Proteins Secreted by Lung Cancer Cells Induce the Onset of Proteinuria via Focal Adhesion Kinase Signaling in Mice.

Paraneoplastic nephrotic syndrome (PNS) is a complication seen in cancer patients. Ultrastructural examination shows the accumulation of proteins and the presence of foot process (FP) effacement in the glomeruli of PNS patients. Previously, we reported that orthotopic xenografts of Lewis lung carcinoma 1 in C57BL/6 mice caused them to develop lung cancer with albuminuria. This implies that these mice can be used as a model of human disease and suggests that Lewis lung carcinoma 1 cell-secreted proteins (LCSePs) contain nephrotoxic molecules and cause inflammation in renal cells. As podocyte effacement was present in glomeruli in this model, such podocyte injury may be attributable to either soluble LCSeP or LCSeP deposits triggering pathological progression. LCSePs in conditioned media was concentrated for nephrotoxicity testing. Integrin-focal adhesion kinase (FAK) signaling and inflammatory responses were evaluated in podocytes either exposed to soluble LCSePs or seeded onto substrates with immobilized LCSePs. FAK phosphorylation and interleukin-6 expression were higher in podocytes attached to LCSePs substrates than in those exposed to soluble LCSePs. Notably, LCSeP-based haptotaxis gave rise to altered signaling in podocytes. When podocytes were stimulated by immobilized LCSePs, FAK accumulated at focal adhesions, synaptopodin dissociated from F-actin, and disrupting the interactions between synaptopodin and α-actinin was observed. When FAK was inhibited by PF-573228 in immobilized LCSePs, the association between synaptopodin and α-actinin was observed in the podocytes. The association of synaptopodin and α-actinin with F-actin allowed FP stretching, establishing a functional glomerular filtration barrier. Therefore, in this mouse model of lung cancer, FAK signaling prompts podocyte FP effacement and proteinuria, indicative of PNS.

High risk of renal outcome of metabolic syndrome independent of diabetes in patients with CKD stage 1-4: The ICKD database.

AIMS: To investigate whether metabolic syndrome (MetS) could predict renal outcome in patients with established chronic kidney disease (CKD). MATERIALS AND METHODS: We enroled 2500 patients with CKD stage 1-4 from the Integrated CKD care programme, Kaohsiung for delaying Dialysis (ICKD) prospective observational study. 66.9% and 49.2% patients had MetS and diabetes (DM), respectively. We accessed three clinical outcomes, including all-cause mortality, RRT, and 50% decline in estimated glomerular filtration rate events. RESULTS: The MetS score was positively associated with proteinuria, inflammation, and nutrition markers. In fully adjusted Cox regression, the hazard ratio (HR) (95% confidence interval) of MetS for composite renal outcome (renal replacement therapy, and 50% decline of renal function) in the DM and non-DM subgroups was 1.56 (1.15-2.12) and 1.31 (1.02-1.70), respectively, while that for all-cause mortality was 1.00 (0.71-1.40) and 1.27 (0.92-1.74). Blood pressure is the most important component of MetS for renal outcomes. In the 2 by 2 matrix, compared with the non-DM/non-MetS group, the DM/MetS group (HR: 1.62 (1.31-2.02)) and the non-DM/MetS group (HR: 1.33 (1.05-1.69)) had higher risks for composite renal outcome, whereas the DM/MetS group had higher risk for all-cause mortality (HR: 1.43 (1.09-1.88)). CONCLUSIONS: MetS could predict renal outcome in patients with CKD stage 1-4 independent of DM.

Recommendations by the Asian Pacific society of nephrology (APSN) on the appropriate use of HIF-PH inhibitors.

Renal anaemia is a common and important complication in patients with chronic kidney disease (CKD). The current standard-of-care treatment for renal anaemia in CKD patients involves ensuring adequate iron stores and administration of erythropoietin stimulating agents (ESA). Hypoxia inducible factor (HIF) is a key transcription factor primarily involved in the cellular regulation and efficiency of oxygen delivery. Manipulation of the HIF pathway by the use of HIF-prolyl hydroxylase inhibitors (HIF-PHI) has emerged as a novel approach for renal anaemia management. Despite it being approved for clinical use in various Asia-Pacific countries, its novelty mandates the need for nephrologists and clinicians generally in the region to well understand potential benefits and harms when prescribing this class of drug. The Asian Pacific society of nephrology HIF-PHI Recommendation Committee, formed by a panel of 11 nephrologists from the Asia-Pacific region who have clinical experience or have been investigators in HIF-PHI studies, reviewed and deliberated on the clinical and preclinical data concerning HIF-PHI. This recommendation summarizes the consensus views of the committee regarding the use of HIF-PHI, taking into account both available data and expert opinion in areas where evidence remains scarce.

Risk factors and prognosis assessment for acute kidney injury: The 2020 consensus of the Taiwan AKI Task Force.

Risk and prognostic factors for acute kidney injury (AKI) have been published in various studies across various populations. We aimed to explore recent advancements in and provide updated recommendations on AKI risk stratification and information about local AKI risk factors. The Taiwan Acute Kidney Injury Task Force reviewed relevant recently published literature and reached a consensus after group meetings. Systemic review and group discussion were performed. We conducted a meta-analysis according to the PRISMA statement for evaluating the diagnostic performance of the furosemide stress test. Several risk and susceptibility factors were identified through literature review. Contrast-associated AKI prediction models after coronary angiography were one of the most discussed prediction models we found. The basic approach and evaluation of patients with AKI was also discussed. Our meta-analysis found that the furosemide stress test can be used as a prognostic tool for AKI progression and to identify patients with AKI who are at low risk of renal replacement therapy. Factors associated with de novo chronic kidney injury or renal non-recovery after AKI were identified and summarized. Our review provided practical information about early identification of patients at high risk of AKI or disease progression for Taiwan local clinics.

Blood pressure modifies outcomes in patients with stage 3 to 5 chronic kidney disease.

Observational studies have demonstrated that low blood pressure is related to poor clinical outcomes in patients with chronic kidney disease (CKD). Subgroup analyses from the SPRINT trial showed that targeting systolic blood pressure under 120 mmHg is less beneficial for patients with CKD. Although malnutrition and inflammation are common in patients with advanced CKD, such patients are usually excluded from clinical trials. Therefore, we hypothesized that malnutrition-inflammation-cachexia syndrome could explain this J-shaped relationship. To test this, we studied 2441 patients with CKD stages 3-5 who received anti-hypertensive treatment for at least one year. Averaged blood pressures of the first year were used in the analyses. Fine-Gray competing risks regression showed a J-shaped relationship between continuous systolic blood pressure and end-stage kidney disease (ESKD) with a nadir risk at a systolic blood pressure of 120 mmHg. Adjusted sub-distribution hazard ratios of categorical systolic blood pressure 100-109 and 110-119 mmHg were 2.17 (95% confidence interval: 1.21-3.89) and 1.37 (0.94-1.99) for ESKD, respectively, compared with systolic blood pressures of 120-129 mmHg. Cox regression also showed J-shaped relationships between continuous systolic or diastolic blood pressures, and the composite outcomes of cardiovascular events and all-cause mortality. Logistic regression demonstrated the odds ratios of blood pressure components for Malnutrition-Inflammation Scores over 4 were J-shaped. Sub-distribution hazard ratios of systolic blood pressure 100-119 mmHg for ESKD was higher in those with a Malnutrition-Inflammation Score over 4, compared to 0.93 (0.53-1.63) in those with a score of 4 or under with significant interaction. Thus, malnutrition-inflammation-cachexia syndrome is associated with low blood pressure and modifies the J-shaped relationship in patients with advanced CKD.

Decreased incidence of gout in diabetic patients using pioglitazone.

Objective: The incidence and prevalence of gout are increasing, but the management is poor. Considering the increased prevalence of gout in the diabetic population, this study evaluated the effects of pioglitazone, an insulin resistance inhibitor, on the incidence of gout in the diabetic population. Methods: We used data from the National Health Insurance program in Taiwan. The pioglitazone cohort contained 30 100 patients and each patient was age and sex matched with three non-pioglitazone users who were randomly selected from the diabetic population. Cox proportional hazards regression analysis was conducted to estimate the effects of pioglitazone on the incidence of gout in the diabetic population. Results: The incidence of gout was significantly lower in pioglitazone users than in non-pioglitazone users [adjusted hazard ratio (aHR) 0.81 (95% CI 0.78, 0.85)]. The HR for the incidence of gout was lower in both male [aHR 0.80 (95% CI 0.75, 0.85)] and female [aHR 0.83 (95% CI 0.78, 0.88)] pioglitazone users than in non-pioglitazone users. An analysis of three age groups (<40, 40-59 and ⩾60 years) revealed that the HRs of both the 40-59 years [aHR 0.78 (95% CI 0.73, 0.83)] and the ⩾60 years [aHR 0.85 (95% CI 0.80, 0.91)] age groups were significantly lower among pioglitazone users than non-pioglitazone users. Conclusion: Compared with the non-pioglitazone users, the incidence of gout in the diabetic population using pioglitazone was less.

Decreased incidence of diabetes in patients with gout using benzbromarone.

Objective: Insulin resistance is inversely correlated with the clearance rate of uric acid, which may indicate that improvement in the clearance rate of uric acid could reduce insulin resistance. Considering the increased prevalence of diabetes mellitus (DM) in the gout population, this study evaluated the effects of benzbromarone, a uricosuric agent, on the incidence of DM in the gout population. Methods: We used data from the Taiwan National Health Insurance program. The benzbromarone user cohort included 8678 patients; each patient was age- and sex-matched with one benzbromarone non-user who was randomly selected from the gout population. The Cox proportional hazard regression analysis was conducted to estimate the effects of benzbromarone on the incidence of DM in the gout population. Results: The incidence of DM was significantly lower in benzbromarone users than in benzbromarone non-users [adjusted hazard ratio (HR) = 0.86; 95% CI: 0.79, 0.94]. The HR for the incidence of DM was lower in male benzbromarone users (adjusted HR = 0.77; 95% CI: 0.69, 0.86) than in benzbromarone non-users. An analysis of three age groups (<40, 40-59 and ⩾60 years) indicated that the HRs of the age groups of 40-59 years (adjusted HR = 0.86; 95% CI: 0.76, 0.98) and ⩾60 years (adjusted HR = 0.82; 95% CI: 0.71, 0.94) were significantly lower among benzbromarone users than among benzbromarone non-users. Conclusion: In the gout population, the incidence of DM was lower in benzbromarone users than in benzbromarone non-users.

Urinary neutrophil gelatinase-associated lipocalin and clinical outcomes in chronic kidney disease patients.

BACKGROUND: Tubulointerstitial damage is a final common pathway of most renal diseases. Whether urinary neutrophil gelatinase-associated lipocalin (uNGAL), a biomarker for renal tubular damage, is of prognostic value for clinical outcomes in chronic kidney disease (CKD) patients has not been well investigated. METHODS: The uNGAL and proteinuria levels were measured among a cohort of 473 advanced CKD patients of various etiologies recruited during 2002-2009. RESULTS: The estimated glomerular filtration rate (eGFR) was 32.3±22.0 mL/min/1.73 m2 with a urine protein-to-creatinine ratio (UPCR) 680 (255-1248) mg/g and 132 (27.9%) participants had diabetes. The baseline uNGAL level was significantly associated with male gender, eGFR, UPCR, and hemoglobin. The hazard ratio (HR) of the highest uNGAL tertile for end-stage renal disease (ESRD) was 3.44 (95% CI 1.47-8.06, p=0.004). With the adjustment of urine creatinine and urine protein, HR of the highest urine NGAL-to-creatinine ratio (UNCR) tertile and the highest urine NGAL-to-protein ratio (UNPR) tertile was 3.06 (95% CI 1.19-7.90, p=0.02) and 2.10 (95% CI 1.13-3.89, p=0.02), respectively. UNPR increased the prediction of survival model for ESRD. HR of the highest UNCR tertile and UNPR tertile for cardiovascular (CV) events was 2.21 (95% CI 0.81-5.98, p=0.08) and 2.79 (95% CI 1.25-6.26, p=0.01), respectively. None of these were associated with all-cause mortality. CONCLUSIONS: Elevated uNGAL in CKD patients is associated with risks for ESRD and probably CV events. UNPR could improve the prediction for ESRD.

Effects of the mTOR inhibitor rapamycin on monocyte-secreted chemokines.

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and its derivative, everolimus, are potent immunosuppressive and antiproliferative drugs. Inflammatory diseases are characterized by immunological dysfunction, and monocyte recruitment underlies the mechanism of cell damage. Chemokines attract inflammatory cells to sites of inflammation. Interleukin-8 (IL-8/CXCL8); the monocyte chemoattractant protein-1 (MCP-1/CCL2); the regulated on activation, normal T cell expressed, presumably secreted protein (RANTES/CCL5); the macrophage inflammatory protein (MIP)-1α (CCL3); and MIP-1ß (CCL4) are involved in the pathogenesis of inflammation. However, whether mTOR inhibitors moderate the production of chemokines in monocytes remains unclear. METHODS: A human monocyte cell line, THP-1, and primary monocytes obtained from human volunteers, were stimulated using lipopolysaccharide (LPS), and then treated with sirolimus. The expression of the MCP-1, RANTES, IL-8, MIP-1α, MIP-1ß, and TNF-α proteins was measured using enzyme-linked immunosorbent assays, and intracellular signalling was examined using western blotting. RESULTS: Sirolimus significantly suppressed the LPS-induced expression of MCP-1, IL-8, RANTES, MIP-1α, and MIP-1ß in the THP-1 cells and human primary monocytes. The mitogen-activated protein kinase (MAPK) inhibitors that were examined suppressed the LPS-induced expression of MCP-1, IL-8, RANTES, MIP-1α, and MIP-1ß. In addition, sirolimus suppressed the LPS-induced phosphorylation of p38 and p65 in the THP-1 and human primary monocytes. CONCLUSION: Sirolimus downregulates the expression of chemokines in monocytes, including MCP-1, RANTES, IL-8, MIP-1α, and MIP-1ß, by inhibiting the NF-κB-p65 and MAPK-p38 signalling pathways.

Association of fluid overload with kidney disease progression in advanced CKD: a prospective cohort study.

BACKGROUND: Fluid overload is a common phenomenon in patients in a late stage of chronic kidney disease (CKD). However, little is known about whether fluid overload is related to kidney disease progression in patients with CKD. Accordingly, the aim of the study was to assess the association of the severity of fluid status and kidney disease progression in an advanced CKD cohort. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: This cohort study enrolled 472 non-dialysis-dependent patients with CKD stages 4-5 who were in an integrated CKD care program from January 2011 to December 2011 and followed up until December 2012 or initiation of renal replacement therapy (RRT). PREDICTORS: Tertile of fluid overload, with cutoff values at 0.6 and 1.6 L. OUTCOMES: RRT, rapid estimated glomerular filtration rate (eGFR) decline (faster than 3 mL/min/1.73 m(2) per year), and change in eGFR. MEASUREMENTS: The severity of fluid overload was measured by a bioimpedance spectroscopy method. eGFR was computed using the 4-variable MDRD (Modification of Diet in Renal Disease) Study equation. RESULTS: During a median 17.3-month follow-up, 71 (15.0%) patients initiated RRT and 187 (39.6%) experienced rapid eGFR decline. The severity of fluid overload was associated with increased risk of RRT (tertile 3 vs tertile 1: adjusted HR, 3.16 [95% CI, 1.33-7.50]). Fluid overload value was associated with increased risk of rapid eGFR decline (tertile 3 vs tertile 1: adjusted OR, 4.68 [95% CI, 2.30-9.52]). Furthermore, the linear mixed-effects model showed that the reduction in eGFR over time was faster in tertile 3 than in tertile 1 (P=0.02). LIMITATIONS: The effect of fluid volume variation over time must be considered. CONCLUSIONS: Fluid overload is an independent risk factor associated with initiation of RRT and rapid eGFR decline in patients with advanced CKD.

Low serum calcium is associated with poor renal outcomes in chronic kidney disease stages 3-4 patients.

BACKGROUND: Mineral disorders are associated with adverse renal outcomes in chronic kidney disease (CKD) patients. Previous studies have associated hypercalcemia and hypocalcemia with mortality; however, the association between serum calcium and renal outcome is not well-described. Whether adding calcium besides phosphorus or in the form of calcium-phosphorus (Ca×P) product into the model of survival analysis could improve the prediction of renal outcomes is not known. METHODS: A prospective cohort of 2144 outpatients with CKD stages 3-4 was evaluated. Cox proportional hazard analysis was performed according to calcium quartiles. RESULTS: The mean calcium level was 9.2±0.7 mg/dL. Low serum calcium (<9.0 mg/dL) was associated with increased risk of requiring renal replacement therapy (RRT) (hazards ratio [HR]:2.12 (95% CI: 1.49-3.02, P<0.05) and rapid renal function progression (odds ratio [OR]: 1.65 (95% CI: 1.19-2.27, P<0.05) compared with high serum calcium (>9.8 mg/dL). Adding calcium into the survival model increased the integrated discrimination improvement by 0.80% (0.12%-1.91%) while calcium-phosphorus product did not improve risk prediction.The combination of high serum phosphorus (>4.2 mg/dL) and low serum calcium (<9.1 mg/dL) was associated with the highest risk of RRT (HR:2.31 (95% CI: 1.45-3.67, P<0.05). CONCLUSION: Low serum calcium is associated with increased risk of RRT and rapid renal function progression in CKD stage 3-4 patients. The integration of serum calcium and phosphorus, but not calcium-phosphorus product should be considered in a predictive model of renal outcome.

Variability in estimated glomerular filtration rate by area under the curve predicts renal outcomes in chronic kidney disease.

Greater variability in renal function is associated with mortality in patients with chronic kidney disease (CKD). However, few studies have demonstrated the predictive value of renal function variability in relation to renal outcomes. This study investigates the predictive ability of different methods of determining estimated glomerular filtration rate (eGFR) variability for progression to renal replacement therapy (RRT) in CKD patients. This was a prospective observational study, which enrolled 1,862 CKD patients. The renal end point was defined as commencement of RRT. The variability in eGFR was measured by the area under the eGFR curve (AUC)%. A significant improvement in model prediction was based on the -2 log likelihood ratio statistic. During a median 28.7-month follow-up, there were 564 (30.3%) patients receiving RRT. In an adjusted Cox model, a smaller initial eGFR AUC%_12M (P < 0.001), a smaller peak eGFR AUC%_12M (P < 0.001), and a larger negative eGFR slope_12M (P < 0.001) were associated with a higher risk of renal end point. Two calculated formulas: initial eGFR AUC%_12M and eGFR slope_12M were the best predictors. Our results demonstrate that the greater eGFR variability by AUC% is associated with the higher risk of progression to RRT.

B7-1 expression regulates the hypoxia-driven cytoskeleton rearrangement in glomerular podocytes.

Chronic hypoxia has been recognized as a common mechanism driving the progression of many glomerular diseases. Glomerular cells, although susceptible to hypoxic injuries, are less studied to unravel the hypoxia-related influences. In the present study, we showed that both lipopolysaccharide (LPS) and hypoxia induced B7-1 and hypoxia-inducible factor (HIF)-1α expression in podocytes. B7-1, an essential player in the regulation of podocyte stress fibers, interacted directly with the NH(2)-terminal oxygenation domain of HIF-1α protein and, therefore, might interfere with the HIF-related oxidative events. The suggestion was supported by the changes in the expression of inducible nitric oxide synthase and nitric oxide. The orderly arranged stress fibers in differentiated podocytes were disrupted by either LPS or hypoxic stimulation, and the disruption could be rescued if they were brought back to normal oxygen tension. Cell motility increased with the stimulation by LPS and hypoxia, most probably mediated by the induction of B7-1 and HIF-1α, respectively. We generated a B7-1 knockdown podocyte cell line using the lentiviral small interfering RNA system. The LPS- and hypoxia-induced stress fiber disruption was largely prevented in the B7-1 knockdown podocytes. The increased cell motility by LPS and hypoxia stimulations was also ameliorated in the B7-knockdown podocytes. In summary, we found that both B7-1 and HIF were upregulated by LPS and hypoxic stimulations in podocytes and they interacted with each other. Hypoxia disrupted the abundant stress fibers and increased cell motility. These hypoxia-induced changes were prevented in B7-knockdown podocytes, and they highlighted the importance of B7-1 expression in the hypoxia-related podocyte injuries.

The Association between Iron Deficiency and Renal Outcomes Is Modified by Sex and Anemia in Patients with Chronic Kidney Disease Stage 1-4.

Iron deficiency is prevalent in women and patients with chronic kidney disease (CKD). Iron deficiency is not only related to anemia but contributes to adverse consequences for the kidney as well. Whether iron status is associated with renal outcomes after considering sex and anemia in patients with CKD stage 1-4 is unclear. Thus, we investigated the association of iron or iron saturation with renal outcomes in a CKD cohort. During a follow-up of 8.2 years, 781 (31.2%) patients met the composite renal outcome of renal replacement therapy and a 50% decline in renal function. In linear regression, iron was associated with sex, hemoglobin (Hb), and nutritional markers. In a fully adjusted Cox regression model, the male patients with normal iron had a significantly decreased risk of renal outcomes (hazard ratio (HR) 0.718; 95% confidence interval (CI) 0.579 to 0.889), but the female patients did not exhibit this association. The non-anemic patients (Hb ≥ 11 g/dL) had a decreased risk of renal outcomes (HR 0.715; 95% CI 0.568 to 0.898), but the anemic patients did not. In the sensitivity analysis, transferrin saturation (TSAT) showed similar results. When comparing iron and TSAT, both indicators showed similar prognostic values. In conclusion, iron deficiency, indicated by either iron or iron saturation, was associated with poor renal outcomes in the male or non-anemic patients with CKD stage 1-4.

Non-insulin-based insulin resistance indices for predicting all-cause mortality and renal outcomes in patients with stage 1-4 chronic kidney disease: another paradox.

Non-insulin-based insulin resistance (IR) indices serve as the indicators of metabolic syndrome (MetS) but have limited value for predicting clinical outcomes. Whether the obesity paradox affects the predictive value of these indicators in patients with chronic kidney disease (CKD) remains unknown. We investigated whether MetS and non-insulin-based IR indices can predict all-cause mortality and renal outcomes in a prospective observational study with stage 1-4 CKD Asians (N = 2,457). These IR indices were associated with MetS. A Cox regression model including body mass index (BMI) revealed an association between MetS and renal outcomes. Among the IR indices, only high triglyceride-glucose (TyG) index was associated with adverse renal outcomes: the hazard ratio of Q4 quartile of the TyG index was 1.38 (1.12-1.70). All-cause mortality was marginally associated with MetS but not high IR indices. Low TyG and TyG-BMI indices as well as low BMI and triglyceride were paradoxically associated with increased risks of clinical outcomes. The triglyceride-to-high-density lipoprotein cholesterol ratio and metabolic score for IR indices were not associated with clinical outcomes. In conclusion, MetS and TyG index predict renal outcome and obesity paradox affects the prediction of IR indices in patients with stage 1-4 CKD.

The prognostic value of URR equals that of Kt/V for all-cause mortality in Taiwan after 10-year follow-up.

Kt/V and URR (urea reduction ratio) measurements represent dialysis adequacy. Single-pool Kt/V is theoretically a superior method and is recommended by the Kidney Disease Outcomes Quality Initiative guidelines. However, the prognostic value of URR compared with Kt/V for all-cause mortality is unknown. The effect modifiers and cut-off values of the two parameters have not been compared. We investigated 2615 incident hemodialysis patients with URR of 72% and Kt/V (Daugirdas) of 1.6. The average patient age was 59 years, 50.7% were female, and 1113 (40.2%) died within 10 years. URR and Kt/V were both positively associated with nutrition factors and female sex and negatively associated with body weight and heart failure. In Cox regression mod-els for all-cause mortality, the hazard ratios (HRs) of high URR groups (65-70%, 70-75%, and > 75%) and the URR < 65% group were 0.748 (0.623-0.898), 0.693 (0.578-0.829), and 0.640 (0.519-0.788), respectively. The HRs of high Kt/V groups (Kt/V 1.2-1.4, 1.4-1.7, and > 1.7) and the Kt/V < 1.2 group were 0.711 (0.580-0.873), 0.656 (0.540-0.799), and 0.623 (0.498-0.779), respec-tively. In subgroup analysis, Kt/V was not associated with all-cause mortality in women. The prognostic value of URR for all-cause mortality is as great as that of Kt/V. URR > 70% and Kt/V > 1.4 were associated with a higher survival rate. Kt/V may have weaker prognostic value for women.

Thiazide and thiazide-like diuretics are associated with improved cardiovascular and renal outcomes in patients with chronic kidney disease.

Introduction: Hypervolemia is a prevalent comorbidity of chronic kidney disease (CKD) patients. Thiazide diuretics (THZ) are the most common treatment for volume overload and hypertension (HTN). This study examines the association between THZ usage and clinical outcomes among CKD patients in a nationwide cohort. Method: The total number of patients in the study was 24,312. After matching with one non-user randomly selected from the CKD population, we identified 8501 patients in the THZ and the comparison cohorts. Cox proportional hazards regression analysis was conducted to estimate the associations of THZ on the incidence of all-cause mortality, end-stage renal disease (ESRD), congestive heart failure (CHF), acute myocardial infarction (AMI), peripheral arterial occlusive disease (PAOD), and stroke. Results: The all-cause mortality rate was significantly lower in THZ users than in non-users (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.60- 0.71). The THZ usage was associated with a lower incidence of ESRD, AMI, PAOD, and stroke (P<0.05). In subgroup analysis, some significant clinical outcomes were related with CKD stages 3 and 4 (P<0.05); however, there were no clinical associations in CKD stage 5. In further THZ subtype analysis, there were clinical associations with fewer deaths, ESRD, AMI, and PAOD accompanying chlorthalidone treatment. Moreover, the indapamide prescription was linked to lower mortality, ESRD, AMI, and PAOD prevalence. However, there were significantly greater incidences of ESRD, CHF, and AMI in the metolazone users. Conclusion: THZ usage is associated with lower mortality and incidence of ESRD, AMI, PAOD, and stroke s in patients with CKD stages 3 and 4.

Association of symptoms of depression with progression of CKD.

BACKGROUND: Depression is related to morbidity and mortality in patients with kidney failure treated by dialysis, but its influence on patients with earlier stages of chronic kidney disease (CKD) is uncertain. This study investigates the association of depressive symptoms with clinical outcomes in patients with CKD not requiring dialysis. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 568 participants with CKD not requiring maintenance dialysis were recruited consecutively at a tertiary hospital in Southern Taiwan and followed up for 4 years. PREDICTORS: Baseline status of depressive symptoms. OUTCOMES: The primary outcome is a composite of progression to end-stage renal disease (ESRD), defined as requiring maintenance dialysis treatment, or all-cause mortality; and secondary outcome was first hospitalization. MEASUREMENTS: Depressive symptoms were assessed by Beck Depression Inventory. Estimated glomerular filtration rate (eGFR) was computed using the 4-variable MDRD (Modification of Diet in Renal Disease) Study equation. RESULTS: 428 participants completed the questionnaires and 160 (37%) had depressive symptoms. During a mean follow-up of 25.2 ± 11.9 months, 136 participants (32%) reached the primary outcome (119 reached ESRD and 17 died) and 110 participants (26%) were hospitalized. High depressive symptoms increased the risk of progression to ESRD or death (HR, 1.66; 95% CI, 1.14-2.44) and first hospitalization (HR, 1.59; 95% CI, 1.03-2.47). Participants with high depressive symptoms had more rapid GFR decrease (eGFR slopes of -2.3 [25th-75th percentile, -5.3 to -0.4] vs -1.2 [25th-75th percentile, -3.5 to 0.3] mL/min/1.73 m(2) per year; P = 0.001) and initial dialysis treatment at a higher eGFR (OR for initiation of dialysis at eGFR >5 mL/min/1.73 m(2), 4.45; 95% CI, 1.44-13.78). LIMITATIONS: A single-center study of Taiwanese, Beck Depression Inventory evaluates only depressive symptom burden. CONCLUSIONS: Depressive symptoms in CKD are independent predictors of adverse clinical outcomes, including faster eGFR decrease, dialysis therapy initiation, death, or hospitalization. Depression should be evaluated early and treated in patients with CKD.

High Ultrafiltration Rate Is Associated with Increased All-Cause Mortality in Incident Hemodialysis Patients with a High Cardiothoracic Ratio.

A high ultrafiltration rate (UFR) is associated with increased mortality in hemodialysis patients. However, whether a high UFR itself or heart failure with fluid overload followed by a high UFR causes mortality remains unknown. In this study, 2615 incident hemodialysis patients were categorized according to their initial cardiothoracic ratios (CTRs) to assess whether UFR was associated with mortality in patients with high or low CTRs. In total, 1317 patients (50.4%) were women and 1261 (48.2%) were diabetic. During 2246 (1087−3596) days of follow-up, 1247 (47.7%) cases of all-cause mortality were noted. UFR quintiles 4 and 5 were associated with higher risks of all-cause mortality than UFR quintile 2 in fully adjusted Cox regression analysis. As the UFR increased by 1 mL/kg/h, the risk of all-cause mortality increased 1.6%. Subgroup analysis revealed that in UFR quintile 5, hazard ratios (HRs) for all-cause mortality were 1.91, 1.48, 1.22, and 1.10 for CTRs of >55%, 50−55%, 45−50%, and <45%, respectively. HRs for all-cause mortality were higher in women and patients with high body weight. Thus, high UFRs may be associated with increased all-cause mortality in incident hemodialysis patients with a high CTR, but not in those with a low CTR.

Hyperuricemia, a Non-Independent Component of Metabolic Syndrome, Only Predicts Renal Outcome in Chronic Kidney Disease Patients without Metabolic Syndrome or Diabetes.

Uric acid (UA) is elevated in metabolic syndrome (MS) and diabetes (DM). UA is associated with central obesity and blood glucose and is proposed as a criterion of MS. Previous reports showed that UA could predict renal outcome in CKD. However, recent clinical trials did not demonstrate the benefits of urate-lowering agents (ULA) for renal outcome. Whether the prognostic value of UA for renal outcome is independent of MS or secondary to MS in CKD patients is unknown. Our study included 2500 CKD stage 1−4 Asian patients divided by UA tertiles and MS/DM. In linear regression, UA was associated with obesity, C-reactive protein, and renal function. In Cox regression, high UA was associated with worse renal outcome in non-MS/DM, but not in MS/DM: hazard ratio (95% confidence interval) of UA tertile 3 was 3.86 (1.87−7.97) in non-MS/DM and 1.00 (0.77−1.30) in MS/DM (p for interaction < 0.05). MS was associated with worse renal outcome, but redefined MS (including hyperuricemia as the 6th criteria) was not. In conclusion, hyperuricemia is associated with worse renal outcome in non-MS/DM and is not an independent component of MS in CKD stage 1−4 patients. Hyperuricemia secondary to MS could not predict renal outcome.