Nondiabetic Chronic Kidney Disease Stage Research Articles

Computational and Human Intelligence Methods for Constructing Practical Risk Prediction Models: An Application to Cardio-Renal Outcomes in Non-Diabetic CKD Patients

AbstractThe current investigation aimed to develop a novel approach for risk prediction modeling of clinical outcomes in common diseases based on computational and human intelligence techniques with no a priori input on risk factors using real-world individual patient-level data from administrative claims. Bootstrapping multivariable Cox regression and ant colony optimization were employed to develop time-to-first-event risk prediction models of cardio-renal outcomes in patients with non-diabetic chronic kidney disease (CKD) as a demonstration case. A cohort of 504,924 non-diabetic CKD stage 3 or 4 patients enrolled from 2008 to 2018 were identified in the US administrative de-identified claims database, Optum Clinformatics® Data Mart. Initial set of potential risk factors was derived from patient-level data at baseline and included more than 540,000 variables. Risk prediction models of hospitalization for heart failure, worsening of CKD stage from baseline and a renal composite outcome of end-stage kidney disease, kidney failure or need for dialysis in non-diabetic CKD stage 3 or 4 were built. Final model optimization was conducted using human intelligence to combine clinically similar features and build equivalence classes to ensure that risk factors included in the final model were routinely collected and easily interpretable by healthcare providers. Demonstrated validity of our approach in non-diabetic CKD offers opportunities for application in other therapeutic areas, with the potential to improve overall prognosis and decrease the clinical and economic burden of common diseases. The approach enables developing practical prediction models for risk estimation in routine clinical practice.

α-Klotho is associated with cardiovascular and all-cause mortality in patients with stage3band 4 chronic kidney disease(CKD): a long-term prospective cohort study.

α-Klotho deficiency may increase cardiovascular risks and worsen survival. We evaluated the association of α-Klotho with cardiovascular and all-cause mortality in pre-dialysis chronic kidney disease (CKD) patients. In this prospective study, 75 non-diabetic CKD stage 3b-4 patients werefollowed-up for a median of 8years. Primary and secondary outcomes were all-cause and cardiovascular mortality, respectively. Human soluble α-Klotho ELISA Assay (IBL-Takara 27,998-96Well), Human Fibroblast Growth Factor-23 ELISA Assay (intact FGF23, Merck Millipore MILLENZ FGF23-32K), and Human Sclerostin ELISA kits (Biomedica, Vienna, BI-20492) were used to measure serum α-Klotho, FGF23 and sclerostin levels in the certified laboratory at the Sechenov University according to the manufacturers' protocols.All patients underwent echocardiography to evaluate left ventricular mass index (LVMI), left ventricular ejection fraction by Simpson method, and cardiac (valve) calcification score by a semi-quantitative point scale. Lateral abdominal radiography by Kauppila method was used to estimate calcificationof the abdominal aorta.Cox multivariate regression and receiver-operating characteristic curve (ROC)-analysis were used to evaluate risk factors for death and their cut-off values. Primary and secondary endpoints were reached in 15 (20%) and 9 (12%) patients, respectively. Median α-Klotho levels in deceased and surviving patients were 344 and 484pg/ml, respectively (p = 0.002). In a multivariate Cox regression model, baseline α-Klotho levels (HR 0.99, 95% CI 0.98-1.00, p = 0.023), aortic calcification (HR 1.18, 95% CI 1.02-1.36, p = 0.029) and left ventricular mass index (LVMI) (HR 1.04, 95% CI 1.00-1.08, p = 0.033) were associated with the primary endpoint, whereas α-Klotho (HR 0.99, 95% CI 0.98-1.00, p = 0.029), aortic calcification (HR 1.23, 95% CI 1.07-1.42, p = 0.003) and LVMI (HR 1.04, 95% CI 1.00-1.08, p = 0.021) were associated with the secondary endpoint. α-Klotho levels had the highest area under the curve (AUC)by ROC analysis, that is, 0.766 (95% CI 0.70-0.82) for the primary endpoint and 0.842 (95% CI 0.79-0.90) for the secondary endpoint with cut-off values of 412pg/ml (HR 3.06, 95% CI 1.36-6.89, p = 0.007) and 368pg/ml (HR 4.84, 95% CI 1.59-14.73, p = 0.005), respectively. In pre-dialysis CKD patients, α-Klotho levels areassociated with all-cause and cardiovascular mortality and may be considered an early prognostic marker.

Renal Resistive Index and Estimated Glomerular Filtration Rate in Nondiabetic Chronic Kidney Disease Stage 3: A Cross-Sectional Analytical Study

Renal Resistive Index and Estimated Glomerular Filtration Rate in Nondiabetic Chronic Kidney Disease Stage 3: A Cross-Sectional Analytical Study

Predictive Value of HbA1c and Metabolic Syndrome for Renal Outcome in Non-Diabetic CKD Stage 1-4 Patients.

Glycated hemoglobin (HbA1c) levels are commonly used to indicate long-term glycemic control. An HbA1c level of 6.5–5.7% is defined as pre-diabetes and is proposed as a criterion for diagnosing metabolic syndrome (MetS). However, HbA1c levels can be affected by chronic kidney disease (CKD). Whether HbA1c is associated with clinical outcomes in nondiabetic CKD patients with or without MetS is still unknown. This study included 1270 nondiabetic CKD stage 1–4 Asian patients, divided by HbA1c and MetS. Through linear regression, HbA1c was positively associated with age, waist circumference, hemoglobin levels, and C-reactive protein and was negatively associated with malnutrition–inflammation. HbA1c levels were 5.5% (0.6%) and 5.7% (0.6%) in non-MetS and MetS, respectively (p < 0.001). In Cox regression, higher-level HbA1c was associated with worse composite renal outcome in MetS patients, but with better renal outcome in non-MetS patients: Hazard ratio (HR) (95% confidence interval [CI]) of HbA1c ≥5.7%, compared with HbA1c <5%, was 2.00 (1.06–3.78) in MetS and 0.25 (0.14–0.45) in non-MetS. An association between HbA1c and all-cause mortality was not found. In conclusion, higher HbA1c levels are associated with worse renal outcomes in nondiabetic CKD stage 1–4 patients modified by the presence of MetS.

Real-world data-driven risk prediction of hospitalization for heart failure in non-diabetic CKD

Abstract Background Heart failure (HF) is a major cause of cardiovascular morbidity and mortality. Despite recent advances in diagnosis and management of HF, the prognosis remains poor. HF and chronic kidney disease (CKD) are interlinked chronic health conditions. The availability of large volume of patient data and modern analytic techniques opens new opportunities for identification of individuals at elevated risk of HF. Purpose Develop risk prediction model for HF hospitalizations (HHF) in patients with non-diabetic CKD by applying data-driven computational intelligence techniques to a US population-based administrative claims database. Methods Individual-level data from the US Optum Clinformatics Data Mart for years 2008–2018 were analysed. To be eligible for inclusion, adult individuals were required to have non-diabetic CKD stage 3 or 4 (index event) and one year continuous insurance coverage prior to the index date (baseline period). Selection criteria and the main clinical outcome, hospitalisation for heart failure (HHF), were identified by using laboratory tests results and/or specific codes from common clinical coding systems. Risk prediction model for HHF was built on patient data in the baseline period composed to more than 6,000 variables. Computational intelligence method based on ant colony optimization was used to develop a time-to-first-event risk prediction model for HHF. Results Of the 64 million individuals in the database, 504,924 satisfied the selection criteria. Median age was 75 years, 60% were female. Among most common baseline comorbidities were hypertension (85%) and hyperlipidaemia (68%). Coronary artery disease, HF, atrial fibrillation and peripheral artery disease were recorded in 24%, 16%, 15% and 14% of individuals. Over a median follow-up of 744 days, 53,282 (11%) patients had recorded HHF, the corresponding incidence rate was 3.95 events/100 patient-years. The developed risk prediction model for HHF in non-diabetic CKD contained 20 risk factors. The five strongest risk factors were history of HF, intake of loop diuretics, severely increased albuminuria, atrial fibrillation or flutter and CKD 4 as observed “yes/no” in the baseline period. Fig. 1 depicts the final risk prediction model. To assess model performance, all patients in the cohort were stratified into five HHF risk groups. For each group, a Kaplan-Meier curve was built based on the HHF outcome data in the database. Fig. 2 shows clear separation between the curves, demonstrating high performance of the developed risk prediction model. Conclusion Despite many existing scores to predict HHF, their use is limited. Some scores rely on availability of rarely collected information, some are applicable for specific patient populations only. Risk prediction model for HHF in non-diabetic CKD is presented, which contains risk factors routinely collected by healthcare providers. Therefore, it might be applicable for HHF risk estimation in various settings. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Bayer AG Forest plot of HHF risk prediction modelKaplan-Meier plot of risk strata

Real-world data-driven risk prediction of hospitalization for heart failure in non-diabetic CKD

Abstract Background Heart failure (HF) is a major cause of cardiovascular morbidity and mortality. Despite recent advances in diagnosis and management of HF, the prognosis remains poor. HF and chronic kidney disease (CKD) are interlinked chronic health conditions. The availability of large volume of patient data and modern analytic techniques opens new opportunities for identification of individuals at elevated risk of HF. Purpose Develop risk prediction model for HF hospitalizations (HHF) in patients with non-diabetic CKD by applying data-driven computational intelligence techniques to a US population-based administrative claims database. Methods Individual-level data from the US Optum Clinformatics Data Mart for years 2008–2018 were analysed. To be eligible for inclusion, adult individuals were required to have non-diabetic CKD stage 3 or 4 (index event) and one year continuous insurance coverage prior to the index date (baseline period). Selection criteria and the main clinical outcome, hospitalisation for heart failure (HHF), were identified by using laboratory tests results and/or specific codes from common clinical coding systems. Risk prediction model for HHF was built on patient data in the baseline period composed to more than 6,000 variables. Computational intelligence method based on ant colony optimization was used to develop a time-to-first-event risk prediction model for HHF. Results Of the 64 million individuals in the database, 504,924 satisfied the selection criteria. Median age was 75 years, 60% were female. Among most common baseline comorbidities were hypertension (85%) and hyperlipidaemia (68%). Coronary artery disease, HF, atrial fibrillation and peripheral artery disease were recorded in 24%, 16%, 15% and 14% of individuals. Over a median follow-up of 744 days, 53,282 (11%) patients had recorded HHF, the corresponding incidence rate was 3.95 events/100 patient-years. The developed risk prediction model for HHF in non-diabetic CKD contained 20 risk factors. The five strongest risk factors were history of HF, intake of loop diuretics, severely increased albuminuria, atrial fibrillation or flutter and CKD 4 as observed “yes/no” in the baseline period. Fig. 1 depicts the final risk prediction model. To assess model performance, all patients in the cohort were stratified into five HHF risk groups. For each group, a Kaplan-Meier curve was built based on the HHF outcome data in the database. Fig. 2 shows clear separation between the curves, demonstrating high performance of the developed risk prediction model. Conclusion Despite many existing scores to predict HHF, their use is limited. Some scores rely on availability of rarely collected information, some are applicable for specific patient populations only. Risk prediction model for HHF in non-diabetic CKD is presented, which contains risk factors routinely collected by healthcare providers. Therefore, it might be applicable for HHF risk estimation in various settings. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Bayer AG Forest plot of HHF risk prediction modelKaplan-Meier plot of risk strata

Delayed Gastric Emptying among Indian Patients with Non-Diabetic Chronic Kidney Disease.

Introduction:Upper gastrointestinal symptoms such as nausea, vomiting, abdominal bloating, and poor appetite are more frequent among chronic kidney disease (CKD) patients and may contribute to poor nutritional intake and malnutrition. Delayed gastric emptying (GE), one of the important contributors to these symptoms, has not been evaluated systematically in different stages of non-diabetic CKD, among Indian patients.Materials and Methods:This hospital-based, cross-sectional analytical study aimed to find out the frequency of delayed GE in non-diabetic CKD (stages: 3,4,5) patients and also to study the correlation between delayed GE and symptoms of gastroparesis, autonomic neuropathy and nutritional parameters. Patients were subjected to evaluation of symptoms of gastroparesis by standardized questionnaire (gastroparesis cardinal symptom index), nutritional status (by anthropometric measures and serum albumin), autonomic function by heart rate variability (HRV) and GE by gastric scintigraphy with a standardized solid rice idli (savory cake) meal labeled with technetium-99m sulfur colloid.Results:Of the 89 non-diabetic CKD (stages-3,4,5) patients evaluated, 22 (≈25%) had delayed GE and 8 (≈9%) rapid GE. Prevalence of delayed GE was higher among stage 5 (15/49, 31%) compared to stages 3 and 4 (7/40, 17.5%), though the difference was statistically insignificant. There was no association between delayed GE and symptoms of gastroparesis and autonomic neuropathy. Though not statistically significant, nutritional parameters (body mass index, skinfold thickness, and serum albumin) were poorer in the delayed GE group compared to the rest.Conclusion:Delayed GE, irrespective of symptoms, may contribute to malnutrition and hence should be looked for in non-diabetic CKD patients with unexplained malnutrition.

Arterial endothelial function, carotid artery intima-media thickness and abdominal aortic calcification in diabetic and nondiabetic CKD stage 4–5 patients not on dialysis

AimsWe aimed to study the effect of diabetes (DM) on endothelial dysfunction assessed by flow-mediated vasodilatation (FMD), carotid intima-media thickness (cIMT) and abdominal aortic calcification score (AAC) in chronic kidney disease (CKD) stage 4–5 patients not on dialysis. MethodsAltogether 199 non-dialysis CKD stage 4–5 patients enrolled in the Chronic Arterial Disease, quality of life and mortality in chronic KIDney injury (CADKID) study with plain lumbar radiograph for the assessment of AAC were included. Data on cIMT and FMD were available for 172 and 161 patients, respectively. ResultsMedian age was 65 (IQR 54–76) years, 88 (44.2%) patients had DM and median eGFR was 12 (IQR 10–14) ml/min/1.73 m2 in the study. FMD [controls: 3.3(2.0–6.7)% vs. DM-patients: 4.3(1.3–6.6)%, p = 0.73] and cIMT [controls: 0.65(0.58–0.87)mm vs. DM-patients: 0.67(0.59–0.81)mm, p = 0.65], were similar between the groups. AAC was higher in patients with DM [controls: 5(1–9) vs. DM-patients: 7(2–13), p = 0.01]. The significant multivariate determinants for AAC were older age (β = 0.22, p < 0.0001), pulse pressure (β = 0.05, p < 0.0001), DM (β = 1.33, p = 0.04) and ProBNP (per µg/l β = 0.18, p = 0.0008). AAC and cIMT were associated with incident cardiovascular death independent of DM. ConclusionsDM is associated with increased AAC but not increased cIMT or attenuated FMD in advanced CKD patients.

Low protein diets for non-diabetic adults with chronic kidney disease.

Low protein diets for non-diabetic adults with chronic kidney disease.

Treatment of Chronic Kidney Disease-Related Metabolic Acidosis With Fruits and Vegetables Compared to NaHCO3 Yields More and Better Overall Health Outcomes and at Comparable Five-Year Cost

Current guidelines recommend treatment of metabolic acidosis in chronic kidney disease (CKD) with Na+-based alkali but base-producing fruits and vegetables (F+V) might yield more and better health outcomes, making the intervention cost-effective. In this post hoc analysis of a clinical trial we randomized 108 macroalbuminuric, nondiabetic CKD stage 3 participants with metabolic acidosis to receive F+V (n=36) calculated to reduce dietary acid by half, oral NaHCO3 (HCO3-, n=36) 0.3 mEq/kg body weight/day, or Usual Care (UC, n=36) assessed annually for 5years. We calculated a mean overall health score for the groups as follows: 1 for improved, 0 for no change, and -1 for worsened at 5years for plasma total CO2, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, change in medication dose (reduction=1, increased=-1, no change=0), and 1 for met goal and 0 for not meeting goal for estimated glomerular filtration rate (>30mL/min/1.73m2) and systolic blood pressure (<130mm Hg). We also assessed the number of participants with cardiovascular disease events (myocardial infarctions+strokes) and group medication and hospitalization costs. Net plasma total CO2 increase at 5years was no different between HCO3- and F+V. Average health scores at 5years differed among groups (P < .01) with F+V (7.4 [mean]±1.6 [standard deviation]) being descriptively larger than HCO3- and UC (2.9±1.6 and 1.2±1.6, respectively). The number of participants suffering cardiovascular disease events differed among groups (P=.009) with none (0) in F+V, 6 in UC, and 2 in HCO3-. Total 5-year household cost per beneficial health outcome differed among groups (P=.005) with UC being highest and that for HCO3- and F+V being comparable. Metabolic acidosis improved comparably with F+V or standard oral NaHCO3, but F+V yielded ancillary beneficial health outcomes, fewer participants with adverse cardiovascular events, and per-household cost that was comparable to NaHCO3.

Direct Renin Inhibition in Non-diabetic chronic Kidney disease (DRINK): a prospective randomized trial.

The potential long-term safety and efficacy of aliskiren in nondiabetic chronic kidney disease (CKD) are unknown. We sought to investigate the renoprotective effect of aliskiren on nondiabetic CKD patients. In this open-label, parallel, randomized controlled trial, nondiabetic CKD Stages 3-4 patients were randomized to receive aliskiren added to an angiotensin II receptor blocker (ARB) at the maximal tolerated dose, or ARB alone. Primary outcome was the rate of change in estimated glomerular filtration rate (eGFR). Secondary endpoints included rate of change in urine protein-to-creatinine ratio (UPCR), cardiovascular events and hyperkalemia. Composite renal outcomes of doubling of baseline serum creatinine or a 40% reduction in eGFR or incident end-stage renal disease or death were analyzed as post hoc analysis. Seventy-six patients were randomized: 37 to aliskiren (mean age 55.1 ± 11.1 years) and 39 to control (mean age 55.0 ± 9.4 years). Their baseline demographics were comparable to eGFR (31.9 ± 9.0 versus 27.7 ± 9.0 mL/min/1.73 m2, P = 0.05) and UPCR (30.7 ± 12.6 versus 47.8 ± 2.8 mg/mmol, P = 0.33) for treatment versus control subjects. After 144 weeks of follow-up, there was no difference in the rate of eGFR change between groups. Six patients in the aliskiren group and seven in the control group reached the renal composite endpoint (16.2% versus 17.9%, P = 0.84). The cardiovascular event rate was 10.8% versus 2.6% (P = 0.217). The hyperkalemia rate was 18.9% versus 5.1% with an adjusted hazard ratio of 7.71 (95% confidence interval 1.14 to 52.3, P = 0.04) for the aliskiren arm. Aliskiren neither conferred additional renoprotective benefit nor increased adverse events, except for more hyperkalemia in nondiabetic CKD patients.

P0809LEFT VENTRICULAR DIASTOLIC DYSFUNCTION IN PATIENTS WITH DIABETIC CHRONIC KIDNEY DISEASE

Abstract Background and Aims Left ventricle diastolic dysfunction (LVDD) is common cardiac changes in diabetic patients without renal insufficiency. LVDD is also frequently occurs in chronic kidney disease (CKD). Diabetic patients with CKD are at increased risk of developing cardiovascular diseases. Therefore, early detection and prevention of risk factors are critical. The aim of this study was to evaluate the impact of type 2 diabetes on left ventricular (LV) diastolic function among CKD stage 3 and 5 patients, and whether markers of fluid balance can predict LVDD. Method A total of 409 patients (age and sex matched non-diabetic CKD stage 3 [nDMCKD3], n = 106; diabetic CKD stage 3 [DMCKD3], n = 106; non-diabetic CKD stage 5 [nDMCKD5], n = 73; diabetic CKD stage 5 [DMCKD5], n = 124) were analyzed. The stage 3 CKD patients were retrospectively reviewed, and stage 5 CKD patients were prospectively analyzed. All cohort patients with stage 5 CKD were hospitalized to plan their first dialysis treatment. The following exclusion criteria were applied: ejection fraction less than 45%, history of coronary artery disease and/or intervention treatment, history of angina or myocardial infarction, abnormalities of cardiac rhythm, moderate or severe valvular heart diseases, systemic immunologic diseases, liver cirrhosis, malignancy, infection, and previous renal transplantation. Coronary artery disease having regional wall motion abnormalities on echocardiographic examination was also ruled out. Clinical and echocardiographic parameters were compared among groups. Echocardiography, bioimpedance spectroscopy, and serum NT-proBNP were analyzed in patients with stage 5 CKD. The LVDD was defined as E/é ratio greater than 15. Extracellular water/total body water (ECW/TBW) and NT-proBNP were used as markers of fluid balance. Results Patients with E/é ratio &amp;gt; 15 presented with more advanced stages of CKD. Prevalence of LVDD in patients with diabetes was higher compared to those without diabetes. Patients in DMCKD5 group demonstrated higher E/é ratios compared to those with nDMCKD5, DMCKD3, and nDMCKD3 (16.63±5.04 vs. 14.12±4.60 vs. 14.69±4.65 vs. 13.07±3.76, p &amp;lt; 0.001). The E/é ratio in patients with DMCKD5 were significantly higher than those with DMCKD3 (16.63±5.04 vs. 14.69±4.65, p = 0.003). In contrast, the E/é ratio was not significantly different between nDMCKD3 and nDMCKD5 patients (13.07±3.76 vs. 14.12±4.60, p = 0.099). The ECW/TBW in patients with DMCKD5 were significantly higher than nDMCKD5 patients (0.51±0.04 vs. 0.48±0.05, p &amp;lt;0.001). In a multiple regression analysis, the presence of diabetes, serum albumin level, NT-proBNP, and ECW/TBW were significantly associated with LVDD in CKD5 patients. Conclusion Our results suggest that an echocardiographic examination and assessment of volume status should routinely be performed in patients with type 2 DMCKD. Early detection of LVDD before clinical symptoms are apparent is important, regardless of the stage of DMCKD. Fluid overload could be one of the aggravating factors of LVDD in DMCKD patients. Early evaluation of volume status and control of fluid overload should be considered important therapeutic approaches for LVDD in DMCKD patients, especially for those in advanced stages.

A Comparative Study of Platelet Parameters in Non-Diabetic Chronic Kidney Disease Stage 3, 4 and End Stage Renal Disease on Maintenance Haemodialysis

A Comparative Study of Platelet Parameters in Non-Diabetic Chronic Kidney Disease Stage 3, 4 and End Stage Renal Disease on Maintenance Haemodialysis

Assessment of Peritoneal Membrane Arteriolar Structure in Conjunction with Traditional Cardiovascular System Evaluation in Chronic Kidney Disease (CKD) Stage 5 Patients

Background/Aims: Cardiovascular complications are responsible for increased mortality and morbidity in chronic kidney disease (CKD) patients. Functional and structural changes of peritoneal membrane are reported in CKD patients both on conservative treatment and on renal replacement therapy (RRT). The aim of the study was to assess the structure of peritoneal membrane small arteries (precapillary arterioles) in diabetic and non-diabetic CKD stage 5 patients before initiation of peritoneal dialysis (PD) and evaluate its relationship with heart and large arteries abnormalities and with selected biochemical parameters. Methods: Evaluation of 42 CKD stage 5 patients before starting PD. Diabetic (n=26) and non-diabetic (n=16) patients were compared. Peritoneal membrane samples were taken during Tenckhoff catheter insertion. Histopathological evaluation of peritoneal precapillary arterioles (arteriolar evaluation) with measurement of wall thickness (WT) and calculation of lumen/vessel (L/V) ratio was performed in each patients. Echocardiography, intima media thickness (IMT), pulse wave velocity (PWV), ambulatory blood pressure monitoring (ABPM) and biochemical parameters assessment: serum albumin (SA), total cholesterol (TCH), hemoglobin (Hgb), parathormone (PTH), serum calcium (Ca), serum phosphorus (P), transferrin saturation (TSAT%), C-reactive protein (CRP) were performed in each participant. Results: There were no statistically significant differences in peritoneal membrane arteriolar indices – wall thickness (WT) and L/V ratio between investigated groups. There was statistically significant higher PWV value in diabetic patients. There were no statistically significant differences in echocardiographic indices, IMT, laboratory data in analyzed groups. There were some linear correlations between: PWV vs IMT (R=0,84; p=0,0006); PWV vs PP (R=0,58; p=0,03) in non-diabetic and linear correlation between: PWV vs age (R=0,75; p=0,02); WT vs DP (R=-0,93; p=0,001); WT vs DBP ( R=0,64; p=0,04) in diabetic group. Conclusion: Peritoneal membrane arteriolar damage seems to be an integrated part of cardiovascular system damage in CKD stage 5 patients.

The Effect of Vitamin D Supplementation on Bone Metabolic Markers in Chronic Kidney Disease.

Use of active forms of vitamin D is advocated in patients with chronic kidney disease (CKD) for treatment of mineral bone disease because of the presumption that native forms of vitamin D would not undergo significant activation to calcitriol, the most active biological form of vitamin D. We present secondary analysis looking at bone turnover in subjects who completed the randomized, double blind, placebo-controlled trial investigating the effect of cholecalciferol supplementation on vascular function in nondiabetic CKD stage G3-G4 and vitamin D ≤20 ng/mL (Clinical Trials Registry of India: CTRI/2013/05/003648). Patients were randomized (1:1) to receive either two directly observed oral doses of 300,000 IU of cholecalciferol or matching placebo at baseline and 8 weeks. Of the 120 subjects enrolled, 58 in the cholecalciferol group and 59 in the placebo group completed the study. At 16 weeks, the serum 25(OH)D and 1,25(OH)2 D levels increased in the cholecalciferol group but not in the placebo group (between-group difference in mean change: 23.40 ng/mL; 95% CI, 19.76 to 27.06; p < 0.001, and 14.98 pg/mL; 95% CI, 4.48 to 27.18; p = 0.007, respectively). Intact parathyroid hormone (iPTH) decreased in the cholecalciferol group (between-group difference in mean change -100.73 pg/mL (95% CI, -150.50 to -50.95; p < 0.001). Serum total and bone-specific alkaline phosphatase (SAP, BAP) and serum C-terminal cross-linked collagen type I telopeptides (CTX-1) were significantly reduced in cholecalciferol group (between group difference for change in mean: -20.25 U/L; 95% CI, -35.14 to -5.38 U/L; p = 0.008 for SAP; -12.54 U/L; 95% CI, -22.09 to -2.98 U/L; p = 0.013 for BAP; and -0.21 ng/mL; 95% CI, -0.38 to -0.05 ng/mL; p = 0.05 for CTX-1). Correlation analysis showed significant correlation of Δ25(OH)D with ΔiPTH (r = -0.409, p < 0.0001), Δ1,25(OH)2 D (r = 0.305, p = 0.001), ΔSAP (r = -0.301, p = 0.002), ΔBAP (r = -0.264, p = 0.004), and ΔCTX-1 (r = -0.210, p = 0.0230). Cholecalciferol supplementation corrects vitamin D deficiency and is effective in lowering serum intact parathyroid hormone and bone turnover markers in early stages of CKD. © 2017 American Society for Bone and Mineral Research.

Reduced Baroreflex Sensitivity, Decreased Heart Rate Variability with Increased Arterial Stiffness in Predialysis.

High cardiovascular morbidity and mortality is observed in predialytic chronic kidney disease (CKD) patients. The underlying mechanism of cardiovascular dysfunction often remains unclear. The present study was designed to perform multiparametric assessment of baroreflex sensitivity (BRS), arterial stiffness indices, and cardiovascular variabilities (heart rate variability [HRV] and blood pressure variability [BPV]) together in predialytic CKD patients; compare it with normal healthy controls; and determine their relationships in predialytic nondiabetic CKD patients. Thirty CKD Stage 4 and 5 predialytic non-diabetic patients and 30 healthy controls were enrolled in the study. BRS was determined by spontaneous sequence method. Short-term HRV and BPV were assessed using 5 min beat-to-beat data of RR intervals and blood pressure by time domain and frequency domain analysis. Arterial stiffness indices - carotid-femoral pulse wave velocity (PWV) and augmentation index - were measured using SphygmoCor Vx device (AtCor Medical, Australia). Predialytic CKD patients had significantly low BRS, high PWV, and low HRV as compared to healthy controls. Independent predictors of reduced systolic BRS in predialytic CKD patient group on multiple regression analysis emerged to be increase in calcium-phosphate product, increase in BPV, and decrease in HRV. Predialytic nondiabetic CKD Stage 4 and 5 patients have poor hemodynamic profile (higher PWV, lower HRV, and reduced BRS) than healthy controls. Reduced HRV and altered calcium-phosphate homeostasis emerged to be significant independent predictors of reduced BRS.

Toll-like receptor 4 signalling mediates inflammation in skeletal muscle of patients with chronic kidney disease.

BackgroundInflammation in skeletal muscle is implicated in the pathogenesis of insulin resistance and cachexia but why uremia up‐regulates pro‐inflammatory cytokines is unknown. Toll‐like receptors (TLRs) regulate locally the innate immune responses, but it is unknown whether in chronic kidney disease (CKD) TLR4 muscle signalling is altered. The aim of the study is to investigate whether in CKD muscle, TLRs had abnormal function and may be involved in transcription of pro‐inflammatory cytokine.MethodsTLR4, phospho‐p65, phospho‐ikBα, tumour necrosis factor (TNF)‐α, phospho p38, Murf 1, and atrogin were studied in skeletal muscle from nondiabetic CKD stage 5 patients (n = 29) and controls (n = 14) by immunohistochemistry, western blot, and RT–PCR. Muscle cell cultures (C2C12) exposed to uremic serum were employed to study TLR4 expression (western blot and RT–PCR) and TLR‐driven signalling. TLR4 signalling was abrogated by a small molecule chemical inhibitor or TLR4 siRNA. Phospho AKT and phospho p38 were evaluated by western blot.ResultsCKD subjects had elevated TLR4 gene and protein expression. Also expression of NFkB, p38 MAPK and the NFkB‐regulated gene TNF‐α was increased. At multivariate analysis, TLR4 protein content was predicted by eGFR and Subjective Global Assessment, suggesting that the progressive decline in renal function and wasting mediate TLR4 activation. In C2C12, uremic serum increased TLR4 as well as TNF‐α and down‐regulated pAkt. These effects were prevented by blockade of TLR4.ConclusionsCKD promotes muscle inflammation through an up‐regulation of TLR4, which may activate downward inflammatory signals such as TNF‐α and NFkB‐regulated genes.

Japanese society for dialysis therapy clinical guideline for "hemodialysis initiation for maintenance hemodialysis".

Yuzo Watanabe, Kunihiro Yamagata, Shinichi Nishi, Hideki Hirakata, Norio Hanafusa, Chie Saito, Motoshi Hattori, Noritomo Itami, Yasuhiro Komatsu, Yoshindo Kawaguchi, Kazuhiko Tsuruya, Yoshiharu Tsubakihara, Kazuyuki Suzuki, Ken Sakai, Hideki Kawanishi, Daijo Inaguma, Hiroyasu Yamamoto, Yoshiaki Takemoto, Noriko Mori, Kazuyoshi Okada, Hiroshi Hataya, Takashi Akiba, Kunitoshi Iseki, Tadashi Tomo, Ikuto Masakane, Tadao Akizawa, and Jun Minakuchi, for “Hemodialysis Initiation for Maintenance Hemodialysis” Guideline Working Group, Japanese Society for Dialysis Therapy

Diffuse Interstitial Fibrosis and Myocardial Dysfunction in Early Chronic Kidney Disease

Early-stage chronic kidney disease (CKD) is an under-recognized highly prevalent cardiovascular (CV) risk factor. Despite a clustering of conventional atherosclerotic risk factors, it is hypothesized that nonatherosclerotic processes, including left ventricular (LV) hypertrophy and fibrosis, account for a significant excess of CV risk. This cross-sectional observational study of 129 age- (mean age 57±10 years) and gender-matched subjects examined: nondiabetic CKD stages 2 to 4 (mean glomerular filtration rate 50±22 ml/min/1.73 m2) with no history of CV disease, subjects who are hypertensive with normal renal function, and healthy controls. Cardiac magnetic resonance imaging was performed for assessment of LV volumes and systolic function (myocardial deformation). Diffuse myocardial fibrosis was assessed using T1 mapping for native myocardial T1 times before contrast and myocardial extracellular volume (ECV) after gadolinium administration in combination with standard late gadolinium enhancement techniques for detection of coarse fibrosis. Patients with CKD had increased native T1 times (986±37 ms) and ECV (0.28±0.04) compared with controls (955±30 ms, 0.25±0.03) and subjects who are hypertensive (956±31 ms, 0.25±0.02, p<0.05). Both T1 times and ECV were correlated with impaired systolic function as assessed by global longitudinal systolic strain (r=-0.22, p<0.05, and r=-0.43, p<0.01, respectively). There were no differences in LV volumes, ejection fraction, or LV mass. T1 times and ECV did not correlate with conventional CV risk factors. In conclusion, diffuse myocardial fibrosis is increased in early CKD and is associated with abnormal global longitudinal strain, an early feature of uremic cardiomyopathy and a key indicator of adverse CV prognosis.

Impact of visit-to-visit variability of blood pressure on deterioration of renal function in patients with non-diabetic chronic kidney disease

An association between visit-to-visit variability (VVV) of blood pressure (BP) and renal damage was recently reported in a cross-sectional study. We aimed to clarify the longitudinal effect of VVV of BP on deterioration of renal function in patients with non-diabetic chronic kidney disease (CKD). We retrospectively studied 56 patients with non-diabetic CKD (stage 3 or 4) who visited our nephrology clinic between September 1994 and May 2011. VVV of BP was defined as the standard deviation and coefficient of variation (CV) of office BP measured at 12 consecutive visits. Main outcomes were the annual decline in the estimated glomerular filtration rate (eGFR) and the composite renal end point defined as a doubling of serum creatinine or the need for dialysis. The median observation period was 83 months. Standard deviation and CV of office systolic BP (SBP) were significantly associated with the slope of the eGFR after adjustments for confounders. The adjusted risk for composite renal end points more than doubled for each increment of 1-standard deviation of the standard deviation of office SBP (hazard ratio (HR) 2.20, P=0.001), and for each increment of 1-standard deviation of the CV of office SBP (HR 2.12, P=0.002). The present study demonstrated that the visit-to-visit variability of BP is an independent determinant of deterioration of renal function in patients with non-diabetic CKD.