Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis.

OBJECTIVE: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype. METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems. RESULTS: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619. CONCLUSIONS: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.

Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA.

OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). METHODS: Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. RESULTS: PR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 × 10-61, odds ratio (OR) 0.10; rs9277341, P = 1.5 × 10-44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 × 10-10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 × 10-25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 × 10-7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. CONCLUSION: We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.

Results of renal artery revascularization in the post-ASTRAL era with 4 years mean follow-up.

Purpose: To investigate contemporary results of percutaneous transluminal renal angioplasty (PTRA).Materials and Methods: A multicentre retrospective study analysing all patients treated with PTRA for primary symptomatic renal artery stenosis (RAS) between 2010 and 2013 at four tertiary centres. Procedures during the preceding four years were counted to evaluate for change in PTRA frequency.Results: The number of PTRA procedures decreased by approximately 50% from 2006 to 2013. Patients treated in the post-ASTRAL period (n = 224) had a significant reduction in mean systolic pressure (168 to 146 mmHg, p < 0.01), diastolic pressure (84 to 76 mmHg, p < 0.01), number of anti-hypertensive drugs (3.54 to 3.05, p < 0.01), and anti-hypertensive treatment index (21.75 to 16.92, p < 0.01) compared to before PTRA. These improvements were maintained at one year and at the last clinical evaluation after a mean follow-up of 4.31 years. Renal function increased transiently without sustained improvement, or deterioration, during later follow-up. Thirteen patients (5.8%) eventually required dialysis, nine of these had eGFR <20 ml/min/1.73 m2 before PTRA. There was no difference in outcomes between subgroups differentiated by different indications for PTRA.Conclusion: The frequency of PTRA has decreased, indicating a higher threshold for invasive treatment of RAS in recent years. The reduction in blood pressures, the reduced need for anti-hypertensive medication, and stabilization of renal function over time suggest a clinical benefit for most patients who are now being treated with PTRA.

Long-term outcome of stenting for atherosclerotic renal artery stenosis and the effect of angiographic restenosis.

BACKGROUND: Symptomatic renal artery stenosis (RAS) is mainly treated with pharmacological blood pressure control, sometimes with percutaneous transluminal renal angioplasty (PTRA). It is unclear if PTRA benefits these patients over time. PURPOSE: To determine long-term renal function, morbidity, and mortality in patients with symptomatic RAS treated with PTRA, and whether long-term outcomes are associated with angiographic restenosis. MATERIAL AND METHODS: Retrospective single-center, long-term follow-up of 57 patients with atherosclerotic RAS treated with PTRA with stent during 1995-2004 and investigated for restenosis with angiography after one year. Outcomes were retrieved from medical records and from mandatory healthcare registries. Mortality rates were related to expected survival in an age- and gender-matched population, using a life-table database. Surviving patients were assessed with blood pressures, laboratory tests, duplex ultrasonography, and radioisotope renography. RESULTS: Median follow-up was 11 years 7 months. Major indications for PTRA were therapy-resistant hypertension and declining renal function. Angiographic restenosis at one year was found in 21 of 57 patients (37%). Thirty-six patients (60%) died during follow-up. Main cause of death was cardiovascular events (54%). Mortality was significantly increased, and morbidity and healthcare utilization were high. Hypertension control during follow-up was stable with persistent need for anti-hypertensive medication, and renal function remained moderately reduced with no long-term difference between patients with vs. without restenosis. CONCLUSION: Long-term prognosis after PTRA for atherosclerotic RAS is dismal, with high mortality and morbidity and reduced renal function, despite maintained hypertension control. Restenosis does not appear to affect late outcome.

Duplex ultrasound for identifying renal artery stenosis: direct criteria re-evaluated.

Background Renal artery duplex ultrasound (RADUS) is an established method for diagnosis of renal artery stenosis (RAS), but there is no consensus regarding optimal RADUS criteria. Purpose To define optimal cutoff values for RADUS parameters when screening for RAS using intra-arterial trans-stenotic pressure gradient measurement (PGM) as reference. Material and Methods The renal arteries of 58 consecutive patients evaluated for renovascular hypertension were examined by RADUS and PGM. Conclusive measurements with both methods were obtained in 76 arteries. Hemodynamically significant RAS was defined as PGM ≥15 mmHg and was found in 43 of the 76 arteries. RADUS parameters included renal artery peak systolic velocity (PSV) and the renal-aortic ratio (RAR) of flow velocities. Receiver operating characteristic curves (ROCs) and Youden's index were used to calculate optimal RADUS criteria for RAS. Results When traditional RADUS criteria for RAS were used, with a combination of PSV ≥180 cm/s and RAR ≥3.5, the sensitivity was 62% and the specificity was 91%. When RADUS criteria were optimized for sensitivity, then RAR ≥2.6 alone resulted in a sensitivity of 89% and a specificity of 69%. Conclusion The RAR ≥2.6 is a more sensitive criterion than traditional RADUS criteria when screening patients with clinical suspicion of RAS.

Outcomes in patients with chronic kidney disease not on dialysis receiving extended dosing regimens of darbepoetin alfa: long-term results of the EXTEND observational cohort study.

BACKGROUND: Extended dosing of the erythropoiesis-stimulating agent (ESA) darbepoetin alfa (DA) once biweekly or monthly reduces anaemia treatment burden. This observational study assessed outcomes and dosing patterns in patients with chronic kidney disease not on dialysis (CKD-NoD) commencing extended dosing of DA. METHODS: Adult CKD-NoD patients starting extended dosing of DA in Europe or Australia in June 2006 or later were followed up until December 2012. Outcomes included haemoglobin (Hb) concentration, ESA dosing, mortality rates and receipt of dialysis and renal transplantation. Subgroup analyses were conducted for selected outcomes. RESULTS: Of 6035 enrolled subjects, 5723 (94.8%) met analysis criteria; 1795 (29.7%) received dialysis and 238 (3.9%) underwent renal transplantation. Mean (standard deviation) Hb concentration at commencement of extended dosing was 11.0 (1.5) g/dL. Mean [95% confidence interval (CI)] Hb 12 months after commencement of extended dosing (primary outcome) was 11.6 g/dL (11.5, 11.6) overall and was similar across countries, with no differences between subjects previously treated with an ESA versus ESA-naïve subjects, subjects with versus without prior renal transplant or diabetics versus non-diabetics. Weekly ESA dose gradually decreased following commencement of extended DA dosing and was similar across subgroups. The decrease in weekly DA dose was accompanied by an increase in the proportion of patients receiving iron therapy. Hb concentrations declined following changes in ESA labels and treatment guidelines. The mortality rate (95% CI) was 7.06 (6.68, 7.46) deaths per 100 years of follow-up. Subjects alive at study end had stable Hb concentrations in the preceding year, while those who died had lower and declining Hb concentrations in their last year. CONCLUSIONS: Long-term, extended dosing of DA maintained Hb concentrations in patients already treated with an ESA and corrected and maintained Hb in ESA-naïve patients.

Circulating anti-glomerular basement membrane antibodies with predominance of subclass IgG4 and false-negative immunoassay test results in anti-glomerular basement membrane disease.

Autoantibodies against a constituent of the glomerular basement membrane (GBM), the α3-chain of type IV collagen, can cause both rapidly progressive glomerulonephritis and alveolar hemorrhage, referred to as anti-GBM disease or Goodpasture disease. Anti-GBM antibodies generally are of immunoglobulin G subclass 1 (IgG1) and can in most cases readily be detected in the circulation using enzyme-linked immunosorbent assays (ELISAs). We report 4 cases in which anti-GBM ELISA yielded negative or borderline results despite life-threatening disease. All 4 patients had positive results by IgG4 anti-GBM ELISA and all had undetectable antineutrophil cytoplasmic antibody. All cases were confirmed with kidney biopsy. Two of the patients showed higher signal in anti-GBM ELISA when using a nondenaturing coating buffer. All 4 were young women with severe alveolar hemorrhage and favorable renal outcome, suggesting that patients with predominance of IgG4 autoantibodies may constitute a distinct subgroup of anti-GBM disease. We conclude that patients with idiopathic alveolar hemorrhage can have anti-GBM disease detected by only IgG subclass-specific tests or kidney biopsy.

Higher serum free thyroxine levels are associated with increased risk of hip fractures in older men.

Overt and subclinical hyperthyroidism are associated with an increased fracture risk, but whether thyroid hormones are associated with fracture risk in individuals with normal thyroid-stimulating hormone (TSH) has mostly been investigated in women. Therefore, we investigated if serum levels of free thyroxine (FT4) or TSH are associated with fracture risk in Swedish men. We followed (median 12.2 yr) elderly men (n = 1825; mean age 75, range 69-81 yr) participating in the Gothenburg and Malmö subcohorts of the prospective, population-based MrOS-Sweden study. The statistical analyses included Cox proportional hazards regression. Men receiving levothyroxine treatment were excluded. In our total cohort, serum FT4 (per SD increase) was associated with increased risk of major osteoporotic fractures (MOFs; n = 479; fully adjusted hazard ratio [HR] 1.14, 95% CI, 1.05-1.24) and hip fractures (n = 207; HR 1.18, 95% CI, 1.04-1.33). Also, in men with normal TSH (n = 1658), FT4 (per SD increase) was significantly associated with increased risk of MOF and hip fractures. Furthermore, men in the highest FT4 quartile had a 1.5-fold increase in hip fracture risk compared with men in the three lower FT4 quartiles, both in the total population and in men with normal TSH (fully adjusted: HR 1.45, 95% CI, 1.04-2.02 and HR 1.51, 95% CI, 1.07-2.12, respectively). In contrast, the risk of MOF was not statistically different in the highest FT4 quartile compared with the three lower FT4 quartiles. Finally, serum TSH was not associated with fracture risk after full adjustment for covariates. In conclusion, serum FT4, but not serum TSH, is a predictor of hip fracture risk in elderly Swedish men. Additionally, there was an association between FT4 (per SD increase) and the risk of MOF.

Brain natriuretic peptides in atherosclerotic renal artery stenosis and effects of renal angioplasty.

BACKGROUND: We hypothesized that plasma levels of brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) would be elevated, and adiponectin concentrations reduced, in patients with atherosclerotic renal artery stenosis (ARAS) and that BNPs might be used to identify patients who would benefit from percutaneous transluminal renal angioplasty (PTRA). METHODS: Data were collected before renal angiography in 91 patients with hypertension and suspected ARAS (significant ARAS; n=47, and non-RAS; n=44) and in 20 healthy controls (C). In ARAS patients analyses were repeated four weeks after PTRA. RESULTS: Ambulatory systolic blood pressure (ASBP) was significantly elevated in the ARAS group vs. both C and non-RAS groups. Baseline plasma BNP and NT-proBNP levels were significantly elevated, and adiponectin concentrations reduced, in the ARAS group vs. C but not vs. the non-RAS group. One month after PTRA, ASBP was reduced vs. baseline (149±16 to 139±15 mm p<0.01). Brain natriuretic peptides were not significantly affected by PTRA. CONCLUSIONS: Patients with ARAS showed elevated of BNP and NT-proBNP concentrations, and reduced levels of adiponectin, compared to healthy controls but not vs. hypertensive individuals without RAS. Our data do no support the use of BNP analyses in the identification of ARAS patients who will have a beneficial blood pressure response to PTRA.

Antieosinophil Antibodies Alone or in Combination with Antineutrophil Cytoplasmic Antibodies (ANCA) Detected in Different Autoimmune Conditions.

Circulating antieosinophil antibodies (AEOSA) have been associated with various autoimmune conditions affecting the liver, kidneys, lungs, and joints but are not part of routine clinical diagnostics. While analyzing human sera for antineutrophil cytoplasmic antibodies (ANCA) by indirect immunofluorescence (IIF) on granulocytes, 0.8% of analyzed samples were found to be reactive with eosinophils. Our aim was to determine the diagnostic relevance and antigenic specificity of AEOSA. AEOSA were seen either in combination with an myeloperoxidase (MPO)-positive p-ANCA (44%; AEOSA+/ANCA+) or on their own (56%; AEOSA+/ANCA-). AEOSA/ANCA positivity was seen in patients with thyroid disease (44%) or vasculitis (31%), while AEOSA+/ANCA- pattern was more common in patients with autoimmune disorders of the gastrointestinal tract and/or liver. Eosinophil peroxidase (EPX) was the main target recognized in 66% of the AEOSA+ sera by enzyme-linked immunosorbent assay (ELISA). Eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) were also identified as target antigens but less frequently and only in combination with EPX. In conclusion, we confirmed that EPX is a major target of AEOSA, illustrating the high antigenic potential of EPX. Our results also demonstrate the presence of concomitant AEOSA/ANCA positivity in a defined patient group. Further research should aim to elucidate the association of AEOSA with autoimmunity.

Reninom ­ en ovanlig men botbar orsak till sekundär hypertoni.

Reninoma - rare juxtaglomerular tumor associated with hypertension We present a case study of two female patients, aged 20-30 years, who were diagnosed with reninoma, a rare juxtaglomerular tumor associated with hypertension, high plasma renin and hypokalemia. Both patients were referred to the Department of Internal Medicine at Sahlgrenska University Hospital, but their cases were ten years apart. In both instances, the renin-secreting tumor was surgically removed, resulting in the normalization of blood pressure without the need for antihypertensive medication. Based on our findings, we recommend physicians interested in hypertension to analyze plasma renin levels before starting antihypertensive treatment in young patients. Additionally, we suggest performing an MRI of the kidneys followed by renal vein catheterization, which can confirm but not exclude the presence of a reninoma. It is important to note that treatment with RAAS (renin-angiotensin-aldosterone system) blockers may mask the effects of reninoma on blood pressure and potassium levels. Since RAAS blockers are contraindicated during pregnancy, it is of particular importance to diagnose reninoma in young women of childbearing age.

An observational cohort study of extended dosing (once every 2 weeks or once monthly) regimens with darbepoetin alfa in patients with chronic kidney disease not on dialysis: the EXTEND study.

BACKGROUND: Darbepoetin alfa (DA) has been shown to be an effective treatment of anaemia in patients with chronic kidney disease (CKD) not on dialysis (NoD). EXTEND is an observational study assessing the effectiveness of DA administered once biweekly (Q2W) or monthly (QM) in a general CKD-NoD population. METHODS: Adult CKD-NoD patients starting DA Q2W/QM treatment in June 2006 or later were eligible. Retrospective and/or prospective data including haemoglobin levels and erythropoiesis-stimulating agent (ESA) dosing were collected for 6 months before and 12 months after DA initiation. Mean Hb levels were calculated every 3 months, and ESA dose was converted to a geometric mean weekly DA equivalent dose and summarized monthly. RESULTS: Data from 4278 patients showed that patients receiving ESA treatment before DA Q2W/QM initiation had a mean (95% confidence interval) Hb level of 11.9 g/dL (11.8-12.0 g/dL) at initiation and 11.6 g/dL (11.6-11.7 g/dL) at Months 10-12, with mean ESA dose of 22 µg/week (21-23 µg/week) prior to initiation, 16 µg/week (15-16 µg/week) at initiation and 16 µg/week (15-16 µg/week) at Month 12. In ESA-naive patients, Hb levels increased from 10.3 g/dL (10.2-10.3 g/dL) at initiation to 11.7 g/dL at Months 4-6 and were maintained at a mean level of 11.7 g/dL (11.7-11.8 g/dL) at Months 10-12, with mean ESA dose of 16 µg/week (16-17 µg/week) at initiation and 16 µg/week (16-17 µg/week) at Month 12. In the 85% of patients receiving DA at extended intervals (Q2W or less frequently) at Month 12, 12 patients (0.3%) experienced DA-related adverse reactions. CONCLUSION: DA Q2W/QM was an effective treatment of anaemia in the general CKD-NoD patient population and a dose increase was not required in patients switching from a previous ESA regimen.

Unilateral adrenal hyperplasia is a usual cause of primary hyperaldosteronism. Results from a Swedish screening study.

BACKGROUND: The existence of unilateral adrenal hyperplasia (AH) has been considered a rare cause of primary hyperaldosteronism (PA). METHODS: In a prospective study we screened for PA in a non-selected (NSP) and selected hypertensive population (SP), to define the cause of PA. We included 353 consecutive patients with hypertension; age 20 to 88 years, 165 women and 188 men, from a university-based Hypertension and Nephrology Outpatient clinics (123 SP) and two primary care centres, (230 NSP) from the same catch-up area. Serum aldosterone and plasma renin activity (PRA) were measured and the ARR calculated. Verifying diagnostic procedure was performed in patients with both elevated aldosterone and ARR. Patients diagnosed with PA were invited for adrenal venous sampling (AVS) and offered laparoscopic adrenalectomy when AVS found the disease to be unilateral. RESULTS: After screening, 46 patients, 13% of the whole population (22.8% SP and 7.8% NSP) had aldosterone and ARR above the locally defined cut-off limits (0.43 nmol/l and 1.28 respectively). After diagnostic verification, 20 patients (6%) had PA, (14.5% SP and 1.4% NSP). Imaging diagnostic procedures with CT-scans and scintigraphy were inconclusive. AVS, performed in 15 patients verified bilateral disease in 4 and unilateral in 10 patients. One AVS failed. After laparoscopic adrenalectomy, 4 patients were found to have adenoma and 5 unilateral AH. One patient denied operation. CONCLUSION: The prevalence of PA was in agreement with previous studies. The study finds unilateral PA common and unilateral AH as half of those cases. As may be suspected PA is found in much higher frequency in specialised hypertensive units compared to primary care centers. AVS was mandatory in diagnosis of unilateral PA.

Anemia is associated with increased risk of non-vertebral osteoporotic fractures in elderly men: the MrOS Sweden cohort.

This study includes 1005 men from the Gothenburg part of the Osteoporotic Fracture in Men Study (MrOS). Included are 66 men with anemia (hemoglobin < 130 g/L). The follow-up time was up to 16 years, and the main results are that anemia is associated with all fractures and non-vertebral osteoporotic fractures. INTRODUCTION: Anemia and osteoporotic fractures are conditions that are associated with increased morbidity and mortality. Clinical studies have suggested that anemia can be used as a predictor of future osteoporotic fractures. METHOD: Men from the Osteoporotic Fractures in Men Study (MrOS) Sweden, Gothenburg, with available hemoglobin (Hb) values (n = 1005, median age 75.3 years (SD 3.2)), were included in the current analyses. Of these, 66 suffered from anemia, defined as Hb < 130 g/L. Median follow-up time for fracture was 10.1 years and the longest follow-up time was 16.1 years. RESULTS: Men with anemia had, at baseline, experienced more falls and had a higher prevalence of diabetes, cancer, prostate cancer, hypertension, and stroke. Anemia was not statistically significantly associated with bone mineral density (BMD). Men with anemia had higher serum levels of fibroblast growth factor 23 (iFGF23) (p < 0.001) and phosphate (p = 0.001) and lower serum levels of testosterone (p < 0.001) and estradiol (p < 0.001). Moreover, men with anemia had an increased risk of any fracture (hazard ratio (HR) 1.97, 95% CI 1.28-3.02) and non-vertebral osteoporotic fracture (HR 2.15, 95% CI 1.18-3.93), after adjustment for age and total hip BMD, in 10 years. The risk for any fracture was increased in 10 and 16 years independently of falls, comorbidities, inflammation, and sex hormones. The age-adjusted risk of hip fracture was increased in men with anemia (HR 2.32, 95% CI 1.06-5.12), in 10 years, although this was no longer statistically significant after further adjustment for total hip BMD. CONCLUSIONS: Anemia is associated with an increased risk for any fracture and non-vertebral osteoporotic fracture in elderly men with a long follow-up time. The cause is probably multifactorial and our results support that anemia can be used as a predictor for future fracture.

Lipoprotein abnormalities in patients with atherosclerotic renovascular disease.

BACKGROUND: Patients with atherosclerotic renovascular disease (ARVD) have a high risk of cardiovascular death. The primary aim was to characterize abnormalities in apolipoprotein (Apo)-defined lipoprotein (Lp) subclasses in patients with ARVD. METHODS: Baseline measurements were performed on 42 patients with ARVD 4 weeks after renal angioplasty (PTRA). All patients were on statin treatment. Twenty age-matched healthy subjects without medications served as controls. Subsequently, patients were randomized to treatment with either candesartan (n = 21), or antihypertensive treatment without inhibitors of the renin-angiotensin-aldosterone system (n = 21) and followed for 11 months. RESULTS: At baseline, ApoC-III (12.7 ± 4.6 vs. 8.8 ± 2.6 (SD) mg/dl, p < 0.05), LpB:C:E (13.3 ± 5.4 vs. 8.4 ± 4.3 mg/dl, p < 0.05), and the sum of ApoC-III-containing lipoproteins, i.e. LpB:C + LpB:C:E + LpA-II:B:C:D:E (46 ± 15 vs. 37 ± 8 mg/dl, p < 0.05), were significantly elevated in ARVD patients versus healthy controls. Multiple regression analyses showed that only plasma renin activity was independently associated with ApoC-III levels at baseline (p < 0.05, r = 0.74). Treatment with candesartan did not correct abnormalities. CONCLUSIONS: Patients with ARVD treated with statins have an atherogenic lipoprotein profile characterized by elevated levels of ApoC-III-containing, triglyceride-rich lipoproteins that could accelerate atherosclerotic disease.

Plasma renin activity has a complex prognostic role in patients with acute coronary syndromes.

BACKGROUND: Plasma renin activity (PRA) has been related to all-cause mortality and cardiovascular events in patients with cardiovascular disease. However, data from patients with acute coronary syndromes (ACS) are sparse. METHODS: Determination of PRA was made in 550 patients with ACS, including a subgroup of 287 patients not on treatment with angiotensin converting enzyme inhibitors, angiotensin receptor blockers or diuretics, and without heart failure. We evaluated the relations between PRA and all-cause mortality after three years and long-term, and to cardiovascular events after median 8.7 years. Adjustments were made for variables that influenced the hazard ratio (HR) > 5% for the relation between PRA and outcome. RESULTS: Baseline PRA was associated with all-cause mortality during three-years (unadjusted HR 1.74 per 1 SD increase in logarithmically transformed PRA; 95% confidence interval (CI) 1.39-2.16, p < 0.0001) and long-term (HR 1.12, CI 1.00-1.25, p = 0.046). After adjustments, only the three-year association remained significant. In unadjusted analyses, PRA was associated with cardiovascular death, but not with nonfatal cardiovascular events. In the subgroup there was an inverse relation between PRA and long-term all-cause mortality. CONCLUSION: Higher PRA was a significant independent predictor of all-cause mortality after three years, but not at long-term follow-up and not significantly associated with cardiovascular incidence. The renin-angiotensin-system pathophysiology is of great interest, not least due to its association with the COVID-19 pandemic. Our findings indicate a need for further research on the prognostic/predictive aspects of the renin-angiotensin-system in ACS.

Erythrocyte sodium-lithium countertransport activity is inversely correlated to adiponectin, retinol binding protein 4 and body height.

BACKGROUND: We have previously described that the sodium/lithium countertransport (SLC) in the erythrocyte cell membrane is closely linked to obesity and insulin resistance. Adiponectin and retinol-binding protein 4 (RBP-4) are believed to affect obesity and insulin resistance. In the present study, we aimed to further characterize the relationship between SLC, inflammatory markers, adiponectin and RBP-4. METHODS: We included 93 clinically healthy 58-year-old men selected to display variations in insulin sensitivity. High sensitivity C-reactive protein (hs-CRP), TNF-alpha, soluble TNF-alpha-receptors (sTNFR) 1 and 2, IL-6 and RBP-4 were measured using antibody-based techniques. Adiponectin was determined by a radioimmunoassay kit. The lithium concentration in the special flux medium was measured by atomic absorption spectrophotometry. RESULTS: In univariate analyses, SLC correlated negatively with RBP-4 (r(s) = -0.256, p = -0.017) and to adiponectin (r(s) = -0.316, p = 0.003) and positively with TNF-alpha (r(s) = 0.346, p = 0.001) and hs-CRP (r(s) = 0.288, p = 0.005). There were no statistically significant correlations with sTNFR 1 or 2 or IL-6. SLC was negatively associated to body height (r(s) = -0.256, p = 0.013). CONCLUSIONS: We are the first to report that SLC correlates negatively with adiponectin and RBP-4. This finding is intriguing, as adiponectin is anti-inflammatory and anti-diabetic whereas RBP-4 supposedly decreases insulin sensitivity. We also observed a negative association between SLC activity and body height indicating that SLC activity is not primarily influenced by fat mass. The positive association of SLC with markers of inflammatory activity such as TNF-alpha and hs-CRP is in line with the proposed link between inflammation and insulin resistance.

High Plasma Erythropoietin Predicts Incident Fractures in Elderly Men with Normal Renal Function: The MrOS Sweden Cohort.

Preclinical studies on the role of erythropoietin (EPO) in bone metabolism are contradictory. Regeneration models indicate an anabolic effect on bone healing, whereas models on physiologic bone remodeling indicate a catabolic effect on bone mass. No human studies on EPO and fracture risk are available. It is known that fibroblast growth factor 23 (FGF23) affects bone mineralization and that serum concentration of FGF23 is higher in men with decreased estimated glomerular filtration rate (eGFR). Recently, a direct association between EPO and FGF23 has been shown. We have explored the potential association between EPO and bone mineral density (BMD), fracture risk, and FGF23 in humans. Plasma levels of EPO were analyzed in 999 men (aged 69 to 81 years), participating in the Gothenburg part of the population-based Osteoporotic Fractures in Men (MrOS) study, MrOS Sweden. The mean ± SD EPO was 11.5 ± 9.0 IU/L. Results were stratified by eGFR 60 mL/min. For men with eGFR ≥60 mL/min (n = 728), EPO was associated with age (r = 0.13, p < 0.001), total hip BMD (r = 0.14, p < 0.001), intact (i)FGF23 (r = 0.11, p = 0.004), and osteocalcin (r = -0.09, p = 0.022). The association between total hip BMD and EPO was independent of age, body mass index (BMI), iFGF23, and hemoglobin (beta = 0.019, p < 0.001). During the 10-year follow-up, 164 men had an X-ray-verified fracture, including 117 major osteoporotic fractures (MOF), 39 hip fractures, and 64 vertebral fractures. High EPO was associated with higher risk for incident fractures (hazard ratio [HR] = 1.43 per tertile EPO, 95% confidence interval [CI] 1.35-1.63), MOF (HR = 1.40 per tertile EPO, 95% CI 1.08-1.82), and vertebral fractures (HR = 1.42 per tertile EPO, 95% CI 1.00-2.01) in a fully adjusted Cox regression model. In men with eGFR<60 mL/min, no association was found between EPO and BMD or fracture risk. We here demonstrate that high levels of EPO are associated with increased fracture risk and increased BMD in elderly men with normal renal function. © 2019 American Society for Bone and Mineral Research.

Albuminuria within the normal range and ultrasound-assessed atherosclerosis in the AIR study: a 9-year follow-up of 58-year-old clinically healthy men.

BACKGROUND: Microalbuminuria, traditionally defined as 30-300 mg urinary albumin/24 h, predicts renal impairment and cardiovascular disease. Studies suggest that also a far lower urinary albumin excretion (UAE) can predict clinical outcome. Intima media thickness (IMT) is an established estimate of atherosclerosis. In this study, we investigated the predictive value of UAE within the normal rate (UAE-n) for the progression of IMT in the carotid and femoral arteries. METHODS: We included 325 clinically healthy men with normoalbuminuria. Anthropometrics, urine and blood samples were taken and IMT in the carotid and femoral arteries were assessed by B-mode ultrasound at baseline and after 3 and 9 years. The annual progression rate of IMT (r-IMT) was calculated. RESULTS: UAE-n correlated with carotid IMT at baseline and after 3 and 9 years, but not with r-IMT. In a regression analysis, only HDL and baseline IMT remained as statistically significant co-variates to mean IMT at 9 years. IMT in the femoral artery and r-IMT at any time-point did not correlate to baseline UAE. CONCLUSION: UAE-n was associated with carotid IMT after 3 and 9 years but not r-IMT or with femoral artery IMT. Carotid IMT after 9 years' follow-up was independently related to baseline IMT and HDL cholesterol. In this cohort of 58-year-old men, our interpretation is that UAE-n is not associated with the increase in carotid and femoral artery IMT observed after 9 years.