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Abstract Background Sarcopenia is common in chronic obstructive pulmonary disease (COPD) and contributes to adverse outcomes. Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of COPD, but its impact on skeletal muscle remains to be determined. Methods We performed a retrospective analysis of 487,207 participants in the UK Biobank with available SERPINA1 genotyping. Associations between AAT genotypes and measures of skeletal muscle mass were determined using multivariable linear and logistic regression models. Models adjusted for age, sex, smoking status, genetic principal components, lung function (FEV₁% predicted), and liver fibrosis risk (FIB-4). We determined that the Z-allele was associated with sarcopenia and mortality using regression models and mediation analysis. Results Compared with PI*MM individuals, carriers of the Z allele (PI*MZ, PI*SZ, PI*ZZ) demonstrated significantly lower fat free mass index (FFMI) and appendicular skeletal muscle index (ASMI), as well as higher odds of sarcopenia by binary definition. Associations persisted after adjustment for lung and liver function. A dose-dependent relationship was observed, with the greatest reductions in muscle mass and highest sarcopenia associated with PI*ZZ individuals (adjusted OR for FFMI-defined sarcopenia 2.02, 95% CI 1.16-3.32). Each additional Z allele was associated with increased mortality risk (adjusted OR 1.09, 95% CI 1.02-1.16), with sarcopenia mediating a modest proportion (∼2.6%) of this association. Conclusions. The SERPINA1 Z allele is associated with reduced muscle mass and increased risk for sarcopenia independent of lung and liver disease. Our findings expand the phenotypic spectrum of AATD-related diseases to include skeletal muscle as a modifiable target for intervention.

Introduction There is an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygotes for the alpha-1 antitrypsin (AAT) Z allele (PI*MZ), but there is significant variation in outcomes. Matrix metalloproteinases (MMPs) contribute to worse airway disease and emphysema. Given that the AAT protein is an antiprotease, we hypothesised that MMPs play a modifying role among AAT-deficient individuals. Methods We studied PI*MZ (n=39) and PI*ZZ (n=27) individuals from the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis Study cohort. MMP (MMP3, MMP9, MMP10, MMP12 and MMP15) gene expression was assessed in bronchoalveolar lavage cells and peripheral blood mononuclear cells. Plasma protein MMP (MMP3, MMP9, MMP10 and MMP12) expression was assessed using SomaScan and BAL MMP15 protein using ELISA. MMP values were log-transformed, and linear regression analyses were used to assess lung function, patient-reported outcomes and CT emphysema adjusted for age, body mass index, sex and duration of smoking. Results Alveolar MMP3 and MMP15 were uniquely associated with worse lung function, patient-reported outcomes and emphysema among PI*MZ individuals. MMP10 was associated with less disease severity among PI*MZ individuals. Discussion Our study shows that alveolar MMP3 and MMP15 may uniquely contribute to disease among PI*MZ individuals, raising the possibility that they could serve as biomarkers or therapeutic targets in this highly prevalent COPD phenotype. Furthermore, we show that MMP10 may serve a protective effect. In aggregate, these data support further studies of the MMP pathway among lung-affected PI*MZ individuals, as they may serve as biomarkers or pharmacological targets in future studies.

Abstract RATIONALE The best described endotype of COPD is alpha-1 antitrypsin (AAT) deficiency, which is due to a genetic abnormality in the SERPINA1 gene. Homozygotes for the Z allele (PI[asterisk]ZZ individuals) carry the genotype most commonly associated with severe AAT deficiency, but a highly prevalent endotype is the heterozygous state (PI[asterisk]MZ individuals). Here we test the hypothesis that individuals with PI[asterisk]MZ genotype are at higher risk for COPD exacerbation and healthcare utilization compared to those with no pathogenic variants in the SERPINA1 gene (PI[asterisk]MM individuals). METHODS Real-world data on 4,456 individuals with available AAT genotyping were extracted from the Cleveland Clinic Health System (CCHS) electronic health records (EHR) and analyzed to compare the risk of moderate COPD exacerbation (defined as a short-term steroid prescription), all-cause emergent care (defined as an express care visit, urgent care visit, or emergency department visit), and all-cause hospitalization between individuals with PI[asterisk]MZ vs. PI[asterisk]MM genotypes. Cox proportional hazards models were used to adjust for age, sex, race, BMI, smoking status, comorbidity count, liver disease diagnosis, and median income by zip code.To assess the effect of AAT levels on outcomes, we categorized participants into three groups based on AAT level and used 90 mg/dL as a threshold given it is the lower limit of the normal reference range and genotype: MM individuals with an AAT level >90 mg/dL, MZ >90 mg/dL and MZ <90 mg/dL. To assess the effect of PI[asterisk]MZ genotype among individuals with pre-existing lung disease, we performed a subgroup analysis of individuals with at least a six-month inhaler prescription. RESULTS In this cohort, 308 individuals had a PI[asterisk]MZ genotype. PI[asterisk]MZ was associated with increased risk for moderate COPD exacerbations (adjusted HR [95% CI]: 1.66 [1.27, 2.17]) and hospitalizations (adjusted HR [95% CI]: 1.44 [1.19, 1.75]) compared to PI[asterisk]MM. The risk of hospitalization was higher among PI[asterisk]MZ individuals with AAT levels <90 mg/dL (adjusted HR [95% CI]: 1.59 [1.14, 2.23]) but not in those with AAT levels >90 mg/dL, as compared to PI[asterisk]MM. Sensitivity analysis in those treated with inhaler therapy showed overall similar results. CONCLUSIONS Increased hospitalizations and moderate COPD exacerbations among PI[asterisk]MZ individuals compared to PI[asterisk]MM individuals merit future prospective studies to better characterize the longitudinal course and healthcare utilization among those with an PI[asterisk]MZ genotype. Given the high prevalence of these carriers globally, PI[asterisk]MZ represents a COPD phenotype that invites additional investigation to identify biomarkers of worse disease and treatable traits.

Abstract Rationale Reliable data about the natural history of lung function decline in alpha-1 antitrypsin (AAT)-deficient Pi*MZ heterozygotes is largely missing. Objectives We hypothesized that, in adults with a tobacco smoking history, lung function deteriorates faster in Pi*MZ compared with the Pi*MM genotype. Methods We identified 1,856 Pi*MM and 79 Pi*MZ participants with ⩾20 pack-years tobacco smoking history from the SPIROMICS (Subpopulations and Intermediate Outcomes Measures in COPD Study) cohort by DNA sequencing and followed them over a median of 4.8 years, comparing radiographic and clinical characteristics between the two groups over time using regression models. Results Adjusted for age, sex, race, smoking pack-year history, and smoking status, Pi*MZ participants had a lower baseline percent predicted forced expiratory volume in 1 second (FEV1) (65.4% vs. 75.1%; difference 95% confidence interval [CI], −15.4% to −3.9%), more radiographic emphysema (<−950 Hounsfield units%, 12.9% vs. 7.8%; difference 95% CI, 2.8% to 7.5%), and nonsignificantly lower lung density. In the longitudinal analysis, the FEV1 annual rate of decline was similar in both groups over the course of the study (−34.5 ml/yr vs. −34.6 ml/yr for Pi*MZ and Pi*MM; difference 95% CI, −16.9 to 17.1 ml/yr). There were no significant differences between Pi*MZ and Pi*MM individuals in the annualized change in lung density, emphysema, patient-reported outcomes, exacerbations, or survival. The proportion with faster FEV1 decline (annual loss ⩾40 ml) was similar in Pi*MZ and Pi*MM groups. In both groups, faster FEV1 decline was associated with more air trapping and small airway disease at baseline. In Pi*MZ only, faster decline was associated with higher blood eosinophil counts (310 vs. 220 cells/μl; difference 95% CI, 30 to 140 cells/μl). In the subgroup analysis limited to a small number of currently smoking participants, no significant differences in longitudinal outcomes were found. Conclusions Despite a lower FEV1 and more emphysema at enrollment, the longitudinal analysis did not demonstrate significantly greater lung function decline or lung density loss in Pi*MZ compared with Pi*MM participants with tobacco smoking history. Limited sample size and duration of longitudinal follow-up constrain generalizability of our findings, thus prohibiting the conclusion that longitudinal trajectories did not differ between these groups. However, our results may suggest that earlier life events could be responsible for more extensive lung disease at enrollment in Pi*MZ compared with Pi*MM tobacco-exposed individuals.

Background. The study investigates the occurrence, severity, and outcomes of acute kidney injury (AKI) in octogenarians following heart valve surgery.Methods. All patients, age>80 years, not on dialysis and without kidney transplant, undergoing heart valve replacement at Mayo Clinic, Rochester, in the years 2002-2003 were enrolled. AKI was diagnosed based on AKIN criteria.Results. 209 octogenarians (88.0% aortic valve, 6.2% mitral valve, 1.0% tricuspid valve, and 4.8% multivalve) with (58.4%) and without CABG were studied. 34 (16.3%) had preexisting CKD. After surgery, 98 (46.8%) developed AKI. 76.5% of the AKI were in Stage 1, 9.2% in Stage 2, and 14.3% in Stage 3. 76.5% CKD patients developed AKI. Length of hospital stay was longer for AKI patients. More AKI patients were discharged to care facilities. Patient survival at 30 days and 1 year for AKI versus non-AKI was 88.8 versus 98.7%,p=0.003, and 76.5 versus 88.3%,p=0.025, respectively. With follow-up of3.94±0.28years, Kaplan-Meier analysis showed a reduced survival for AKI octogenarians. Preexisting CKD and large volume intraoperative fluid administration were independent AKI predictors.Conclusions. Nearly half of the octogenarians developed AKI after valve replacement surgery. AKI was associated with significant functional impairment and reduced survival.

The elderly chronic kidney disease (CKD) population is growing. Both aging and CKD can disrupt calcium (Ca2+) homeostasis and cause alterations of multiple Ca2+-regulatory mechanisms, including parathyroid hormone, vitamin D, fibroblast growth factor-23/Klotho, calcium-sensing receptor and Ca2+-phosphate product. These alterations can be deleterious to bone mineral metabolism and soft tissue health, leading to metabolic bone disease and vascular calcification and aging, termed CKD-mineral and bone disorder (MBD). CKD-MBD is associated with morbid clinical outcomes, including fracture, cardiovascular events and all-cause mortality. In this paper, we comprehensively review Ca2+ regulation and bone mineral metabolism, with a special emphasis on elderly CKD patients. We also present the current treatment-guidelines and management options for CKD-MBD.