Correlation of pre-existing radial artery macrocalcifications with late patency of primary radiocephalic fistulas in diabetic hemodialysis patients

ObjectiveThe aim of this study was to evaluate the impact of pre-existing radial artery macrocalcification (Mönckeberg type of arteriosclerosis) on patency rates of radiocephalic fistulas (RCFs) in diabetic end-stage renal disease (ESRD) patients undergoing hemodialysis.MethodsIn this observational prospective study, the long-term patency rates (primary outcome measures) of RCFs in ESRD diabetics who had Mönckeberg radial (±brachial) artery disease (calcified [C] group) were compared with those obtained in ESRD diabetics who had healthy, noncalcified vessels before RCF construction (healthy [H] group). Vessel calcification was assessed by plain two-dimensional radiography. For inclusion in the C-group, uniform linear railroad track-type macrocalcifications of at least 6 cm in length, in the medial wall of the radial artery ipsilateral to RCF creation, were required. Patients were included in the H-group if the radial artery ipsilateral to the RCF creation was free of any macrocalcification, of either intima or media type. Any intimal-like plaque with irregular and patchy distribution was an exclusion criterion for both groups. Patients in both groups also were required to have suitable upper limb vascular anatomy on the basis of ultrasound imaging before RCF creation (cephalic vein of minimum diameter of 1.6 mm, without stenosis or thrombosis in all outflow areas, and radial artery of minimum diameter of 1.5 mm, without proximal hemodynamically significant stenosis). Secondary outcome measures included all-cause mortality. Kaplan-Meier statistics were used for comparison between groups.ResultsThe arm radiograph at the site of possible fistula construction showed abnormality in 39 patients (C-group, 47 RCFs), whereas 33 patients had noncalcified (“healthy”) vascular anatomy (H-group, 40 RCFs). Mean duration of the diabetic disease at the time of RCF creation was 8.9 ± 5.6 years (range, 2-25 years) for the H-group and 14 ± 9.9 years (range, 1-40 years) for the C-group (P = .018). The mean follow-up period for H-group and C-group was 51.9 ± 35.9 months (range, 0.1-126 months) and 26.1 ± 31.6 months (range, 0.1-144 months), respectively (P = .0006). Forty-four patients died during the follow-up period. Primary patency rates at 12, 24, 36, and 48 months for C-group vs H-group were 50.2% vs 80%, 36.5% vs 72.3%, 32.4% vs 67.9%, and 29.1% vs 59.3% (P = .0019). Respective values for secondary patency rates were 52.4% vs 87.5%, 40.9% vs 82.4%, 36.6% vs 78.1%, and 33.2% vs 72.8% (P = .00064). Patient survival rates at 24 and 48 months were 56.1% and 46.4% for C-group and 92.4% and 67.4% for H-group, respectively (P = .05).ConclusionsESRD diabetics with radial artery Mönckeberg calcifications receiving RCFs had worse late clinical outcomes compared with ESRD diabetics with healthy distal arm vessels receiving the same access. The long-term benefit of RCFs may be lost in diabetics with extensively calcified vessels, and preferably the brachial artery should be used instead

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Association of Plasma Adiponectin and Oxidized Low-Density Lipoprotein with Carotid Intima-Media Thickness in Diabetic Nephropathy

Aims. We sought to determine the association between levels of adiponectin and oxidized low-density lipoprotein (ox-LDL) in patients with diabetic nephropathy as well as their effect on carotid intima-media thickness (cIMT). Methods. Adiponectin and ox-LDL were determined in 25 diabetic patients without nephropathy and 94 patients at different stages of diabetic nephropathy including subjects on hemodialysis. cIMT was measured using real-time B-mode ultrasonography. Results. Plasma adiponectin levels increased significantly with severity of diabetic nephropathy (P=0.002), on the contrary to ox-LDL which decreased with disease severity (P<0.001). cIMT was significantly higher at late stages of diabetic nephropathy compared with early stages (P=0.022). Adiponectin was a significant negative predictor of ox-LDL levels (β=-5.45, P=0.023), independently of confounding factors. There was no significant correlation between cIMT and adiponectin or ox-LDL either in the total sample population or according to disease staging. Cluster analysis showed that patients with the highest cIMT values, highest levels of adiponectin, and lowest levels of ox-LDL were included in one cluster and all assigned to stage 5 of diabetic nephropathy. Conclusions. There was no significant association between adiponectin or ox-LDL and cIMT and, therefore, other factors affecting this surrogate marker of cardiovascular disease in diabetic nephropathy should be sought

C-Terminal Fragment of Agrin (CAF): A Novel Marker for Progression of Kidney Disease in Type 2 Diabetics

BACKGROUND Diabetes is the leading cause of CKD in the developed world. C-terminal fragment of agrin (CAF) is a novel kidney function and injury biomarker. We investigated whether serum CAF predicts progression of kidney disease in type 2 diabetics. METHODS Serum CAF levels were measured in 71 elderly patients with diabetic nephropathy using a newly developed commercial ELISA kit (Neurotune®). Estimated glomerular filtration rate (eGFR) and proteinuria in spot urine were assessed at baseline and after 12 months follow up. The presence of end stage renal disease (ESRD) was evaluated after 24 months follow-up. Correlation and logistic regression analyses were carried out to explore the associations of serum CAF levels with GFR, proteinuria, GFR loss and incident ESRD. Renal handling of CAF was tested in neurotrypsin-deficient mice injected with recombinant CAF. RESULTS We found a strong association of serum CAF levels with eGFR and a direct association with proteinuria both at baseline (r = 0.698, p<0.001 and r = 0. 287, p = 0.02) as well as after 12 months follow-up (r = 0.677, p<0.001 and r = 0.449, p<0.001), respectively. Furthermore, in multivariate analysis, serum CAF levels predicted eGFR decline at 12 months follow-up after adjusting for known risk factors (eGFR, baseline proteinuria) [OR (95%CI) = 4.2 (1.2-14.5), p = 0.024]. In mice, injected CAF was detected in endocytic vesicles of the proximal tubule. CONCLUSION Serum CAF levels reflect renal function and are highly associated with eGFR and proteinuria at several time points. Serum CAF was able to predict subsequent loss of renal function irrespective of baseline proteinuria in diabetic nephropathy. CAF is likely removed from circulation by glomerular filtration and subsequent endocytosis in the proximal tubule. These findings may open new possibilities for clinical trial design, since serum CAF levels may be used as a selection tool to monitor kidney function in high-risk patients with diabetic nephropathy

Accumulation of recombinant hCAF22 in mouse proximal tubule.

<p>Mice were injected with saline or hCAF22 and all sections stained in parallel with the antibodies as indicated. A. Localization of full length agrin (red) and hCAF22 (green) in NT KO kidney injected with saline. B. Localization of full length agrin (red) and hCAF22 (green) in NT KO mouse kidney 20 min after hCAF22 injections. C. Localizations of hCFA22 (green) and actin (red) in NT KO mouse kidney 20 min after hCAF22 injections. D. Localization of full length agrin (red) and hCAF22 (green) in NT KO mouse kidney 60 min after hCAF22 injections. E-F. Localizations of hCFA22 (green) and actin (red) in NT KO mouse kidney 60 min after hCAF22 injections. A- E Original magnifications between 400–630 x, for F original magnification 1000 x.</p

Anthropometric, clinical and biochemical characteristics of patients with TD2M and CKD with stable (or increased) and with decreased GFR at one year follow-up.

<p>Continuous variables are presented as mean (S.D.) or median (interquartile range, IQR).</p><p>^a<i>P</i> values of Mann-Whitney <i>U</i> or one-way ANOVA test for differences of variables among patients with stable or decreased eGFR at one year follow-up.</p><p>* Statistical significance at the 0.05 level (two-tailed).</p><p>BMI, body mass index; HbA1c, glycosylated hemoglobin A1c; RAAS blockade, use of medicines affecting renin–angiotensin system; Crea T0, serum creatinine levels at timepoint 0 (baseline); Crea T1, serum creatinine levels at timepoint 1 (12 months); eGFR T0, estimated GFR assessed by the CKD-EPI formula at timepoint 0 (baseline); eGFR T1, estimated GFR assessed by the CKD-EPI formula at timepoint 1 (12 months); PU T0, Proteinuria assessed by protein to creatinine ratio at timepoint 0 (baseline); PU T1, Proteinuria assessed by protein to creatinine ratio at timepoint 1 (12 months); ΔGFR T0-T1, Algebric difference between eGFR at timepoint 1 and eGFR at timepoint 0; ΔPU T0-T1, Algebric difference between Proteinuria at timepoint 1 (12 months) and Proteinuria at timepoint 0 (baseline); ESRD, progression to end stage renal disease; Total-CAF, serum levels of C-terminal agrin fragment; Decreased GFR, patients with loss of eGFR ≥ 1 ml/min/1.73m² during the 12 month follow-up.</p><p>Anthropometric, clinical and biochemical characteristics of patients with TD2M and CKD with stable (or increased) and with decreased GFR at one year follow-up.</p

Correlation analysis of CAF levels with variables of laboratory and clinical significance and scatterplots of CAF with GFR and proteinuria.

<p>Values represent Spearman’s correlation coefficients. ^a Correlation is significant at the 0.05 level (2-tailed). HbA1c, glycosylated hemoglobin A1c; T0, Time point 0 (Baseline); T1, Time point 2 (12 months); Δ-Proteinuria T0-T1, Increase of proteinuria (≥500mg/day) during the first year of follow-up.</p

Association of GFR-decline with serum CAF and additional clinical regressors.

<p>^a OR, odds ratio</p><p>^b CI, 95% confidence interval</p><p>* Significance levels at 0.05</p><p>BMI, body mass index; eGFR T0, estimated GFR assessed by the CKD-EPI formula at baseline; PU T0, Proteinuria assessed by protein to creatinine ratio at baseline; logCAF, serum CAF levels (log-transformed). GFR, estimated glomerular filtration rate; SCreat, Serum creatinine; renin-angiotensin-aldosterone system blockade (RAAS-Block).</p><p>Association of GFR-decline with serum CAF and additional clinical regressors.</p