Prevalence and prognostic impact of physical frailty in interstitial lung disease: A prospective cohort study.

BACKGROUND AND OBJECTIVE: Physical frailty is associated with increased mortality and hospitalizations in older adults. We describe the prevalence of physical frailty and its prognostic impact in patients with a spectrum of fibrotic interstitial lung disease (ILD). METHODS: Patients with fibrotic ILD at the McMaster University ILD programme were prospectively followed up from November 2015 to March 2020. Baseline data were used to classify patients as non-frail (score = 0), pre-frail (score = 1-2) or frail (score = 3-5) based on modified Fried physical frailty criteria. The association between physical frailty and mortality was assessed using time-to-event models, adjusted for age, sex, lung function and diagnosis using the ILD Gender-Age-Physiology (ILD-GAP) score. RESULTS: We included 463 patients (55% male, mean [SD] age 68 [11] years); 82 (18%) were non-frail, 258 (56%) pre-frail and 123 (26%) frail. The most common ILD diagnoses were idiopathic pulmonary fibrosis (n = 183, 40%) and connective tissue disease-associated-ILD (n = 79, 17%). Mean time since diagnosis was 2.7 ± 4.6 years. There were 56 deaths within the median follow-up of 1.71 (interquartile range [IQR] 1.24, 2.31) years. Both frail and pre-frail individuals had a higher risk of death compared to those categorized as non-frail at baseline (adjusted hazard ratio [aHR] 4.14, 95% CI 1.27-13.5 for pre-frail and aHR 4.41, 95% CI 1.29-15.1 for frail). CONCLUSION: Physical frailty is prevalent in patients with ILD and is independently associated with an increased risk of death. Assessment of physical frailty provides additional prognostic value to recognized risk scores such as the ILD-GAP score, and may present a modifiable target for intervention.

Renal Hemodynamic Function and RAAS Activation Over the Natural History of Type 1 Diabetes.

RATIONALE & OBJECTIVE: The renin-angiotensin-aldosterone system (RAAS) is associated with renal and cardiovascular disease in diabetes. Unfortunately, early RAAS blockade in patients with type 1 diabetes mellitus (T1DM) does not prevent the development of complications. We sought to examine the role of hyperfiltration and RAAS activation across a wide range of T1DM duration to better understand renal hemodynamic status in patients with T1DM. STUDY DESIGN: Post hoc analysis of blood samples. SETTING & PARTICIPANTS: 148 Canadian patients with T1DM: 28 adolescents (aged 16.2±2.0 years), 54 young adults (25.4±5.6 years), and 66 older adults (65.7±7.5 years) studied in a clinical investigation unit. EXPOSURE: Angiotensin II infusion (1ng/kg/min; a measure of RAAS activation) during a euglycemic clamp. OUTCOMES: Glomerular filtration rate measured using inulin clearance, effective renal plasma flow measured using para-aminohippurate, afferent (RA) and efferent (RE) arteriolar resistances, and glomerular hydrostatic pressure estimated using the Gomez equations. RESULTS: In a stepwise fashion, glomerular filtration rate, effective renal plasma flow, and glomerular hydrostatic pressure were higher, while renal vascular resistance and RA were lower in adolescents versus young adults versus older adults. RE was similar in adolescents versus young adults but was higher in older adults. Angiotensin II resulted in blunted renal hemodynamic responses in older adults (renal vascular resistance increase of 3.3% ± 1.6% vs 4.9% ± 1.9% in adolescents; P<0.001), suggesting a state of enhanced RAAS activation. LIMITATIONS: Homogeneous study participants limit the generalizability of findings to other populations. Studying older adult participants with T1DM may be associated with a survivorship bias. CONCLUSIONS: A state of relatively low RAAS activity and predominant afferent dilation rather than efferent constriction characterize early adolescents and young adults with T1DM. This state of endogenous RAAS inactivity in early T1DM may explain why pharmacologic blockade of this neurohormonal system is often ineffective in reducing kidney disease progression in this setting. Older adults with long-standing T1DM who have predominant afferent constriction and RAAS activation may experience renoprotection from therapies that target the afferent arteriole. Further work is required to understand the potential role of non-RAAS pharmacologic agents that target RA in patients with early and long-standing T1DM.

Association between uric acid, renal haemodynamics and arterial stiffness over the natural history of type 1 diabetes.

AIMS: To examine the relationship between normal plasma uric acid (PUA) levels, renal haemodynamic function, arterial stiffness and plasma renin and aldosterone over a wide range of type 1 diabetes (T1D) durations in adolescents, young adults and older adults. MATERIALS AND METHODS: PUA, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), vascular stiffness parameters (aortic augmentation index [AIx], carotid AIx, carotid femoral pulse wave velocity [cfPWV]), and plasma renin and aldosterone were measured during a euglycaemic clamp in people with T1D: 27 adolescents (mean ± SD age 16.8 ± 1.9 years), 52 young adults (mean ± SD age 25.6 ± 5.5 years) and 66 older adults (mean ± SD age 65.7 ± 7.5 years). RESULTS: PUA was highest in patients with the longest T1D duration: 197 ± 44 µmol/L in adolescents versus 264 ± 82 µmol/L in older adults (P < 0.001). Higher PUA correlated with lower GFR only in older adults, even after correcting for age, glycated haemoglobin and sex (ß = -2.12 ± 0.56; P = 0.0003), but not in adolescents or young adults. Higher PUA correlated with lower carotid AIx (ß = -1.90, P = 0.02) in adolescents. In contrast, PUA correlated with higher cfPWV (P = 0.02) and higher plasma renin (P = 0.01) in older adults with T1D. CONCLUSIONS: The relationship between higher PUA with lower GFR, increased arterial stiffness and renin angiotensin aldosterone system (RAAS) activation was observed only in older adults with longstanding T1D. T1D duration may modify the association between PUA, renal haemodynamic function and RAAS activation, leading to renal vasoconstriction and ischaemia. Further work must determine whether pharmacological PUA-lowering prevents or reverses injurious haemodynamic and neurohormonal sequelae of longstanding T1D, thereby improving clinical outcomes.

Risk factors for diabetic kidney disease in adults with longstanding type 1 diabetes: results from the Canadian Study of Longevity in Diabetes.

Objectives: Diabetic kidney disease (DKD) is an independent predictor of cardiovascular morbidity and mortality in type 1 diabetes (T1D). We aimed to explore clinical and biochemical factors, including the achievement of American Diabetes Association (ADA) recommended targets associated with DKD in people living with T1D for ≥50 years. Methods: This was a post hoc analysis of a cross-sectional study of 75 participants enrolled in the Canadian Study of Longevity in T1D. We explored diabetes-related complications, including neuropathy, retinopathy, cardiovascular disease, and DKD. Study participants were dichotomized based on the achievement of ADA recommended targets as the low-target group (achieving ≤4 targets, n = 31) and high-target group (achieving >4 targets, n = 44). The outcome of interest was DKD defined by estimated glomerular filtration rate (eGFR) values <60/mL/min/1.73 m2 and/or 24-h albumin excretion >30 mg. Multivariable logistic regression models were employed to estimate odds ratios (ORs) for DKD with 95% confidence intervals (CIs). Results: Of the 75 participants with prolonged T1D duration (45% male, mean age 66 years), 25 participants had DKD and 50 did not. There was no statistical difference between the high- and low-target groups in terms of age and body mass index. eGFR was significantly higher and the prevalence of diabetic retinopathy was significantly lower in the high-target group. Older age at diagnosis of T1D and lower frequency component to high-frequency component ratio increased the odds of having DKD. Conclusions: In adults with prolonged T1D duration, older age at diagnosis and lower heart rate variability may be associated with DKD.

Renal hemodynamic dysfunction and neuropathy in longstanding type 1 diabetes: Results from the Canadian study of longevity in type 1 diabetes.

AIMS: To determine the relationship between renal hemodynamic function and neuropathy in adults with ≥50-years of type 1 diabetes (T1D) compared to nondiabetic controls. METHODS: Glomerular filtration rate (GFR, inulin), effective renal plasma flow (ERPF, p-aminohippurate), modified Toronto Clinical Neuropathy Score (mTCNS), corneal confocal microscopy, nerve conduction, and heart rate variability (autonomic function) were measured; afferent (RA) and efferent (RE) arteriolar resistances were estimated using the Gomez equations in 74 participants with T1D and in 75 controls. Diabetic kidney disease (DKD) non-resistors were defined by eGFRMDRD < 60 ml/min/1.73 m2 or 24-h urine albumin excretion >30 mg/day. Linear regression was applied to examine the relationships between renal function (dependent variable) and neuropathy measures (independent variable), adjusted for age, sex, HbA1c, systolic blood pressure, low density lipoprotein cholesterol, and 24-h urine albumin to creatinine ratio. RESULTS: Higher mTCNS associated with lower renal blood flow (ß ± SE:-9.29 ± 4.20, p = 0.03) and greater RE (ß ± SE:32.97 ± 15.43, p = 0.04) in participants with T1D, but not in controls. DKD non-resistors had a higher mTCNS and worse measures of corneal nerve morphology compared to those without DKD. Renal hemodynamic parameters did not associate with autonomic nerve function. CONCLUSIONS: Although neurological dysfunction in the presence of diabetes may contribute to impaired renal blood flow resulting in ischemic injury in patients with T1D, early autonomic dysfunction does not appear to be associated with kidney function changes.

Temperature control in critically ill patients with fever: A meta-analysis of randomized controlled trials.

PURPOSE: Fever is frequently encountered in ICU. It is unclear if targeted temperature control is beneficial in critically ill patients with suspected or confirmed infection. We conducted a systemic review and meta-analysis to answer this question. METHODS: We systematically reviewed major databases before January 2020 to identify randomized controlled trials (RCTs) that compared antipyretic with placebo for temperature control in non-neurocritical ill adult patients with suspected or confirmed infection. Outcomes of interest were 28-day mortality, temperature level, hospital mortality, length of stay, shock reversal, and patient comfort. RESULT: 13 RCTs enrolling 1963 patients were included. No difference in 28-day mortality between antipyretic compared with placebo (risk ratio [RR] 1.03; 95% CI 0.79-1.35). Lower temperature levels were achieved in the antipyretic group (MD [mean difference] -0.41; 95% CI -0.66 to -0.16). Antipyretic use did not affect the risk of hospital mortality (RR 0.97; 95% CI 0.73-1.30), ICU length of stay (MD -0.07; 95% CI -0.70 to 0.56), or shock reversal (RR 1.11; 95% CI 0.76-1.62). CONCLUSION: Antipyretic therapy effectively reduces temperature in non-neurocritical ill patients but does not reduce mortality or impact other outcomes.

Accumulation of Deficits as a Key Risk Factor for Cardiovascular Morbidity and Mortality: A Pooled Analysis of 154 000 Individuals.

Background Frailty is associated with higher mortality in individuals at high cardiovascular disease (CVD) risk. We hypothesize that frailty is a more important prognostic factor than CVD risk factors and aim to determine the prognostic value of a cumulative deficit frailty index in patients with or at high risk for CVD. Methods and Results We conducted an individual-level pooled analysis of participants with or at risk for CVD, recruited in 14 multicenter clinical trials. The cumulative deficit index was calculated as the proportion of 26 deficits exhibited. Individuals were categorized as nonfrail, prefrail, or frail if they had indexes of ≤0.1, >0.1 to 0.21, or >0.21, respectively. CVD risk was assessed using the Framingham score. Outcomes included CVD event (new or recurrent myocardial infarction, stroke, or heart failure) and mortality. We studied 154 696 patients (mean age, 70.8 years; 63% men) with median follow-up of 3.2 years. There were 17 535 CVD events and 15 067 deaths. The frail group (n=13 872) had higher risk of a CVD event (incidence rate ratio, 1.97; 95% CI, 1.85-2.08), all-cause mortality (hazard ratio, 1.91; 95% CI, 1.79-2.03), and CVD mortality (hazard ratio, 1.91; 95% CI, 1.77-2.05) than the nonfrail group (n=101 343). Associations remained unchanged after adjusting for CVD risk factors. The index statistically outperformed the Framingham score in its ability to discriminate CVD events (C-statistic, 0.60 [95% CI, 0.60-0.61] versus 0.58 [95% CI, 0.57-0.58], respectively; P<0.001). Conclusions In individuals with or at high risk of developing CVD, the cumulative deficit index is associated with increased CVD events and mortality, independent of CVD risk factors, and adds incremental prognostic value.

Investigations and management of chronic cough: a 2020 update from the European Respiratory Society Chronic Cough Task Force.

Chronic cough affects approximately 10% of the general population, is highest amongst people aged 50 to 60 years, and is twice as common in women than men. It is described to last 8 weeks or longer in adults and does not respond well to treatment with over-the-counter medications and those targeting potential associated conditions. This is a debilitating condition with physical, social, and psychological consequences. The purpose of this review was to highlight the key messages on the management of chronic cough from the task force commissioned by the European Respiratory Society. The assessment of patients with chronic cough should include a thorough detailed history and examination to identify potential causes. The impact and severity can be assessed in a clinic using questionnaires. Potential causes of the condition vary and include, for example, angiotensin­converting enzyme inhibitors, smoking, asthma, nonasthmatic eosinophilic bronchitis, gastroesophageal reflux disease, and upper airways cough syndrome. In many patients, coughing is persistent despite optimum medical therapy of the underlying medical condition and is hence referred to as refractory chronic cough. In some cases, no cause can be found and the cough is classified as unexplained chronic cough. If treatment of any underlying disease is unsuccessful at controlling cough, then neuromodulatory treatment such as a low­dose opioid, gabapentin, pregabalin or speech and language therapy may be considered. There is no licensed treatment for chronic cough, but a new class of treatment targeting the purinergic P2X3 receptor is currently in phase 2 and 3 of development.

Estimating GFR by Serum Creatinine, Cystatin C, and ß2-Microglobulin in Older Adults: Results From the Canadian Study of Longevity in Type 1 Diabetes.

INTRODUCTION: Glomerular filtration rate (GFR) is routinely used for clinical assessment of kidney function. However, the accuracy of estimating equations in older adults is uncertain. METHODS: In 66 adults with ≥50 years type 1 diabetes (T1D) duration and 73 nondiabetic controls from age/sex-matched subgroups (65 ± 8 years old and 77[55%] were women) we evaluated the performance of estimated GFR (eGFR) by creatinine (Modification of Diet and Renal Disease [MDRD], Chronic Kidney Disease-Epidemiology [CKD-EPI]cr), cystatin C (CKD-EPIcys, CKD-EPIcr-cys), and ß2-microglobulin (ß2M) compared with measured GFR by inulin clearance (mGFR). Performance was evaluated using metrics of bias (mean difference), precision (SD), and accuracy (proportion of eGFR that differed by >20% of mGFR). RESULTS: Mean mGFR was 104 ± 18 ml/min per 1.73 m2 (range: 70-154 ml/min per 1.73 m2) and was not different between T1D and controls (103 ± 17 vs. 105 ± 19 ml/min per 1.73 m2, P = 0.39). All equations significantly underestimated mGFR (bias: -15 to -30 ml/min per 1.73 m2, P < 0.001 for all comparisons) except for ß2M, which had bias of 1.9 ml/min per 1.73 m2 (P = 0.61). Bias was greatest in cystatin C-based equations. Precision was lowest for ß2M (SD: 43.5 ml/min per 1.73 m2, P < 0.001 for each comparison). Accuracy was lowest for CKD-EPIcysC (69.1%, P < 0.001 for each comparison). Cystatin C-based equations demonstrated greater bias and lower accuracy in older age subgroups (<60, 60-69, ≥70 years). All equations demonstrated greater bias across higher ranges of mGFR (60-89, 90-119, ≥120 ml/min per 1.73 m2). Results were similar between T1D and controls except that ß2M had lower performance in T1D. CONCLUSION: Better estimates of GFR in older adults are needed for research and clinical practice, as this subgroup of the population has an amplified risk for the development of chronic kidney disease (CKD) that requires accurate GFR estimation methods.

Elevated plasma cyclic guanosine monophosphate may explain greater efferent arteriolar tone in adults with longstanding type 1 diabetes: A brief report.

Cyclic guanosine monophosphate (cGMP) influences intrarenal hemodynamics in animal models, but the relationship between cGMP and renal function in adults with type 1 diabetes (T1D) remains unclear. In this study, plasma cGMP correlated with efferent arteriolar resistance, effective renal plasma flow, and renal vascular resistance in adults with T1D.

Statin therapy in the treatment of active cancer: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Preclinical evidence suggests statins may have anti-tumor properties. Large observational studies are also consistent with improved survival and cancer-specific outcomes among cancer patients on statins. We sought to evaluate the randomized controlled trials of statins in addition to usual anti-cancer therapy. METHODS: A systematic search of MEDLINE, Embase, CINAHL, Cochrane Library, Web of Science, Papers First and Clinicaltrials.gov was performed from inception through to July 4, 2017 to identify randomized clinical trials that investigated statin therapy in cancer patients. Our primary outcome was overall survival and our secondary outcome was progression-free survival. We calculated summary hazard ratio's (HR) and 95% confidence intervals (CI) based on random-effects models using aggregate data. PROSPERO (CRD42017065503). RESULTS: Ten studies with 1,881 individuals were included with 1,572 deaths and a median follow-up of 23 months. All trials included patients with advanced (stage 3 or higher) disease. There was minimal between-study statistical heterogeneity (I2 = 1.8%, for OS; I2 = 0%, for PFS). The pooled HR for overall survival in patients randomized to statins plus standard anti-cancer therapy versus standard therapy alone was 0.94 (95% CI, 0.85 to 1.04). In the 9 studies that reported progression-free survival (1,798 participants), the pooled HR for statin plus standard therapy versus standard therapy alone was 0.97 (95% CI, 0.87 to 1.07). CONCLUSIONS: In patients with advanced cancer and a prognosis <2 years, the addition of statins to standard anti-cancer therapy does not appear to improve overall survival or progression-free survival. Future research should assess if cancer patients with better prognosis benefit from longer-term statin therapy.

Diabetes Care Disparities in Long-standing Type 1 Diabetes in Canada and the U.S.: A Cross-sectional Comparison.

OBJECTIVE: To assess national differences in diabetes care and quality of life (QOL) between individuals with long-standing type 1 diabetes (≥50 years) in Canada and the U.S. RESEARCH DESIGN AND METHODS: Cross-sectional data from identical surveys administered in the Canadian Study of Longevity in Diabetes and the Joslin Medalist Study, collected in 2013-2016 and 2005-2011, respectively, were compared. Laboratory values and ophthalmic examination were completed by clinical care physicians for Canadians and the Joslin Clinic for Americans. Univariate comparisons and multivariable regression for HbA1c, QOL, insulin pump use, and coronary artery disease (CAD) were performed. Nephropathy, CAD, and peripheral arterial disease (PAD) were self-reported; neuropathy was defined by a Michigan Neuropathy Screening Instrument (Questionnaire component) score ≥3, and proliferative retinopathy was documented from ophthalmic examination. QOL was self-reported on an ordinal scale. RESULTS: Three hundred sixty-one Canadians and 668 Americans had similar ages (mean 65.78 years [SD 8.67] vs. 66.38 years [7.66], P = 0.27) and durations of diabetes (median 53.00 years [interquartile range 51.00, 58.00] vs. 53.00 years [51.00, 57.00], P = 0.51). Canadians had higher HbA1c (mean 7.53% [SD 1.03] [59 mmol/mol] vs. 7.22% [0.98] [55 mmol/mol], P < 0.0001), lower QOL (36.9% vs. 48.7% with "excellent" QOL, P = 0.0002), and less CAD (29.7% vs. 41.2%, P = 0.0003) and insulin pump use (43.3% vs. 55.6%, P = 0.0002). Other complication rates were similar. Residual differences for Canadians compared with Americans remained after adjustment for age, sex, CAD, PAD, education, and relevant a priori selected variables: 0.28% higher HbA1c (P = 0.0004); and odds ratios of 0.68 (95% CI 0.51, 0.90), 0.46 (0.31, 0.68), and 0.71 (0.52, 0.96) for higher QOL, CAD, and insulin pump use, respectively. CONCLUSIONS: Although Canadians and Americans have similar rates of complications other than CAD, further research is required to understand why Canadians have higher HbA1c levels, lower QOL, and less insulin pump use.

Validity of a point-of-care nerve conduction device for polyneuropathy identification in older adults with diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes.

OBJECTIVE: Point-of-care nerve conduction devices (POCD) have been studied in younger patients and may facilitate screening for polyneuropathy in non-specialized clinical settings. However, performance may be impaired with advanced age owing to age-related changes in nerve conduction. We aimed to evaluate the validity of a POCD as a proxy for standard nerve conduction studies (NCS) in older adults with type 1 diabetes (T1D). METHODS: Sural nerve amplitude potential (AMP) and sural nerve conduction velocity (CV) was measured in 68 participants with ≥ 50 years T1D duration and 71 controls (from age/sex-matched subgroups) using POCD and NCS protocols. Agreement was determined by the Bland-Altman method, and validity was determined by receiver operating characteristic curves. RESULTS: T1D were 53% female, aged 66±8yr and had diabetes duration 54yr[52,58]. Controls were 56%(p = 0.69) female and aged 65±8yr(p = 0.36). Mean AMPPOCD and CVPOCD for the 139 participants was 7.4±5.8µV and 45.7±11.2m/s and mean AMPNCS and CVNCS was 7.2±6.1µV and 43.3±8.3m/s. Mean difference of AMPPOCD-AMPNCS was 0.3±3.8µV and was 2.3±8.5m/s for CVPOCD-CVNCS. A AMPPOCD of ≤6µV had 80% sensitivity and 80% specificity for identifying abnormal AMPNCS, while a CVPOCD of ≤44m/s had 81% sensitivity and 82% specificity to identify abnormal CVNCS. Abnormality in AMPPOCD or CVPOCD was associated with 87% sensitivity, while abnormality in both measures was associated with 97% specificity for polyneuropathy identification. CONCLUSIONS: The POCD has strong agreement and diagnostic accuracy for identification of polyneuropathy in a high-risk subgroup and thus may represent a sufficiently accurate and rapid test for routinely detecting those with electrophysiological dysfunction.

Atherosclerosis and Microvascular Complications: Results From the Canadian Study of Longevity in Type 1 Diabetes.

OBJECTIVE: Type 1 diabetes carries a significant risk for cardiovascular mortality, but it is unclear how atherosclerosis associates with microvascular complications. We aimed to determine the relationships between atherosclerotic burden and neuropathy, retinopathy, and diabetic kidney disease (DKD) in adults with a ≥50-year history of type 1 diabetes. RESEARCH DESIGN AND METHODS: Adults with type 1 diabetes (n = 69) underwent coronary artery calcification (CAC) volume scoring by wide-volume computerized tomography. Microvascular complications were graded as follows: neuropathy by clinical assessment, electrophysiology, vibration and cooling detection thresholds, heart rate variability, and corneal confocal microscopy; retinopathy by ultra-wide-field retinal imaging; and DKD by renal hemodynamic function measured by inulin and para-aminohippurate clearance at baseline and after intravenous infusion of angiotensin II. The cohort was dichotomized to high (≥300 Agatston units [AU]) or low (<300 AU) CAC and was stratified by diabetes status. A comparator group without diabetes (n = 73) matched for age and sex also underwent all study procedures except for retinal imaging. RESULTS: CAC scores were higher in participants with type 1 diabetes (median Agatston score 1,000 [interquartile range = 222, 2,373] AU vs. 1 [0.75] AU in comparators, P < 0.001). In participants with type 1 diabetes, high CAC scores associated with markers of neuropathy and retinopathy, but not with DKD, or renal hemodynamic function at baseline or in response to angiotensin II. CONCLUSIONS: The presence of high CAC in adults with longstanding type 1 diabetes was associated with large nerve fiber neuropathy and retinopathy but not with renal hemodynamic function, suggesting that neuropathy, retinopathy, and macrovascular calcification share common risk factors.

Renin-angiotensin-aldosterone system activation in long-standing type 1 diabetes.

BACKGROUND: In type 1 diabetes (T1D), adjuvant treatment with inhibitors of the renin-angiotensin-aldosterone system (RAAS), which dilate the efferent arteriole, is associated with prevention of progressive albuminuria and renal dysfunction. Uncertainty still exists as to why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). We hypothesized that those with DKD would be distinguished from DKD resistors by the presence of RAAS activation. METHODS: Renal and systemic hemodynamic function was measured before and after exogenous RAAS stimulation by intravenous infusion of angiotensin II (ANGII) in 75 patients with prolonged T1D durations and in equal numbers of nondiabetic controls. The primary outcome was change in renal vascular resistance (RVR) in response to RAAS stimulation, a measure of endogenous RAAS activation. RESULTS: Those with DKD had less change in RVR following exogenous RAAS stimulation compared with DKD resistors or controls (19%, 29%, 31%, P = 0.008, DKD vs. DKD resistors), reflecting exaggerated endogenous renal RAAS activation. All T1D participants had similar changes in renal efferent arteroilar resistance (9% vs. 13%, P = 0.37) irrespective of DKD status, which reflected less change versus controls (20%, P = 0.03). In contrast, those with DKD exhibited comparatively less change in afferent arteriolar vascular resistance compared with DKD resistors or controls (33%, 48%, 48%, P = 0.031, DKD vs. DKD resistors), indicating higher endogenous RAAS activity. CONCLUSION: In long-standing T1D, the intrarenal RAAS is exaggerated in DKD, which unexpectedly predominates at the afferent rather than the efferent arteriole, stimulating vasoconstriction. FUNDING: JDRF operating grant 17-2013-312.

Adiposity Impacts Intrarenal Hemodynamic Function in Adults With Long-standing Type 1 Diabetes With and Without Diabetic Nephropathy: Results From the Canadian Study of Longevity in Type 1 Diabetes.

OBJECTIVE: Central adiposity is considered to be an important cardiorenal risk factor in the general population and in type 1 diabetes. We sought to determine the relationship between central adiposity and intrarenal hemodynamic function in adults with long-standing type 1 diabetes with and without diabetic nephropathy (DN). RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes (n = 66, duration ≥50 years) and age-/sex-matched control subjects (n = 73) were studied. The cohort was stratified into 44 DN Resistors (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2 and <30 mg/day urine albumin) and 22 patients with DN (eGFR ≤60 mL/min/1.73 m2 or ≥30 mg/day urine albumin). Intrarenal hemodynamic function (glomerular filtration rate for inulin [GFRINULIN], effective renal plasma flow for p-aminohippuric acid [ERPFPAH]) was measured. Afferent arteriolar resistance, efferent arteriolar resistance, renal blood flow, renal vascular resistance [RVR], filtration fraction, and glomerular pressure were derived from the Gomez equations. Fat and lean mass were quantified by DXA. RESULTS: Whereas measures of adiposity did not associate with GFRINULIN or ERPFPAH in healthy control subjects, trunk fat mass inversely correlated with GFRINULIN (r = -0.46, P < 0.0001) and ERPFPAH (r = -0.31, P = 0.01) and positively correlated with RVR (r = 0.53, P = 0.0003) in type 1 diabetes. In analyses stratified by DN status, greater central adiposity related to lower GFRINULIN values in DN and DN Resistors, but the relationships between central adiposity and ERPFPAH and RVR were attenuated and/or reversed in patients with DN compared with DN Resistors. CONCLUSIONS: The adiposity-intrarenal hemodynamic function relationship may be modified by the presence of type 1 diabetes and DN, requiring further study of the mechanisms by which adiposity influences renal hemodynamic function.

Sex differences in neuropathic pain in longstanding diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes.

AIM: Neuropathy and neuropathic pain are common complications of type 1 diabetes (T1D). We aimed to determine if sex-specific differences in neuropathic pain are present in adults with longstanding T1D. METHODS: Canadians with ≥50 years of T1D (n = 361) completed health history questionnaires that included assessment of neuropathy (defined by Michigan Neuropathy Screening Instrument questionnaire components ≥3; NEUROPATHYMNSI-Q) and neuropathic pain. Multivariable logistic regression was used to determine sex-differences in neuropathic pain controlling for neuropathy. RESULTS: Participants had mean age 66 ±â€¯9 years, median diabetes duration 53[51,58] years, mean HbA1c 7.5 ±â€¯1.0%, and 207(57%) were female. Neuropathic pain was present in 128(36%) of all participants, more prevalent among those with NEUROPATHYMNSI-Q compared to those without [96(63%) vs. 31(15%), p < 0.001], and more prevalent in females compared to males [87(42%) vs. 41(27%), p = 0.003]. Independent of the presence of NEUROPATHYMNSI-Q and other factors, female sex was associated with the presence of neuropathic pain [OR 2.68 (95% CI 1.4-5.0), p = 0.002]. CONCLUSIONS: We demonstrated a novel sex-specific difference in neuropathic pain in females compared to males with longstanding T1D, independent of the presence of neuropathy. Further research using more objective measures of neuropathy than the MNSI is justified to further understand this sex-specific difference.

Agreement between automated and manual quantification of corneal nerve fiber length: Implications for diabetic neuropathy research.

AIMS: Quantification of corneal nerve fiber length (CNFL) by in vivo corneal confocal microscopy represents a promising diabetic neuropathy biomarker, but applicability is limited by resource-intensive image analysis. We aimed to evaluate, in cross-sectional analysis of non-diabetic controls and patients with type 1 and type 2 diabetes with and without neuropathy, the agreement between manual and automated analysis protocols. METHODS: Sixty-eight controls, 139 type 1 diabetes, and 249 type 2 diabetes participants underwent CNFL measurement (N=456). Neuropathy status was determined by clinical and electrophysiological criteria. CNFL was determined by manual (CNFLManual, reference standard) and automated (CNFLAuto) protocols, and results were compared for correlation and agreement using Spearman coefficients and the method of Bland and Altman (CNFLManual subtracted from CNFLAuto). RESULTS: Participants demonstrated broad variability in clinical characteristics associated with neuropathy. The mean age, diabetes duration, and HbA1c were 53±18years, 15.9±12.6years, and 7.4±1.7%, respectively, and 218 (56%) individuals with diabetes had neuropathy. Mean CNFLManual was 15.1±4.9mm/mm2, and mean CNFLAuto was 10.5±3.7mm/mm2 (CNFLAuto underestimation bias, -4.6±2.6mm/mm2 corresponding to -29±17%). Percent bias was similar across non-diabetic controls (-33±12%), type 1 (-30±20%), and type 2 diabetes (-28±16%) subgroups (ANOVA, p=0.068), and similarly in diabetes participants with and without neuropathy. Levels of CNFLAuto and CNFLManual were both inversely associated with neuropathy status. CONCLUSIONS: Although CNFLAuto substantially underestimated CNFLManual, its bias was non-differential between diverse patient groups and its relationship with neuropathy status was preserved. Determination of diagnostic thresholds specific to CNFLAuto should be pursued in diagnostic studies of diabetic neuropathy.

Neuropathy and presence of emotional distress and depression in longstanding diabetes: Results from the Canadian study of longevity in type 1 diabetes.

AIM: To determine the association of neuropathy and other complications with emotional distress and depression among patients with longstanding type 1 diabetes (T1DM). METHODS: Canadians with ≥50years of T1DM completed a questionnaire including assessment of distress and depression by the Problem Areas in Diabetes Scale (PAID) and Geriatric Depression Scale (GDS), respectively. Complications were determined using the Michigan Neuropathy Screening Instrument (Questionnaire Component), fundoscopy reports, renal function tests, and self-reported peripheral-(PVD) and cardiovascular (CVD) disease. Associations were analyzed by Poisson regression. RESULTS: Among 323 participants, 137 (42.4%) had neuropathy, 113 (36.5%) nephropathy, 207 (69.5%) retinopathy, 95 (29.4%) CVD, and 31 (9.8%) PVD. The neuropathy subgroup had higher prevalence of distress (13 (9.5%) vs. 6 (3.3%), p=0.029) and depression (34 (24.9%) vs. 12 (6.5%), p<0.001). Adjusting for diabetes complications, neuropathy was associated with higher PAID (adjusted RR 1.44 (95% CI 1.14-1.82), p=0.003) and GDS scores (adjusted RR1.57 (1.18-2.11), p=0.002). Independent of potential confounders, neuropathy remained associated with higher PAID (adjusted RR 1.39 (1.10-1.76), p=0.006) and GDS scores (adjusted RR 1.37 (1.03-1.83), p=0.032). Associations with neuropathy were not fully explained by neuropathic pain. CONCLUSION: Compared to other complications, neuropathy had the greatest association with distress and depression in longstanding T1DM, independent of pain. Strategies beyond pain management are needed to improve quality of life in diabetic neuropathy.