Nondiabetic Stage Research Articles

Retrospective study on the effect of Niaoduqing particles on outcome of non-diabetic patients with stage IV chronic kidney disease.

This study was to investigate the improvement value of Niaoduqing particles in the outcome of non-diabetic patients with stage IV chronic kidney disease (CKD). The non-diabetic patients with stage IV CKD who were to receive Niaoduqing particles were set as the study group (252 cases), and the patients with the same disease who only received Western medicine in the public database were set as the control group (220 cases). The follow-up visits were 3 months/time for 1 year. Deaths due to various causes, doubling of creatinine levels, and end-stage renal disease were used as hard end points to stop follow-up. The clinical indexes of the 2 groups were observed and compared. The results showed that the rate of compound outcome was significantly lower in the study group (28.17%) than in the control group (36.82%), the glomerular filtration rate was significantly higher than that in the control group, and the levels of uric acid and urea were significantly lower than that in the control group (P < .05). Niaoduqing particles can reduce creatinine and urea nitrogen, stabilize renal function, delay dialysis time, and improve the incidence of compound outcome in patients with non-diabetic stage IV CKD, which is worthy of clinical promotion.

Association between blood glucose levels and arterial stiffness marker: comparing the second derivative of photoplethysmogram and cardio-ankle vascular index scores.

This study aimed to compare the association between fasting plasma glucose (FPG) and glycosylated hemoglobin A1c (HbA1c) levels using the second derivative of photoplethysmogram (SDPTG) index and the cardio-ankle vascular index (CAVI). Electronic medical records of 276 participants (160 men, 116 women) who visited the health promotion center of a university hospital were examined. Age, sex, body mass index (BMI), blood pressure, and lipid profile were considered as risk factors for arterial stiffness, together with the FPG, HbA1c, CAVI, and SDPTG indices. Hierarchical regression models were constructed, and all participants were divided into low-normal, high-normal, prediabetic, and diabetic groups to examine the group-based differences in CAVI and SDPTG indices. FPG and HbA1c were independently predictive of increased CAVI, and their predictive powers for CAVI were equivalent (β = 0.214 and 0.200, respectively). Risk factors, including age, BMI, and male sex, were also predictive of CAVI (β= 0.593-0.630, -0.256 - -0.280, and 0.142-0.178, respectively). None of the FPG and HbA1c values were predictive of the SDPTG indices. The CAVI was higher in the diabetes group than in the other three groups according to HbA1c level, while the d/a index of the SDPTG decreased in the prediabetes group and increased in the diabetes group. CAVI may not be substituted for SDPTG indices when evaluating arterial stiffness based on the glucose level. Moreover, the progression rate of arterial stiffness may differ between the diabetic and nondiabetic stages.

Effect of Vitamin D Supplementation on Serum Hepcidin Levels in Non-Diabetic Chronic Kidney Disease Patients.

Vitamin D deficiency and anemia frequently coexist. Moreover, vitamin D deficiency is found to play a role in chronic kidney disease (CKD)-associated anemia. We investigated the effect of cholecalciferol on serum hepcidin levels in vitamin D-deficient, non-diabetic individuals with CKD in a randomized, double-blind, placebo-controlled trial. This study was performed on stored samples of our previously published randomized, double-blind, placebo-controlled trial of cholecalciferol supplementation in non-diabetic patients with stage III-IV CKD and vitamin D deficiency. Stable patients of either sex, aged 18-70 years, with non-diabetic stage III-IV CKD (estimated glomerular filtration rate between 15 and 60 ml/min/1.73 m2), and having serum 25-hydroxyvitamin D3 [25(OH) D] levels ≤20 ng/ml were included. Participants received either two directly observed oral doses of cholecalciferol (300,000 IU) or matching placebo at baseline and at eight weeks. Follow-up was done at 16 weeks. Serum hepcidin levels were analyzed at baseline and at 16 weeks. A total of 120 CKD patients were enrolled. Serum 25(OH) D levels were similar in the placebo and cholecalciferol groups at baseline (13.21 ± 4.78 ng/ml and 13.40 ± 4.42 ng/ml; P = 0.88). After 16 weeks, the serum 25(OH) D levels were found to be 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). Serum hepcidin levels were similar at baseline (median [IQR]: 33.6 [8.6-77.8] ng/ml vs. 24.6 [9.3-70.7] ng/ml, P = 0.903) and did not vary between groups at 16 weeks (median [IQR]: 41.5 [10.9-75.0] ng/ml vs. 34.8 [12.3-63.75] ng/ml, P = 0.703). Our study provides preliminary data based on which a larger adequately powered clinical trial can be conducted to conclusively assess the impact of vitamin D supplementation on hepcidin levels and anemia in patients with CKD and vitamin D deficiency.

Neurological Soft Signs in Non-diabetic End Stage Renal Disease Patients: Evaluation and Prediction

ABSTRACT Patients on hemodialysis suffer from several serious complex neurological complications resulting in significant disability. Early detection of these complications during the asymptomatic phase may consent to early intervention to prevent or minimize the disability. To assess and predict neurological soft signs (NSS) in non-diabetic end-stage renal disease (ESRD) patients on hemodialysis (HD) who do not suffer any apparent neurological symptoms. An analytical, cross-sectional study was done in Hemodialysis units in the Suez Canal University Hospitals. 96 ESRD adult patients on hemodialysis are exposed to: Medical history was taken via personal interview, laboratory tests, and clinical assessment of NSS using Heidelberg scale, and brain CT was done for 50 high-risk patients (hypertensive or those on dialysis for more than 5 years) to detect the presence of any probable neuro-radiological brain abnormalities. 79.2% of our studied ESRD patients on HD had positive NSS with a mean value of total score 8.5 ± 5.9. Strong positive correlations were present between NSS and Hb levels, duration of hemodialysis, and hypertension. CT had revealed no abnormality. NSS represent a reliable, affordable tool for regular bedside assessment of ESRD patients with HD who do not suffer any neurological symptoms for early detection of asymptomatic neurological lesions, especially since the CT brain scan did not show such changes early. The duration of hemodialysis, Hb level, and hypertension were independent predictors for the occurrence of silent neurological lesions in ESRD patients.

MO526REAL-WORLD EVIDENCE ON CLINICAL OUTCOMES IN NON-DIABETIC CKD

Abstract Background and Aims Chronic kidney disease (CKD) represents a global public health problem, with significant morbidity and mortality due to cardiovascular disease during CKD progression and due to kidney failure. Although non-diabetic CKD accounts for up to 70% of the global CKD burden, its clinical consequences are poorly understood, and data are needed to help identify individuals at high risk of adverse outcomes. This analysis uses real-world evidence to provide insights into clinical characteristics, care and outcomes in individuals with non-diabetic CKD in routine clinical practice. Method Individual-level data from the US administrative claims database, Optum Clinformatics Data Mart, from January 1, 2008 to December 31, 2018 were analysed. Adults with non-diabetic CKD stage 3 or 4 and ≥365 days continuous insurance coverage were included and followed until insurance disenrollment, end of data availability or death. Individuals with diabetes mellitus, CKD stage 5 or end-stage kidney disease (ESKD) prior to the index date, or who experienced kidney failure (acute or unspecified), kidney transplant or dialysis in the baseline period, were excluded from the analysis. Study outcomes, captured in the database, were defined using common clinical coding systems. Primary outcomes were hospitalisation for heart failure (HHF), a kidney composite of ESKD/kidney failure/need for dialysis, and worsening of CKD stage from baseline. Individual CKD stage was assigned based on estimated glomerular filtration rate (eGFR) values (priority) or the respective International Classification of Diseases code at index and during follow-up. Further prespecified kidney outcomes included individual components of the kidney composite, acute kidney injury, and absolute and relative change in eGFR from baseline. Event-based outcomes were assessed by time-to-first-event analysis. Summary statistics for time-course analysis of metric outcomes were generated on a quarterly basis. Results In total, 504,924 of 64 million individuals in the Optum Clinformatics Data Mart satisfied the selection criteria. Over a median follow-up of 744 (interquartile range 328–1432) days, the incidence rates of primary outcomes of HHF, the kidney composite and worsening of CKD stage from baseline were 3.95, 10.33 and 4.38 events/100 patient-years (PY), respectively. The incidence rates of the components of the kidney composite outcome, namely ESKD/need for dialysis, kidney failure (acute and unspecified) and need for dialysis were 1.78, 9.53 and 0.49 events/100 PY, respectively. Kidney failure events were driven mainly by acute kidney injury, with an incidence of 8.61 events/100 PY. In individuals with at least one available eGFR value at baseline and one value during follow-up (n=295,174), the incidence rates of relative decreases in eGFR of ≥30%, ≥40% and ≥57% from baseline were 1.98, 0.97 and 0.30 events/100 PY, respectively; in this cohort, more rapid eGFR decline was associated with increased risk of HHF and the kidney composite outcome. In individuals with a baseline eGFR value and at least one follow-up eGFR value and an available urine albumin-to-creatinine ratio (n=25,824), time-course analysis of eGFR showed that eGFR decline mostly occurred in individuals with moderately-to-severely increased albuminuria (≥30 mg/g). Conclusion This analysis generates real-world evidence on clinical outcomes in a cohort of individuals with non-diabetic CKD treated in routine clinical practice in the US. Despite known limitations of claims databases (e.g. low availability of some laboratory data, limited individual follow-up time and tactical coding), individuals with moderate-to-severe non-diabetic CKD are shown to be at high risk of serious clinical outcomes. This highlights the high unmet medical need, and urgency for new treatments and targeted interventions for patients with non-diabetic CKD.

Association of Glomerular Filtration Rate and Carotid Intima-Media Thickness in Non-Diabetic Chronic Kidney Disease Patients over a 4-Year Follow-Up.

Patients with chronic kidney disease (CKD) have increased risk of cardiovascular events. However, the association of glomerular filtration rate (GFR) and carotid intima-media thickness (CIMT) in non-diabetic CKD patients is under-investigated. This prospective study was conducted at University Clinical Hospital Mostar over a 4-year period and enrolled a total of 100 patients with stage 2 and 4 CKD (50 patients per group). Stage 4 CKD group had significantly higher baseline CIMT values (1.13 ± 0.25 vs. 0.74 ± 0.03 mm, P < 0.001), and more atherosclerotic plaques at the study onset (13 (26%) vs. 0 (0%), P < 0.001) compared to stage 2 CKD. A statistically significant 4-year increase in GFR (coefficient of 2.51, 3.25, 2.71 and 1.50 for 1-year, 2-year, 3-year and 4-year follow-up, respectively, P < 0.05) with non-significant CIMT alterations has been observed in stage 2 CKD. Furthermore, linear mixed effects analysis revealed significant decrease in GFR (coefficient of −6.69, −5.12, −3.18 and −1.77 for 1-year, 2-year, 3-year and 4-year follow-up, respectively, P < 0.001) with increase in CIMT (coefficient of 0.20, 0.14, 0.07 and 0.03 for 1-year, 2-year, 3-year and 4-year follow-up, respectively, P < 0.001) in stage 4 CKD. GFR and CIMT showed significant negative correlation in both CKD groups during all follow-up phases (P < 0.001). Furthermore, multiple linear regression analysis revealed significant independent prediction of CIMT by baseline GFR (B = −0.85, P < 0.001), while there was no significant prediction of CIMT with other covariates. In conclusion, this study demonstrates significant association of GFR and CIMT in non-diabetic stage 2 and stage 4 CKD during the 4-year follow-up.

Bupi Yishen Formula Versus Losartan for Non-Diabetic Stage 4 Chronic Kidney Disease: A Randomized Controlled Trial.

Chinese herbal medicine (CHM) might have benefits in patients with non-diabetic chronic kidney disease (CKD), but there is a lack of high-quality evidence, especially in CKD4. This study aimed to assess the efficacy and safety of Bupi Yishen Formula (BYF) vs. losartan in patients with non-diabetic CKD4. This trial was a multicenter, double-blind, double-dummy, randomized controlled trial that was carried out from 11-08-2011 to 07-20-2015. Patients were assigned (1:1) to receive either BYF or losartan for 48 weeks. The primary outcome was the change in the slope of the estimated glomerular filtration rate (eGFR) over 48 weeks. The secondary outcomes were the composite of end-stage kidney disease, death, doubling of serum creatinine, stroke, and cardiovascular events. A total of 567 patients were randomized to BYF (n = 283) or losartan (n = 284); of these, 549 (97%) patients were included in the final analysis. The BYF group had a slower renal function decline particularly prior to 12 weeks over the 48-week duration (between-group mean difference of eGFR slopes: −2.25 ml/min/1.73 m2/year, 95% confidence interval [CI]: −4.03,−0.47), and a lower risk of composite outcome of death from any cause, doubling of serum creatinine level, end-stage kidney disease (ESKD), stroke, or cardiovascular events (adjusted hazard ratio = 0.61, 95%CI: 0.44,0.85). No significant between-group differences were observed in the incidence of adverse events. We conclude that BYF might have renoprotective effects among non-diabetic patients with CKD4 in the first 12 weeks and over 48 weeks, but longer follow-up is required to evaluate the long-term effects. Clinical Trial Registration: http://www.chictr.org.cn, identifier ChiCTR-TRC-10001518.

SUN-270 Atherosclerotic vascular disease and inflammation in CKD patients in South Africa

Chronic inflammation is a known risk factor for cardiovascular disease (CVD) among chronic kidney disease (CKD) patients. Current evidence supports the pivotal role of inflammation in atherosclerosis, which is reinforced by the association between traditional inflammatory markers, such as the high sensitivity C-reactive protein (hs-CRP), and CVD. We evaluated the association between inflammatory markers and atherosclerotic vascular disease (AsVD) in stage 3 CKD, end-stage kidney disease (ESKD) patients on dialysis and kidney transplant recipients (KTRs). This was a cross-sectional study of 40 adult (aged 18-65 years) non-diabetic stage 3 CKD patients, 40 peritoneal dialysis (PD) patients, 40 haemodialysis (HD) patients, 41 KTRs and 41 age- and sex-matched healthy controls. Serum was analysed for creatinine, albumin, lipid profile and inflammatory markers including hs-CRP, pentraxin-3, tumour necrosis factor alpha (TNF-α) and the ligand of the receptor for advanced glycation end-products (EN-RAGE). Echocardiography was performed on all patients and carotid intima media thickness (CIMT) was assessed in both right and left carotid arteries at 1 cm proximal to the carotid bulb. The levels of all the inflammatory markers assessed were elevated in CKD patients compared to controls. Pentraxin-3 levels were significantly higher in stage 3 CKD, PD, HD and KTRs (p < 0.05) compared to controls, while hs-CRP levels were significantly increased in stage 3 CKD, PD and HD patients, (p < 0.05). Tumour necrosis factor-alpha levels were significantly higher in PD patients compared to controls, (p < 0.001). EN-RAGE levels were significantly higher among KTRs compared to controls, (p < 0.05). Age, increased WHR and low HDL-C levels were associated with AsVD. Pentraxin-3 correlated positively with other inflammatory markers (except hs-CRP) and negatively with serum albumin levels (r = -0.316, p = 0.004). Hypertension, elevated total cholesterol, TNF-α and EN-RAGE levels were predictors of high pentraxin-3 levels while age (> 40 years) [OR 5.18, p < 0.001], the male gender [OR 2.45, p = 0.031] and low HDL-C [OR 2.93, p = 0.009] independently predicted AsVD. Inflammation is present in all the kidney disease groups and persists in the post-transplant period. Age (> 40 years), male gender and low HDL-C independently predicted AsVD. Aggressive treatment of lipid disorders and eradication of inflammation may be beneficial in reducing the burden of CVD in CKD.

SUN-269 THE UTILITY AND RELATIONSHIP OF LIPOPROTEIN MARKERS TO ATHEROSCLEROTIC VASCULAR DISEASEIN BLACK CKD AND KIDNEY TRANSPLANT RECIPIENTS IN SOUTH AFRICA

Dyslipidaemia is a well-recognized risk factor for cardiovascular disease (CVD) in chronic kidney disease (CKD). We evaluated the relationship of lipoprotein biomarkers to AsVD among stage 3 CKD and ESKD patients on renal replacement therapy (peritoneal dialysis (PD) and haemodialysis (HD) and KTRs) This was a cross-sectional study of 40 adult (18-65 years) non-diabetic stage 3 CKD patients, 40 PD and 40 HD patients, 41 KTRs and 41 age- and sex-matched healthy controls. An interviewer-administered questionnaire was used to obtain information on participants’ sociodemographic and cardiovascular risk factors. Serum was analysed for creatinine, albumin, lipid profile, lipoprotein markers including lipoprotein(a) Lp-PLA2 and apolipoprotein A1 and inflammatory markers such as hsCRP, pentraxin-3, TNF-α and EN-RAGE. Lipoprotein ratios including Castelli indices 1 and 2, atherogenic coefficient (AC), atherogenic index of plasma (AIP), non-HDL-C and lipoprotein combined index (LCI) were calculated. Echocardiography was performed on all patients and carotid intima media thickness (CIMT) was assessed The levels of Lp(a) and Lp-PLA2 were increased in all kidney disease groups. Significantly higher levels of Lp(a) were seen in PD, HD, KTRs and the combined kidney disease group, compared to controls (p < 0.02) while lower levels of APO A1 were seen in all kidney disease groups. Significantly higher values of Castelli index 1, AC and non-HDL-C were seen in PD patients when compared to controls and CKD stage 3, (p < 0.031). Castelli 1 and 2 and AC correlated positively with CIMT in the combined kidney disease patients. Age (> 40 years) [OR 5.00, p < 0.001], male gender [OR 3.24, p = 0.005], low HDL-C levels [OR 3.14, p = 0.008] and elevated Lp (a) levels [OR 2.23, p = 0.048] independently predicted AsVD. Lipoprotein (a) predicted AsVD better than other lipid markers evidenced by higher AUC on ROC curve. The burden of abnormal lipid biomarkers was greater among ESKD patients and the highest burden was in PD patients while lipoprotein ratios were increased in the kidney disease patients. KTRs had a more favourable lipid biomarker profile compared to dialysis patients. Lipoprotein(a) was a better surrogate marker for AsVD among female kidney disease patients when compared with other lipoprotein biomarkers, and lipid profile parameters. Therapeutic efforts directed at lowering Lp(a) levels may be beneficial in CKD patients

Relationship between pulse pressure and inflammation with left ventricular diastolic dysfunction in chronic kidney disease patients.

Diastolic dysfunction (DD) is an important cause of cardiovascular disease (CVD) mortality in chronic kidney disease (CKD) patients. Non-traditional risk factors, such as arterial stiffness and inflammation, are implicated in the pathogenesis of DD in CKD patients. To determine the association between inflammatory markers (interleukin (IL)-12, IL-18, highly sensitive C-reactive protein (hsCRP)) and non-invasive markers of arterial stiffness (24-h pulse pressure (PP)) with DD in stages 3-4 CKD patients. We performed a sub-analysis of 78 non-diabetic stages 3-4 CKD subjects to determine the relationship between 24-h PP, IL-12, IL-18 and hsCRP with DD. DD was present in 38 subjects (49%). Subjects with DD were significantly older (61.0 ± 1.9 vs 50.2 ± 2.0 years; P < 0.001) and had higher 24-h PP (48(95% confidence interval 45, 52) vs 43(95% confidence interval 41, 45) mmHg; P < 0.005); 24-h PP was associated with DD (P = 0.02), but this was no longer significant after adjustment for age (P = 0.31). Serum IL-12, IL-18 and hsCRP levels were not significantly different between subjects with or without DD. Asymptomatic subclinical DD was present in 50% of a cohort of stages 3-4 CKD patients but was not associated with IL-12, IL-18 or hsCRP. The association between 24-h PP and DD was no longer apparent following adjustment for age, but given the small sample size, our findings will need to be explored in larger-sized cohorts of individuals with moderate-stage CKD.

Effect of vitamin D supplementation on serum sclerostin levels in chronic kidney disease

Vitamin D deficiency, cardiovascular disease and abnormal bone mineral metabolism are common in chronic kidney disease (CKD). Abnormal bone mineral metabolism has been linked to vascular calcification in CKD. Sclerostin has emerged as an important messenger in cross talk between bone-vascular axis. We analyzed sclerostin in subjects who participated in the randomized, double blind, placebo controlled trial investigating the effect of cholecalciferol supplementation on vascular function in non­diabetic CKD stage G3-4 and vitamin D ≤ 20 ng/ml [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 baseline, serum levels of sclerostin were similar in both groups (cholecalciferol - median;190pg/ml, IQR;140–260 pg/ml and placebo - median;180 pg/ml, IQR; 140–240 pg/ml, p = 0.67). 16 weeks after cholecalciferol supplementation, there was no change in level of sclerostin (mean change;1.10 pg/ml, 95%CI; −27.34 to 29.34 pg/ml, p = 0.25). However, a significant decrease in sclerostin level was noted in the placebo group (mean change; −31.94 pg/ml, 95%CI; −54.76 to −9.13 pg/ml, p = 0.002). Change (Δ) in sclerostin level at 16 weeks correlated negatively with Δ eGFR (r = −0.20, p = 0.03) and positively with Δuric acid (r = 0.37, p < 0.001) but not with Δ25(OH) D (r = 0.06, p = 0.54), Δ iPTH (r = − 0.03, p = 0.78) ΔFGF23 (r = − 0.08, p = 0.38) and Δ125 (OH)2 D (r = − 0.04, p = 0.65). In conclusion, high dose cholecalciferol supplementation did not change sclerostin levels in non-diabetic stage 3–4 CKD subjects.

Vascular function and cholecalciferol supplementation in CKD: A self-controlled case series

Vitamin D deficiency is common and associated with mortality in chronic kidney disease (CKD) patients. Cardiovascular disease (CVD) is the commonest cause of mortality in CKD patients. In a randomized, double blind, placebo controlled trial, we have recently reported favorable effects of vitamin D supplementation on vascular & endothelial function and inflammatory biomarkers in vitamin D deficient patients with non-diabetic stage 3–4 CKD (J Am Soc Nephrol 28: 3100–3108, 2017). Subjects in the placebo group who had still not received vitamin D after completion of the trial received two oral doses 300,000 IU of oral cholecalciferol at 8 weeks interval followed by flow mediated dilatation (FMD), pulse wave velocity (PWV), circulating endothelial and inflammatory markers (E-Selectin, vWF, hsCRP and IL-6), 125 (OH)2D, iPTH and iFGF-23 assessment at 16 weeks. 31 subjects completed this phase of the study. Last values recorded in the preceding clinical trial were taken as baseline values. Serum 25(OH)D and 1,25(OH)2D increased and FMD significantly improved after cholecalciferol supplementation [mean change in FMD%: 5.8% (95% CI: 4.0–7.5%, p < 0.001]. Endothelium independent nitroglycerine mediated dilatation, PWV, iPTH, iFGF-23 and IL-6 also showed favorable changes. The data further cement the findings of beneficial effects of correction of vitamin D deficiency on vascular function.

Metabolomics and Gene Expression Analysis Reveal Down-regulation of the Citric Acid (TCA) Cycle in Non-diabetic CKD Patients

Chronic kidney disease (CKD) is a public health problem with very high prevalence and mortality. Yet, there is a paucity of effective treatment options, partly due to insufficient knowledge of underlying pathophysiology. We combined metabolomics (GCMS) with kidney gene expression studies to identify metabolic pathways that are altered in adults with non-diabetic stage 3–4 CKD versus healthy adults. Urinary excretion rate of 27 metabolites and plasma concentration of 33 metabolites differed significantly in CKD patients versus controls (estimate range−68% to +113%). Pathway analysis revealed that the citric acid cycle was the most significantly affected, with urinary excretion of citrate, cis-aconitate, isocitrate, 2-oxoglutarate and succinate reduced by 40–68%. Reduction of the citric acid cycle metabolites in urine was replicated in an independent cohort. Expression of genes regulating aconitate, isocitrate, 2-oxoglutarate and succinate were significantly reduced in kidney biopsies. We observed increased urine citrate excretion (+74%, p=0.00009) and plasma 2-oxoglutarate concentrations (+12%, p=0.002) in CKD patients during treatment with a vitamin-D receptor agonist in a randomized trial. In conclusion, urinary excretion of citric acid cycle metabolites and renal expression of genes regulating these metabolites were reduced in non-diabetic CKD. This supports the emerging view of CKD as a state of mitochondrial dysfunction.

Relationship between Central Arterial Stiffness and Insulin Resistance in Chinese Community-Dwelling Population without Diabetes Mellitus.

Objective Insulin resistance (IR) is a pathological condition present not only in patients with type 2 diabetes mellitus (DM), but also in community-dwelling population without DM. Both central arterial stiffness and IR are closely correlated with cardiovascular morbidity and mortality. The relationship between central arterial stiffness and IR has not been described in Chinese community-dwelling population without DM. The current analysis was designed to investigate the relationship between central arterial stiffness and IR in Chinese community-dwelling population without DM. Methods There were 1150 participants fully assessed for not only homeostasis model assessment of insulin resistance (HOMA-IR) but also carotid-femoral pulse wave velocity (cfPWV). Results Median age was 39 (18–80) years, and 69.7% were men. Bivariate correlation analysis showed that cfPWV was significantly related to HOMA-IR (P < 0.05). Logistic regression analysis indicated that cfPWV was independently associated with HOMA-IR (P < 0.05). Conclusions This community-based analysis testified that the relationship between central arterial stiffness and IR was evident as early as during nondiabetic stage. Early interventions in Chinese community-dwelling population without DM to improve the IR are also important in the prevention of cardiovascular diseases.

Rationale and study design of a randomized controlled trial to assess the effects of maintaining hemoglobin levels using darbepoetin alfa on prevention of development of end-stage kidney disease in non-diabetic CKD patients (PREDICT Trial).

Anemia associated with high mortality is a common complication of chronic kidney disease (CKD). Target hemoglobin (Hb) levels for CKD treatment remain controversial: Recent guidelines recommend a maximum of 13 g/dL to avoid increased risk of CVD. However, some smaller studies show slower progression of renal function loss with high Hb targets. Recently, darbepoetin alfa targeting Hb 11-13 g/dL was reported to improve renal composite outcome of Japanese patients compared with a low Hb group maintained at 9.0-11.0 g/dL using epoetin alfa (HR 0.66; 95% CI 0.47-0.93). The high Hb group showed significant reduction of left ventricular mass index and improved quality of life. Sub-analysis revealed greater beneficial effects in non-diabetic stage 5 CKD patients. This randomized controlled trial, PREDICT, aims to confirm the impact of targeting Hb levels of 11-13 g/dL using darbepoetin alfa with reference to a low Hb target of 9-11 g/dL. We calculated the number of subjects (N = 440) necessary to detect a statistically significant level of α = 0.05 (two-sided) and statistical power of 80% for a minimum follow-up period of 2 years on the basis of a previous study. The study enrolled 498 non-diabetic Japanese patients with eGFR 8-20 mL/min/1.73 m(2). The primary outcome is a composite renal endpoint (starting chronic dialysis, transplantation, eGFR 6 mL/min/1.73 m(2) or less, 50% decrease in eGFR). Average follow-up period is 2 years and the study ends in 2016. PREDICT will determine the optimum target Hb for Japanese patients with non-diabetic CKD. (ClinicalTrials.gov No. NCT01581073).

Insulin resistance in chronic kidney disease is ameliorated by spironolactone in rats and humans

In this study, we examined the association between chronic kidney disease (CKD) and insulin resistance. In a patient cohort with nondiabetic stages 2-5 CKD, estimated glomerular filtration rate (eGFR) was negatively correlated and the plasma aldosterone concentration was independently associated with the homeostasis model assessment of insulin resistance. Treatment with the mineralocorticoid receptor blocker spironolactone ameliorated insulin resistance in patients, and impaired glucose tolerance was partially reversed in fifth/sixth nephrectomized rats. In these rats, insulin-induced signal transduction was attenuated, especially in the adipose tissue. In the adipose tissue of nephrectomized rats, nuclear mineralocorticoid receptor expression, expression of the mineralocorticoid receptor target molecule SGK-1, tissue aldosterone content, and expression of the aldosterone-producing enzyme CYP11B2 increased. Mineralocorticoid receptor activation in the adipose tissue was reversed by spironolactone. In the adipose tissue of nephrectomized rats, asymmetric dimethylarginine (ADMA; an uremic substance linking uremia and insulin resistance) increased, the expression of the ADMA-degrading enzymes DDAH1 and DDAH2 decreased, and the oxidative stress increased. All of these changes were reversed by spironolactone. In mature adipocytes, aldosterone downregulated both DDAH1 and DDAH2 expression, and ADMA inhibited the insulin-induced cellular signaling. Thus, activation of mineralocorticoid receptor and resultant ADMA accumulation in adipose tissue has, in part, a relevant role in the development of insulin resistance in CKD.

Hemodynamic and hormonal patterns of untreated essential hypertension in men and women

Knowledge of hemodynamic factors accounting for the development of hypertension should help to tailor therapeutic approaches and improve blood pressure control. Few data exist regarding sex differences of hemodynamic factors contributing to hypertension progression among patients with untreated nondiabetic stage I and II prehypertension (PreHyp) as defined by the Joint National Committee-7 guidelines (JNC-7). We utilized noninvasive impedance cardiography, applanation tonometry and plasma measures of angiotensin II, angiotensin (1-7), serum aldosterone, high-sensitivity C-reactive protein (hs-CRP) and cytokine biomarkers of inflammation to characterize the hemodynamic and hormonal profile of 100 patients with untreated hypertension (39 women). Despite there being no differences between women and men in terms of office blood pressure, heart rate and body mass index, men demonstrated lower values of pulse pressure, systemic vascular resistance, brachial artery pulse wave velocity and augmentation index. In each of the three hypertension categories, the increased blood pressure in men was associated with significant augmentations in stroke volume and cardiac output compared with women. Sex-related hemodynamic differences were associated in women with higher plasma levels of leptin, hs-CRP, plasma angiotensin II and serum aldosterone, and no differences in the serum concentrations of cytokinins. In women but not men, hs-CRP correlated with plasma concentrations of transforming growth factor β1 (TGFβ1) and body weight; in addition, plasma TGFβ1 correlated with levels of serum vascular cell adhesion molecule 1. The impact of sex differences in the hemodynamic factors accounting for the elevation in arterial pressure in subjects with essential hypertension has been poorly characterized or this information is not available. We suggest that this gap in knowledge may adversely influence choices of drug treatment since our study shows for the first time significant differences in the hemodynamic and hormonal mechanisms accounting for the increased blood pressure in women compared to men.

Effect of paricalcitol on renin and albuminuria in non-diabetic stage III-IV chronic kidney disease: a randomized placebo-controlled trial

BackgroundVitamin D receptor activators reduce albuminuria, and may improve survival in chronic kidney disease (CKD). Animal studies suggest that these pleiotropic effects of vitamin D may be mediated by suppression of renin. However, randomized trials in humans have yet to establish this relationship.MethodsIn a randomized, placebo-controlled, double-blinded crossover study, the effect of oral paricalcitol (2 μg/day) was investigated in 26 patients with non-diabetic, albuminuric stage III-IV CKD. After treatment, plasma concentrations of renin (PRC), angiotensin II (AngII) and aldosterone (Aldo) were measured. GFR was determined by 51Cr-EDTA clearance. Assessment of renal NO dependency was performed by infusion of NG-monomethyl-L-arginine (L-NMMA). Albumin excretion rate (AER) was analyzed in 24-h urine and during 51Cr-EDTA clearance.ResultsParicalcitol did not alter plasma levels of renin, AngII, Aldo, or urinary excretion of sodium and potassium. A modest reduction of borderline significance was observed in AER, and paricalcitol abrogated the albuminuric response to L-NMMA.ConclusionsIn this randomized, placebo-controlled trial paricalcitol only marginally decreased AER and did not alter circulating levels of renin, AngII or Aldo. The abrogation of the rise in albumin excretion by paricalcitol during NOS blockade may indicate that favourable modulation of renal NO dependency could be involved in mediating reno-protection and survival benefits in CKD.Trial registrationClinicalTrials.gov identifier: NCT01136564

Blood pressure and chronic kidney disease progression in a multi-racial cohort: the Multi-Ethnic Study of Atherosclerosis

The relationship between blood pressure (BP) and kidney function among individuals with chronic kidney disease (CKD) remains controversial. This study evaluated the association between BP and estimated glomerular filtration rate (eGFR) decline among adults with nondiabetic stage 3 CKD. The Multi-Ethnic Study of Atherosclerosis participants with an eGFR 30-59 ml min(-1) per 1.73 m2 at baseline without diabetes were included. Participants were followed over a 5-year period. Kidney function change was determined by annualizing the change in eGFR using cystatin C, creatinine and a combined equation. Risk factors for progression of CKD (defined as a decrease in annualized eGFR>2.5 ml min(-1) per 1.73 m2) were identified using univariate analyses and sequential logistic regression models. There were 220 participants with stage 3 CKD at baseline using cystatin C, 483 participants using creatinine and 381 participants using the combined equation. The median (interquartile range) age of the sample was 74 (68-79) years. The incidence of progression of CKD was 16.8% using cystatin C and 8.9% using creatinine (P=0.002). Systolic BP>140 mm Hg or diastolic BP>90 mm Hg was significantly associated with progression using a cystatin C-based (odds ratio (OR), 2.49; 95% confidence interval (CI), 1.12-5.52) or the combined equation (OR, 2.07; 95% CI, 1.16-3.69), but not when using creatinine after adjustment for covariates. In conclusion, with the inclusion of cystatin C in the eGFR assessment hypertension was an important predictor of CKD progression in a multi-ethnic cohort with stage 3 CKD.

Serum gamma-glutamyltransferase levels are inversely related to endothelial function in chronic kidney disease

Gamma-glutamyltransferase (GGT) is an enzyme responsible for the extracellular catabolism of the antioxidant glutathione and recently implicated in the pathogenesis of atherosclerosis. Endothelial dysfunction is a prodromal feature of atherogenesis. Since oxidative stress is highly present in uremia and causally linked to endothelial dysfunction, we hypothesized that GGT may be a factor implicated in this process. Serum GGT and C-reactive protein (CRP) levels, estimated glomerular filtration rate (eGFR), and 24-h proteinuria were measured in 214 nondiabetic stages 3-5 CKD patients. The endothelium-dependent vasodilatation (FMD) of the brachial artery was assessed by using high-resolution ultrasound. We investigated the relationship between FMD and circulating serum GGT. Serum GGT levels were negatively associated with FMD (r = -0.41, p < 0.001) and eGFR (r = -0.34, p < 0.001) in univariate analysis. Multivariate regression analysis showed that the association between GGT and FMD persisted after adjustment for age, sex, smoking, renal function (eGFR), inflammation (CRP), proteinuria, and homeostatic model assessment index. Circulating GGT levels significantly associate with endothelial dysfunction, an important early feature of the atherogenic process. GGT might be an early marker of oxidative or other cellular stress that it is possibly directly related to the pathogenesis of endothelial dysfunction.