Perfluoroalkyl substances and kidney function in chronic kidney disease, anemia, and diabetes

Background: Anemia often complicates chronic kidney disease (CKD), leading to insufficient tissue oxygenation and hypoxic injury, the factor thought to underlie progression from CKD to renal failure. Perfluorocarbons are potent oxygen transporters used in organ preservation and synthetic blood development. Data are scarce on their relationship with kidney function, especially in diabetes where anemia and hypoxia are more prevalent. We investigated the relationship of perfluoroalkyl acids (PFAS) with kidney function and variation by diabetes and anemia status. Methods: Data on 53,650 adults (5,210 with diabetes) were obtained from the C8 Health Project. CKD was defined as an estimated glomerular filtration rate (eGFR) \u3c60 mL/min/1.73 m2. Four PFAS were investigated: perfluorohexane sulfonate (PFHxS), perfluorooctanoic acid, perfluorooctane sulfonate, and perfluorononanoic acid. Findings: Each PFAS was positively associated with eGFR among those with CKD or anemia; this was the strongest among those with both CKD and anemia, followed by those with CKD uncomplicated by anemia. These relationships were more pronounced among those with diabetes (all P\u3c0.01). In the absence of both CKD and anemia, PFAS was inversely associated with eGFR. Among persons with both anemia and diabetes, when further stratified by CKD stage, compared to an eGFR \u3c30, ORs (95% CI) for being in the eGFR ≥ 90, 60–89, 45–59, and 30–45 range, respectively, were 3.20 (2.00–5.13), 2.64 (1.83–3.80), 3.18 (2.17–4.67), and 1.99 (1.38–2.86) for each ng/dL increase in PFHxS. Results were similar for each PFAS. Interpretation: PFAS are inversely associated with kidney function in CKD and diabetes, with a stronger relation observed when anemia is present

Persistent Polypharmacy and Fall Injury Risk: The Health, Aging and Body Composition Study

Background Older adults receive treatment for fall injuries in both inpatient and outpatient settings. The effect of persistent polypharmacy (i.e. using multiple medications over a long period) on fall injuries is understudied, particularly for outpatient injuries. We examined the association between persistent polypharmacy and treated fall injury risk from inpatient and outpatient settings in community-dwelling older adults. Methods The Health, Aging and Body Composition Study included 1764 community-dwelling adults (age 73.6 ± 2.9 years; 52% women; 38% black) with Medicare Fee-For-Service (FFS) claims at or within 6 months after 1998/99 clinic visit. Incident fall injuries (N = 545 in 4.6 ± 2.9 years) were defined as the initial claim with an ICD-9 fall E-code and non-fracture injury, or fracture code with/without a fall code from 1998/99 clinic visit to 12/31/08. Those without fall injury (N = 1219) were followed for 8.1 ± 2.6 years. Stepwise Cox models of fall injury risk with a time-varying variable for persistent polypharmacy (defined as ≥6 prescription medications at the two most recent consecutive clinic visits) were adjusted for demographics, lifestyle characteristics, chronic conditions, and functional ability. Sensitivity analyses explored if persistent polypharmacy both with and without fall risk increasing drugs (FRID) use were similarly associated with fall injury risk. Results Among 1764 participants, 636 (36%) had persistent polypharmacy over the follow-up period, and 1128 (64%) did not. Fall injury incidence was 38 per 1000 person-years. Persistent polypharmacy increased fall injury risk (hazard ratio [HR]: 1.31 [1.06, 1.63]) after adjusting for covariates. Persistent polypharmacy with FRID use was associated with a 48% increase in fall injury risk (95%CI: 1.10, 2.00) vs. those who had non-persistent polypharmacy without FRID use. Risks for persistent polypharmacy without FRID use (HR: 1.22 [0.93, 1.60]) and non-persistent polypharmacy with FRID use (HR: 1.08 [0.77, 1.51]) did not significantly increase compared to non-persistent polypharmacy without FRID use. Conclusions Persistent polypharmacy, particularly combined with FRID use, was associated with increased risk for treated fall injuries from inpatient and outpatient settings. Clinicians may need to consider medication management for FRID and other fall prevention strategies in community-dwelling older adults with persistent polypharmacy to reduce fall injury risk

Caffeine Consumption Contributes to Skin Intrinsic Fluorescence in Type 1 Diabetes.

Background: A variant (rs1495741) in the gene for the N-acetyltransferase 2 (NAT2) protein is associated with skin intrinsic fluorescence (SIF), a noninvasive measure of advanced glycation end products and other fluorophores in the skin. Because NAT2 is involved in caffeine metabolism, we aimed to determine whether caffeine consumption is associated with SIF and whether rs1495741 is associated with SIF independently of caffeine. Materials and Methods: SIF was measured in 1,181 participants with type 1 diabetes from the Epidemiology of Diabetes Interventions and Complications study. Two measures of SIF were used: SIF1, using a 375-nm excitation light-emitting diode (LED), and SIF14 (456-nm LED). Food frequency questionnaires were used to estimate mean caffeine intake. To establish replication, we examined a second type 1 diabetes cohort. Results: Higher caffeine intake was significantly associated with higher SIF1LED 375 nm[0.6, 0.2] (P=2×10−32) and SIF14LED 456 nm[0.4, 0.8] (P=7×10−31) and accounted for 4% of the variance in each after adjusting for covariates. When analyzed together, caffeine intake and rs1495741 both remained highly significantly associated with SIF1LED 375 nm[0.6, 0.2] and SIF14LED 456 nm[0.4, 0.8]. Mean caffeinated coffee intake was also positively associated with SIF1LED 375 nm[0.6, 0.2] (P=9×10−12) and SIF14LED 456 nm[0.4, 0.8] (P=4×10−12), but no association was observed for decaffeinated coffee intake. Finally, caffeine was also positively associated with SIF1LED 375 nm[0.6, 0.2] and SIF14LED 456 nm[0.4, 0.8] (P\u3c0.0001) in the replication cohort. Conclusions: Caffeine contributes to SIF. The effect of rs1495741 on SIF appears to be partially independent of caffeine consumption. Because SIF and coffee intake are each associated with cardiovascular disease, our findings suggest that accounting for coffee and/or caffeine intake may improve risk prediction models for SIF and cardiovascular disease in individuals with diabetes

A Targeted Multiomics Approach to Identify Biomarkers Associated with Rapid eGFR Decline in Type 1 Diabetes

Background: Individuals with type 1 diabetes (T1D) demonstrate varied trajectories of estimated glomerular filtration rate (eGFR) decline. The molecular pathways underlying rapid eGFR decline in T1D are poorly understood, and individual-level risk of rapid eGFR decline is difficult to predict. Methods: We designed a case-control study with multiple exposure measurements nested within 4 well-characterized T1D cohorts (FinnDiane, Steno, EDC, and CACTI) to identify biomarkers associated with rapid eGFR decline. Here, we report the rationale for and design of these studies as well as results of models testing associations of clinical characteristics with rapid eGFR decline in the study population, upon which "omics" studies will be built. Cases (n = 535) and controls (n = 895) were defined as having an annual eGFR decline of >= 3 andPeer reviewe

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes

Background Rare variants ingenecodingregions likely have agreater impactondisease-relatedphenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage. Methods Gene-basedexome array analyses of15,449genes infivelarge incidence cohortsof individualswith type 1diabetes andproteinuriawere analyzedfor survival time toESKD, testing the top gene in a sixth cohort (n52372/1115 events all cohorts) and replicating in two retrospective case-control studies (n51072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. Results Protein coding variants in the hydroxysteroid 17- b dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (n54196; P value53.331027). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies. Conclusions HSD17B14 gene ismechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.Peer reviewe