into three groups according to the tertiles of 24-h urinary calcium and phosphorus excretion, respectively. Clinical parameters and laboratory findings were compared among the three groups. Cox proportional hazards models were used to estimate the associations of urinary calcium and phosphorus excretion with CKD progression and adjusted for baseline eGFR, urinary protein excretion, mean arterial pressure, and use of RAAS inhibitor. A cubic spline curve was used to explore the association between urinary calcium excretion and CKD progression, as well as urinary phosphorus excretion and CKD progression. Moreover, the subgroup effects of urinary calcium and phosphorus excretion on CKD progression were estimated using Cox regression. CKD progression was defined as double of baseline serum creatinine or occurrence of ESRD. RESULTS: During a median of 18.23 months of follow-up, the composite renal outcomes were noted in 27%. Cumulative renal outcomes were significantly lower in the highest tertile of urinary calcium excretion and phosphorus excretion in Kaplan-Meier analyses. The multivariate Cox proportional hazards regression analyses indicated that both the highest tertile of urinary calcium and phosphorus excretion was associated with a lower risk for CKD progression compared with the lowest tertile. Restricted cubic spline analyses of the association between urinary calcium excretion and CKD progression indicated a linear association. Additionally, there was also a linear association between urinary phosphorus excretion and CKD progression. Subgroup analyses showed that higher urinary phosphorus excretion was particularly associated with a lower risk of CKD progression in non-diabetic kidney disease (NDKD) patients. CONCLUSION: Higher urinary calcium and phosphorus excretion were associated with decreased risk of CKD progression in T2DM patients.

Current Challenges and Future Perspectives of Renal Tubular Dysfunction in Diabetic Kidney Disease.

Over decades, substantial progress has been achieved in understanding the pathogenesis of proteinuria in diabetic kidney disease (DKD), biomarkers for DKD screening, diagnosis, and prognosis, as well as novel hypoglycemia agents in clinical trials, thereby rendering more attention focused on the role of renal tubules in DKD. Previous studies have demonstrated that morphological and functional changes in renal tubules are highly involved in the occurrence and development of DKD. Novel tubular biomarkers have shown some clinical importance. However, there are many challenges to transition into personalized diagnosis and guidance for individual therapy in clinical practice. Large-scale clinical trials suggested the clinical relevance of increased proximal reabsorption and hyperfiltration by sodium-glucose cotransporter-2 (SGLT2) to improve renal outcomes in patients with diabetes, further promoting the emergence of renal tubulocentric research. Therefore, this review summarized the recent progress in the pathophysiology associated with involved mechanisms of renal tubules, potential tubular biomarkers with clinical application, and renal tubular factors in DKD management. The mechanism of kidney protection and impressive results from clinical trials of SGLT2 inhibitors were summarized and discussed, offering a comprehensive update on therapeutic strategies targeting renal tubules.

Characteristics of urinary sodium excretion in patients with chronic kidney disease in Jiangsu, China.

The current study aimed to assess the dietary salt intake in patients with CKD in Jiangsu province and investigate the relationship of urinary sodium excretion with blood pressure. A total of 800 patients with CKD stages 1-4 were recruited. All enrolled patients were asked to collect complete 24-h urine specimen. At the same time, patient's demographic and laboratory data were recorded. The mean age was 47.45 ± 15.25 years old, including 423 men and 377 women. There was no significant difference in urinary sodium excretion among different stages of CKD (p = .748). This study revealed that the median urinary sodium excretion of all patients was 127.20 mmol/d (IQR 91.03-172.06), corresponding to a salt intake of 7.4 g/d. Among them, only 167 (20.9%) cases had salt intake <5 g/d. Moreover, urinary sodium excretion in overweight group and obese group was higher than that in normal weight group (p = .001, p Ë‚ .001). Likewise, urinary sodium excretion in men was higher than that in women (p Ë‚ .001). Spearman correlation analysis indicated that urinary sodium excretion positively correlated with urinary protein excretion (r = .178, p Ë‚ .001), SBP (r = .109, p = .002), and DBP (r = .086, p = .015). After adjusting for age, gender, BMI, eGFR, urinary protein excretion, and history of taking antihypertensive drug, multivariate linear regression demonstrated that higher level of urinary sodium excretion associated with increased level of SBP, DBP, and MAP (ß = 0.020, p = .049; ß = 0.015, p = .040; ß = 0.016, p = .025, respectively). In conclusion, the dietary salt intake in CKD patients, especially in male, overweight and obese subjects, remains high in Jiangsu province. It is vital to decline salt intake to control blood pressure in Jiangsu patients with CKD.

Association of platelet-to-lymphocyte ratio with kidney clinicopathologic features and renal outcomes in patients with diabetic kidney disease.

BACKGROUND: Growing evidence points to the pivotal role of inflammation in the pathogenesis of diabetic kidney disease (DKD). However, as an inflammation-based prognostic score, the significance of platelet-to-lymphocyte ratio (PLR) in biopsy-proven DKD remains uncertain. Therefore, the current study aimed to evaluate the association of PLR with the clinicopathological features and the progression of DKD. METHODS: In total, 167 patients with biopsy-proven T2DKD were retrospectively recruited. Clinicopathological characteristics were compared according to the tertiles of baseline PLR. Pearson's or Spearman correlations were used to examine the associations between PLR and baseline characteristics. Assessment of the prospective relationship of PLR with the kidney outcomes defined as a doubling of baseline serum creatinine or onset of end stage renal disease (ESRD), were investigated by Kaplan-Meier survival analysis. Moreover, a cubic spline curve was further calculated to explore the significance of PLR in DKD prognosis. On top of that, identification of the risk factors associated with DKD progression was executed by a model of Cox proportional hazards. RESULTS: Median follow-up period was 23.77 months, during which 92 (55.1%) patients confronted DKD progression. Pearson's correlation indicated that urinary protein increased along with PLR rising (r = 0.193, P = 0.012). Kaplan-Meier survival curves revealed a significantly increased probability of event-free survival in the lowest tertile of PLR compared to those in the highest tertile (P = 0.018). A statistical linear correlation between PLR and DKD development was demonstrated by a restricted cubic spline analysis (P for nonlinear = 0.784). In addition, the analyses of multivariate Cox regression indicated that elevated PLR had an association with a greater risk of DKD progression (HR 1.004, 95%CI [1.000-1.008], P = 0.035), which was verified to be an independent risk factor for renal outcomes. CONCLUSIONS: Our findings demonstrated that the PLR was associated with proteinuria and prognosis in DKD patients. It was an independent risk factor for kidney progression in biopsy-proven DKD.

Value of monitoring urine ammonia at time of biopsy in patients with lupus nephritis.

OBJECTIVE: Although lupus nephritis (LN) is mostly characterized by glomerular involvement, tubular injury is indispensable in its pathogenesis and progression. The purpose of this study is to examine associations between urinary acidification function and clinical and pathological features in LN. METHODS: A total of 103 patients with renal biopsy-proven LN were included, and clinical parameters and laboratory data were obtained from the medical records. Plasma samples, 24-h urine samples and the urinary acidification function, including urine pH, titratable acid, and ammonia, were collected within 3 days before the day of renal biopsy. The correlations between defects of acid excretion and clinical and pathological features were then assessed. Logistic regression analysis was used to assess factors associated with the presence of nephrotic range proteinuria. RESULTS: The urine ammonia level was inversely correlated with SLEDAI-2 K scores, rSLEDAI scores, serum creatinine levels and proteinuria, while it was positively correlated with eGFR. And urine titratable acid was only inversely correlated with rSLEDAI scores and proteinuria. Moreover, urine ammonia had significant negative correlations with AI scores, interstitial inflammatory cell infiltration, CI scores, glomerular sclerosis, fibrous crescents, tubular atrophy and interstitial fibrosis. And urine titratable acid was mainly inversely correlated with CI scores. Furthermore, univariate logistic analyses identified that both urine titratable acid and ammonia were correlated with the presence of nephrotic range proteinuria. After the adjustment for chronicity index and eGFR in a multivariate logistic analysis, only urine titratable acid was still identified as an independent risk factor for the occurrence of nephrotic range proteinuria. CONCLUSIONS: Urine ammonia was associated with clinical and pathological features of chronicity and tubulointerstitial disease activity among patients with lupus nephritis. Furthermore, the strong association between urinary protein and titratable acid excretion at the time of kidney biopsy is significant even after adjusting for the chronicity index and eGFR at biopsy.

Association of Glomerular Complement C4c Deposition With the Progression of Diabetic Kidney Disease in Patients With Type 2 Diabetes.

Objectives: As accumulating data supporting the potential role of the complement system in the pathogenesis of diabetic kidney disease (DKD), the present study aimed to explore the association of glomerular complement C4c deposition with the baseline clinicopathological characteristics and the prognosis of DKD in type 2 diabetes (T2DM) patients. Methods: A total of 79 T2DM patients with biopsy-proven DKD were enrolled. Clinicopathological features and renal outcomes were compared between groups divided by the glomerular C4c deposition patterns and median values of serum C4. Renal outcomes were defined by doubling of serum creatinine level or progression to end-stage renal disease (ESRD). A Cox proportional hazards model was employed to identify the risk factors associated with renal events. Results: Patients with glomerular C4c deposition had worse renal insufficiency than those without C4c deposits, along with higher 24-h urinary protein, triglyceride, but lower serum albumin and higher interstitial inflammation score. Besides, serum C4 levels positively correlated with urinary protein and serum C3 levels. During 21.85 ± 16.32 months of follow-up, Kaplan-Meier curve analysis showed significantly faster deterioration of renal function for patients with positive glomerular C4c deposition as well as higher levels of serum C4. More specifically, more than 50% of the patients with glomerular C4c had co-deposition of C3c or C1q, and patients with glomerular complement complex of C4c and one or two of C3/C1q deposition had more severe proteinuria and a higher rate of DKD progression than those with negative C4c deposits. The univariate Cox regression indicated that factors of combined serum and glomerular C4, urinary protein, serum creatinine, serum C3, combined glomerular C4c and IgM and interstitial inflammation were associated with an increased risk of DKD, but only glomerular C4c intensity (HR 1.584, 95% CI [1.001, 2.508], p = 0.0497), as well as baseline age and diabetic neuropathy, were independent risk factors for renal survival by the multivariate Cox analysis. Conclusions: Glomerular C4c deposition was associated with deteriorated renal function and outcomes in patients with T2DKD. Glomerular C4c deposition was an independent risk factor for DKD progression.