Search

Daratumumab has shown promising first results in systemic amyloid light-chain (AL) amyloidosis. We analyzed a consecutive series of 168 patients with advanced AL receiving either daratumumab/dexamethasone (DD, n = 106) or daratumumab/bortezomib/dexamethasone (DVD, n = 62). DD achieved a remission rate (RR) of 64% and a very good hematologic remission (VGHR) rate of 48% after 3 months. Median hematologic event-free survival (hemEFS) was 11.8 months and median overall survival (OS) was 25.6 months. DVD achieved a 66% RR and a 55% VGHR rate. Median hemEFS was 19.1 months and median OS had not been reached. Cardiac organ responses were noted in 22% with DD and 26% with DVD after 6 months. Infectious complications were common (Common Terminology Criteria [CTC] grade 3/4: DD 16%, DVD 18%) and likely related to a high rate of lymphocytopenia (CTC grade 3/4: DD 20%, DVD 17%). On univariable analysis, hyperdiploidy and gain 1q21 conferred an adverse factor for OS and hemEFS with DD, whereas translocation t(11;14) was associated with a better hemEFS. N-terminal prohormone of brain natriuretic peptide >8500 ng/L could not be overcome for survival with each regimen. Multivariable Cox regression analysis revealed plasma cell dyscrasia (difference between serum free light chains [dFLC]) >180 mg/L as an overall strong negative prognostic factor. Additionally, nephrotic-range albuminuria with an albumin-to-creatinine-ratio (ACR) >220 mg/mmol was a significantly adverse factor for hemEFS (hazard ratio, 2.1 and 3.1) with DD and DVD. Daratumumab salvage therapy produced good results and remission rates challenging any therapy in advanced AL. Outcome is adversely influenced by the activity of the underlying plasma cell dyscrasia (dFLC) and nephrotic-range albuminuria (ACR).

RATIONALE & OBJECTIVE: Canagliflozin reduces the risk for cardiovascular and kidney outcomes in type 2 diabetes. This study aimed to assess the relative and absolute effects of canagliflozin on clinical outcomes across different KDIGO (Kidney Disease: Improving Global Outcomes) risk categories based on estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio.STUDY DESIGN: Post hoc analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) Program.SETTINGS & PARTICIPANTS: The CANVAS Program randomly assigned 10,142 participants with type 2 diabetes at high cardiovascular risk and with eGFR≥30mL/min/1.73m2 to treatment with canagliflozin or placebo.INTERVENTION(S): Canagliflozin or matching placebo.OUTCOMES: The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with a set of other cardiovascular and kidney prespecified outcomes.RESULTS: Of 10,142 participants, 10,031 (98.9%) had available baseline eGFR and urinary albumin-creatinine ratio data. The proportion of participants in low-, moderate-, high-, and very high-risk KDIGO categories was 58.6%, 25.8%, 10.6%, and 5.0%, respectively. The relative effect of canagliflozin on the primary outcome (HR, 0.86; 95% CI, 0.75-0.97) was consistent across KDIGO risk categories (P trend=0.2), with similar results for other cardiovascular and kidney outcomes. Absolute reductions in the primary outcome were greater within higher KDIGO risk categories (P trend=0.03) with a similar pattern of effect for the composite of cardiovascular death or hospitalization for heart failure (P trend=0.06) and for chronic eGFR slope (P trend = 0.04).LIMITATIONS: Predominantly a low kidney risk population, relatively few participants in higher KDIGO risk categories, and exclusion of individuals with eGFRCONCLUSIONS: Although the relative effects of canagliflozin are similar across KDIGO risk categories, absolute risk reductions are likely greater for individuals at higher KDIGO risk. The KDIGO classification system may be able to identify individuals who might derive greater benefits for end-organ protection from treatment with canagliflozin.FUNDING: This post hoc analysis was not specifically funded. The original CANVAS Program trials were funded by Janssen Research & Development, LLC and were conducted as a collaboration between the funder, an academic steering committee, and an academic research organization, George Clinical.TRIAL REGISTRATION: The original trials of the CANVAS Program were registered at ClinicalTrials.gov with study numbers NCT01032629 and NCT01989754.

Background: Periodontitis may be a possible risk factor for atherosclerosis. The current pilot study explored arterial wall thickness and other variables associated with atherosclerosis in healthy subjects with and without periodontitis. Methods: Patients with moderate (N = 34) and severe periodontitis (N = 15) and controls (N = 14) were recruited. Intima media thickness (IMT) of the common carotid arteries (CCA), internal carotid arteries (ICA), and bifurcations of carotid arteries (BCA) was estimated bilaterally using B-mode ultrasound. An overall IMT-was calculated as the mean of these six measurements. C reactive protein (CRP), fibrinogen, and von Willebrand factor (vWf) were measured in plasma as indicators of systemic inflammation and atherosclerotic disease. Microalbuminuria was determined as a marker of endothelial cell dysfunction. Results: IMT for CCA were 0.64, 0.68, and 0.69 mm for control, moderate, and severe periodontitis, respectively (not significant). IMT for BCA did not vary among groups. IMT of ICA was largest for severe periodontitis (0.81 mm); corresponding values for controls and moderate periodontitis were 0.58 and 0.55 mm, respectively (P= 0.023). Severe periodontitis patients had an overall IMT of 0.76 mm, while moderate periodontitis patients and controls had lower values (0.64 and 0.65 mm, respectively; P= 0.153). After adjusting for potential confounding factors, the increased IMT for ICA in severe periodontitis was also significant (P-adj = 0.040). CRP (P= 0.020, P-adj = 0.050) and vWf (P= 0.019, P-adj = 0.013) were higher in periodontitis than controls; microalbuminuria was not different between groups. Power calculations suggest that a 4-fold expansion of the severe patient and control groups will result in a high chance (power level 80%) that a clinically significant association between the overall IMT and periodontitis will be observed. Conclusion: The present pilot study indicates that a full study investigating the relationship between periodontitis and atherosclerosis is warranted.

Background Imerslund-Gräsbeck Syndrome (IGS) is a rare genetic disorder characterised by juvenile megaloblastic anaemia. IGS is caused by mutations in either of the genes encoding the intestinal intrinsic factor-vitamin B12 receptor complex, cubam. The cubam receptor proteins cubilin and amnionless are both expressed in the small intestine as well as the proximal tubules of the kidney and exhibit an interdependent relationship for post-translational processing and trafficking. In the proximal tubules cubilin is involved in the reabsorption of several filtered plasma proteins including vitamin carriers and lipoproteins. Consistent with this, low-molecular-weight proteinuria has been observed in most patients with IGS. The aim of this study was to characterise novel disease-causing mutations and correlate novel and previously reported mutations with the presence of low-molecular-weight proteinuria. Methods Genetic screening was performed by direct sequencing of the CUBN and AMN genes and novel identified mutations were characterised by in silico and/or in vitro investigations. Urinary protein excretion was analysed by immunoblotting and high-resolution gel electrophoresis of collected urines from patients and healthy controls to determine renal phenotype. Results Genetic characterisation of nine IGS patients identified two novel AMN frameshift mutations alongside a frequently reported AMN splice site mutation and two CUBN missense mutations; one novel and one previously reported in Finnish patients. The novel AMN mutations were predicted to result in functionally null AMN alleles with no cell-surface expression of cubilin. Also, the novel CUBN missense mutation was predicted to affect structural integrity of the IF-B12 binding site of cubilin and hereby most likely cubilin cell-surface expression. Analysis of urinary protein excretion in the patients and 20 healthy controls revealed increased urinary excretion of cubilin ligands including apolipoprotein A-I, transferrin, vitamin D-binding protein, and albumin. This was, however, only observed in patients where plasma membrane expression of cubilin was predicted to be perturbed. Conclusions In the present study, mutational characterisation of nine IGS patients coupled with analyses of urinary protein excretion provide additional evidence for a correlation between mutation type and presence of the characteristic low-molecular-weight proteinuria.

Screening of the general population for subclinical atherosclerosis is controversial. We assessed the prevalence of subclinical atherosclerosis in healthy middle-aged individuals by 4 non-invasive modalities. In 277 randomly selected males (n = 121) and females (n = 156), aged 50 or 60 years, without known cardiovascular disease or diabetes, intima-media thickness/presence of carotid plaques by ultrasound; coronary artery calcification (CAC) by non-contrast enhanced cardiac CT; occurrence of peripheral artery disease (PAD) by ankle brachial index (ABI), and vascular leakage by urine albumin creatinine ratio (ACR), were evaluated. Traditional risk factors were obtained and HeartScore was calculated. A total of 56 % had morphological signs of atherosclerosis in one of the vascular territories; 41 % had CAC and 31 % a carotid plaque. Among individuals with atherosclerosis, 28 % had lesions in both vascular territories. Subclinical atherosclerosis was significantly more frequent in older males. Signs of PAD and microalbuminuria were very uncommon and detected in only 1 % of the entire population. No association was found between morphological signs of subclinical atherosclerosis and ABI or ACR. More than half of randomly selected apparently healthy middle aged individuals had subclinical atherosclerosis located in the coronary or carotid arteries.

32 diabetic and 31 metabolic healthy pregnant women are studied to answer the following questions: Is there a difference in the albumin-excretion rate (AER) during the pregnancy in primary normoalbuminuric type 1 diabetics and non-diabetics? Is there a difference 6 months post partum between the 2 groups? The average age of the diabetics (D) is 28, of the non-diabetics (ND) 27 years; the diabetics suffer from diabetes mellitus 12.5 years. In the 16th week of pregnancy, we find a AER (D vs. ND) of 5.0 vs. 2.37 micrograms/min (not significant [n.s.]), creatinin in serum 0.77 vs. 0.75 mg/dl (p < 0.05), creatinin clearance 92.5 vs. 103.4 ml/min (n.s.). In the 28th and in the 34th to 38th week, there is no significant elevation of the AER compared to the 16th week; but there is a significant elevation in the diabetics vs. the non-diabetics. 6 months post partum, the AER (D vs. ND) are: 6.13 vs. 5.11 micrograms/min (n.s. vs. 16th week and D vs. ND); in each group one person is found with a positive microalbuminuria (MA): 48.2 micrograms/min (D) and 27.4 mg/min (ND). Another diabetic woman shows post partum an isolated higher value of creatinin in serum: 1.5 mg/dl (without MA). This parameter is post partum significant higher (0.97 [D], 0.96 [ND] mg/dl) than in the 16th week of pregnancy (0.77 [D], 0.75 [ND] mg/dl). The creatinin clearance decreases post partum (pp): 92.2 ml/min (pp) vs. 102.0 ml/min (28th week) in the diabetics (n.s.) and 80.6 ml/min (pp) vs. 111.0 ml/min (28th week) in the non-diabetics (p < 0.05). Concerning the studied renal parameters, there is a significant difference of the albumin-excretion rates during the pregnancy between preconceptional normoalbuminuric type 1 diabetic and non-diabetic women, but 6 months post partum, there is no significant difference. The diabetics show a significant increase of the creatinin in urine and in serum and no significant change of the creatinin clearance 6 months post partum. Acta Med Austriaca