Estimated glomerular filtration rate calculated by serum creatinine lacks precision and accuracy in adults with type 2 diabetes with preserved renal function.

AIMS: We evaluated the performance of creatinine-based equations that are currently used to estimate glomerular filtration rate (GFR) in people with type 2 diabetes compared to measured GFR using gold-standard methods. METHODS: In this post-hoc analysis, 32 participants underwent repeated measurement of GFR by inulin clearance (mGFR). GFR was estimated by serum creatinine using the MDRD (eGFRMDRD) and CKD-EPI (eGFRCKD-EPI) equations four times over the course of one month. Performance was evaluated using measurements of bias (mean difference), precision (SD), and inaccuracy (proportion of eGFR that differed by >20 % of mGFR). Treatment and time effects on bias were evaluated using linear mixed effects models. RESULTS: At baseline, participants (38 % female) were age 60 ± 8 years, had diabetes duration of 9 ± 7 years, HbA1c 56 ± 9 mmol/mol (7.2 ± 0.8 %), and BMI 31.0 ± 6.2 kg/m2. Mean mGFR was 113 ± 24, mean eGFRMDRD was 93 ± 12, and mean eGFRCKD-EPI was 94 ± 9 mL/min/1.73 m2. When 128 observations (32 participants measured 4 times) were evaluated, both equations substantially underestimated mGFR. For eGFRMDRD, mean bias was -21.5 mL/min/1.73 m2, precision was 22.7 mL/min/1.73 m2, and 46 % of observations differed by >20 %. Results were similar for eGFRCKD-EPI. No time or treatment effects on bias were observed. CONCLUSIONS: In adults with type 2 diabetes and preserved renal function, eGFR equations underestimated mGFR, lacked precision and accuracy, and performance was lower at higher ranges of mGFR. Current eGFR equations by serum creatinine are inaccurate in adults with type 2 diabetes with preserved renal function, highlighting the necessity to develop new methods to measure kidney function at earlier stages of diabetic kidney disease.

Baseline Decrement in Patients with Mild Myasthenia Gravis Predicts Immunomodulation Treatment.

To explore whether higher degrees of electrophysiological abnormalities are associated with a more frequent exposure to a more aggressive treatment regimen, we performed a retrospective chart review of patients attending the neuromuscular clinic from June 2012 to December 2015 and included 87 patients. We compared treatment regimens during the follow-up period between patients with high and low jitter and decrement. Myasthenia gravis patients with high jitter or decrement at baseline were more frequently treated with intravenous immunoglobulins (IVIG) and/or plasma exchange (PLEX) during the follow-up period. In patients with mild disease, IVIG or PLEX treatment was associated with high decrement.

La diminution initiale du potentiel moteur de patients atteints de myasthénie grave peut permettre de prédire le type d'immuno-modulation thérapeutique prodiguée. Afin d'explorer dans quelle mesure des niveaux plus élevés d'anomalies électro-physiologiques peuvent être associés à une exposition davantage fréquente à des régimes de traitement plus vigoureux, nous avons effectué un examen rétrospectif des dossiers de patients, 87 au total, s'étant présentés à une clinique neuromusculaire de juin 2012 à décembre 2015. Nous avons alors comparé les régimes de traitement des patients montrant de basses mesures de gigue (jitter) et une faible diminution d'amplitude du potentiel d'action au cours de leur période de suivi avec les régimes de traitement d'autres patients pour qui ces mesures étaient élevées. Les patients atteints de myasthénie grave (MG) dont les mesures de gigue et la diminution d'amplitude du potentiel d'action étaient initialement élevées ont été plus fréquemment traités, lors d'un suivi, avec des immunoglobulines intraveineuses et/ou des échanges plasmatiques. Chez les patients atteints de la forme bénigne de cette maladie, ces deux traitements ont été associés à une diminution d'amplitude du potentiel d'action plus élevée.

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.

The relationships between markers of tubular injury and intrarenal haemodynamic function in adults with and without type 1 diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes.

OBJECTIVE: Our aim was to define the relationships between plasma biomarkers of kidney injury and intrarenal haemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], renal vascular resistance [RVR]) in adults with type 1 diabetes (T1D). METHODS: The study sample comprised patients with longstanding T1D (duration ≥50 years), among whom 44 were diabetic kidney disease (DKD) resistors (eGFR >60 mL/min/1.73 m2 and <30 mg/d urine albumin excretion) and 22 had DKD, in addition to 73 control participants. GFRINULIN and ERPFPAH were measured, RVR was calculated, and afferent (RA )/efferent (RE ) areteriolar resistances were derived from Gomez equations. Plasma neutrophil gelatinase-associated lipocalin (NGAL), ß2 microglobulin (B2M), osteopontin (OPN) and uromodulin (UMOD) were measured using immunoassay kits from Meso Scale Discovery. RESULTS: Plasma NGAL, B2M and OPN were higher and UMOD was lower in DKD patients vs DKD resistors and non-diabetic controls. In participants with T1D, plasma NGAL inversely correlated with GFR (r = -0.33; P = 0.006) and ERPF (r = -0.34; P = 0.006), and correlated positively with RA (r = 0.26; P = 0.03) and RVR (r = 0.31; P = 0.01). In participants without T1D, NGAL and B2M inversely correlated with GFR (NGAL r = -0.18; P = 0.13 and B2M r = -0.49; P < 0.0001) and with ERPF (NGAL r = -0.19; P = 0.1 and B2M r = -0.42; P = 0.0003), and correlated positively with RA (NGAL r = 0.19; P = 0.10 and B2M r = 0.3; P = 0.01) and with RVR (NGAL r = 0.20; P = 0.09 and B2M r = 0.34; P = 0.003). Differences were significant after adjusting for age, sex, HbA1c, SBP and LDL. There were statistical interactions between T1D status, B2M and intrarenal haemodynamic function (P < 0.05). CONCLUSIONS: Elevated NGAL relates to intrarenal haemodynamic dysfunction in T1D, whereas elevated NGAL and B2M relate to intrarenal haemodynamic dysfunction in adults without T1D. These data may define a diabetes-specific interplay between tubular injury and intrarenal haemodynamic dysfunction.

Retinopathy and RAAS Activation: Results From the Canadian Study of Longevity in Type 1 Diabetes.

OBJECTIVE: The importance of renin-angiotensin-aldosterone system (RAAS) activation in retinopathy for long-standing diabetes is not well understood. We determined retinopathy stage and evaluated associations with other vascular complications before and after physiological RAAS activation in adults with long-standing (≥50 years duration) type 1 diabetes. RESEARCH DESIGN AND METHODS: Participants underwent retinal examination by digital funduscopic photography and optical coherence tomography and were classified as having nonproliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), or no diabetic retinopathy (NDR) with or without diabetic macular edema (DME). Neuropathy was measured by clinical neuropathy examination scores, electrophysiologically, and by corneal confocal microscopy. Renal function was measured by inulin and para-aminohippurate clearance methods. Arterial stiffness was measured by applanation tonometry. Renal function, blood pressure, and arterial stiffness were measured before and after RAAS activation with angiotensin II (ANGII). Associations were determined using linear regression. RESULTS: Twelve (16%) of the 75 participants had NDR, 24 (32%) had NPDR, and 39 (52%) had PDR. A low overall prevalence of DME (4%) was observed. Those with PDR had worse nerve function and reduced corneal nerve density, were more likely to have macrovascular disease, and had increased arterial stiffness in response to ANGII compared with those with NPDR or NDR. Prevalence of kidney disease or renal hemodynamic function did not differ by retinopathy status. CONCLUSIONS: PDR was associated with neuropathy severity and cardiovascular and peripheral vascular disease. In those with PDR, RAAS activation may be linked to vascular stiffening, an effect that persists in long-standing type 1 diabetes.

High frequency of MGUS in DSP.

INTRODUCTION: Monoclonal gammopathy has been reported in several polyneuropathies. In this study, we sought to explore the frequency and characteristics of monoclonal gammopathy in patients with diabetic sensorimotor polyneuropathy (DSP). METHODS: Patients with type 1 and type 2 diabetes mellitus (DM 1, DM 2) and controls without diabetes were evaluated between November 2008 and December 2013. RESULTS: Fifty controls, 66 patients with DM 1, and 106 patients with DM 2 were included, with average ages of 43 ± 18, 45 ± 17, and 65 ± 10 years, respectively; the frequency of monoclonal gammopathy was 0%, 8%, and 15%, respectively. In patients with DSP, the frequency of monoclonal gammopathy increased to 14% in DM 1 and 21% in DM 2; the most common monoclonal proteins were immunoglobulin (Ig) M and IgG, respectively. DISCUSSION: DSP might be associated with a high frequency of monoclonal gammopathy, with different characteristics in DM 1 and in DM 2. Muscle Nerve 57: 1018-1021, 2018.

Repetitive nerve stimulation cutoff values for the diagnosis of myasthenia gravis.

INTRODUCTION: Repetitive nerve stimulation (RNS) showing ≥ 10% decrement is considered the cutoff for myasthenia gravis (MG), but this has never been validated. The objective of this study was to find an optimal validated cutoff value for decrement on RNS. METHODS: We performed retrospective chart review of patients who had electrophysiological assessment for possible MG from 2013 to 2015. RESULTS: A total of 122 patients with MG and 182 controls were identified. RNS sensitivities for generalized and ocular MG using the traditional ≥10% cutoff value were 46% and 15%, respectively, for frontalis recordings, and 35% and 19%, respectively, for nasalis recordings. Using a decrement cutoff value of 7% for frontalis and 8% for nasalis increased the sensitivities by 6-11%, with specificities of 95-96%. CONCLUSIONS: For RNS in facial muscles, we suggest a cutoff value of 7-8%, which increases test sensitivity by 6-11%, while preserving high specificity for the diagnosis of MG. Muscle Nerve, 2016 Muscle Nerve 55: 166-170, 2017.

Electrophysiological testing is correlated with myasthenia gravis severity.

INTRODUCTION: Electrophysiological studies play an important role in the diagnosis of myasthenia gravis (MG). The objectives of this study was to explore the correlation of jitter and decrement with various clinical symptoms and signs and disease severity. METHODS: We performed a retrospective chart review of 75 MG patients who attended the neuromuscular clinic from April 2013 to May 2014. We compared clinical characteristics between patients with high jitter (>100 µs) and decrement (>10%), and patients with lower values to explore the correlations and optimal thresholds of jitter and decrement for different clinical features. RESULTS: High jitter and decrement values were associated with more severe disease, manifested by more frequent symptomatic bulbar and limb muscle weakness, more frequent ocular and limb muscle weakness on examination, higher quantitative MG score, and generalized disease. CONCLUSIONS: The yield of the electrophysiological assessment in MG extends beyond disease diagnosis and correlates with disease severity and the presence of generalized disease. Muscle Nerve 56: 445-448, 2017.

Cardiovascular disease guideline adherence and self-reported statin use in longstanding type 1 diabetes: results from the Canadian study of longevity in diabetes cohort.

BACKGROUND: Older patients with longstanding type 1 diabetes have high cardiovascular disease (CVD) risk such that statin therapy is recommended independent of prior CVD events. We aimed to determine self-reported CVD prevention guideline adherence in patients with longstanding diabetes. RESEARCH DESIGN AND METHODS: 309 Canadians with over 50 years of type 1 diabetes completed a medical questionnaire for presence of lifestyle and pharmacological interventions, stratified into primary or secondary CVD prevention subgroups based on absence or presence of self-reported CVD events, respectively. Associations with statin use were analyzed using multivariable logistic regression. RESULTS: The 309 participants had mean ± SD age 65.7 ± 8.5 years, median diabetes duration 54.0 [IQR 51.0, 59.0] years, and HbA1c of 7.5 ± 1.1 % (58 mmol/mol). 159 (52.7 %) participants reported diet adherence, 296 (95.8 %) smoking avoidance, 217 (70.5 %) physical activity, 218 (71.5 %) renin-angiotensin-system inhibitor use, and 220 (72.1 %) statin use. Physical activity was reported as less common in the secondary prevention subgroup, and current statin use was significantly lower in the primary prevention subgroup (65.5 % vs. 84.8 %, p = 0.0004). In multivariable logistic regression, the odds of statin use was 0.38 [95 % CI 0.15-0.95] in members of the primary compared to the secondary prevention subgroup, adjusting for age, sex, hypertension history, body mass, HbA1c, cholesterol, microvascular complications, acetylsalicylic acid use, and renin-angiotensin system inhibitor use. CONCLUSION: Despite good self-reported adherence to general CVD prevention guidelines, against the principles of these guidelines we found that statin use was substantially lower in those without CVD history. Interventions are needed to improve statin use in older type 1 diabetes patients without a history of CVD.

Cardiac autonomic neuropathy and early progressive renal decline in patients with nonmacroalbuminuric type 1 diabetes.

BACKGROUND AND OBJECTIVES: Cardiac autonomic neuropathy predicts future adverse renal outcomes in the general population. This study sought to determine its relationship with early progressive renal decline in type 1 diabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A subset of participants with normoalbuminuria (n=204) or microalbuminuria (n=166) from the First Joslin Kidney Study underwent assessment for cardiac autonomic neuropathy using heart rate variability during baseline visits performed from January 1991 to April 1992. Cardiac autonomic neuropathy was defined as an R-R variation (mean circular resultant) <20. Participants also had baseline and follow-up measurement of eGFR. Early progressive renal decline was evaluated according to two definitions: early GFR loss (slope of eGFR estimated by cystatin C <-3.3%/year) and incident advanced CKD (stage ≥3, defined by eGFR [calculated by Modification of Diet in Renal Disease method] <60 ml/min per 1.73 m(2)). Association with baseline cardiac autonomic neuropathy was assessed by adjusted logistic regression and Cox proportional hazards. RESULTS: Among the 370 participants, 47 (13%) had baseline cardiac autonomic neuropathy, 51 (14%) had early GFR loss, and 68 (18%) had incident advanced CKD over a median 14-year follow-up. Early GFR loss occurred in 15 (32%) of the 47 patients with baseline autonomic neuropathy and in 32 (10%) of the 323 without baseline autonomic neuropathy (P<0.001). Baseline autonomic neuropathy was strongly associated with odds of early GFR loss (adjusted odds ratio, 4.09; 95% confidence interval, 1.65 to 10.12; P=0.002). Incident advanced CKD was observed in 22 (47%) of those with baseline autonomic neuropathy and 46 (14%) of those without baseline autonomic neuropathy (P<0.001). Autonomic neuropathy was independently associated with incident advanced CKD (adjusted hazard ratio, 2.76; 95% confidence interval, 1.44 to 5.30; P=0.002). CONCLUSIONS: Cardiac autonomic neuropathy was a strong independent predictor of the long-term risk of early progressive renal decline in type 1 diabetes. Future research should explore the mechanisms by which autonomic neuropathy may be associated with renal function loss.

Impact of glycemia on survival of glioblastoma patients treated with radiation and temozolomide.

Evidence suggests hyperglycemia is associated with worse outcomes in glioblastoma (GB). This study aims to confirm the association between glycemia during radiotherapy (RT) and temozolomide (TMZ) treatment and overall survival (OS) in patients with newly diagnosed GB. This retrospective study included GB patients treated with RT and TMZ from 2004 to 2011, randomly divided into independent derivation and validation datasets. Time-weighted mean (TWM) glucose and dexamethasone dose were collected from start of RT to 4 weeks after RT. Univariate (UVA) and multivariable (MVA) analyses investigated the association of TWM glucose and other prognostic factors with overall survival (OS). In total, 393 patients with median follow-up of 14 months were analyzed. In the derivation set (n = 196) the median OS was 15 months and median TWM glucose was 6.3 mmol/L. For patients with a TWM glucose ≤6.3 and >6.3 mmol/L, median OS was 16 and 13 months, respectively (p = 0.03). On UVA, TWM glucose, TWM dexamethasone, age, extent of surgery, and performance status were associated with OS. On MVA, TWM glucose remained an independent predictor of OS (p = 0.03) along with TWM dexamethasone, age, and surgery. The validation set (n = 197), with similar baseline characteristics, confirmed that TWM glucose ≤6.3 mmol/L was independently associated with longer OS (p = 0.005). This study demonstrates and validates that glycemia is an independent predictor for survival in GB patients treated with RT and TMZ.

Evaluation of proxy tests for SFSN: evidence for mixed small and large fiber dysfunction.

BACKGROUND: Though intra-epidermal nerve fiber density (IENFD) is considered the gold standard for diagnosis of small fiber sensory neuropathy (SFSN), we aimed to determine if novel threshold values derived from standard tests of small or large fiber function could serve as diagnostic alternatives. METHODS: Seventy-four consecutive patients with painful polyneuropathy and normal nerve conduction studies (NCS) were defined as SFSN cases or controls by distal IENFD <5.4 and ≥5.4 fibers/mm, respectively. Diagnostic performance of small fiber [cooling (CDT) and heat perception (HP) thresholds, axon reflex-mediated neurogenic vasodilatation] and large fiber function tests [vibration perception thresholds (VPT) and sural nerve conduction parameters] were determined by receiver operating-characteristic (ROC) curve analyses. RESULTS: The 26(35%) SFSN cases had mean IENFD 3.3±1.7 fibers/mm and the 48(65%) controls 9.9±2.9 fibers/mm. Male gender (p = 0.02) and older age (p = 0.02) were associated with SFSN cases compared to controls. VPT were higher and CDT lower in SFSN cases, but the largest magnitude of differences was observed for sural nerve amplitude. It had the greatest area under the ROC curve (0.75) compared to all other tests (p<0.001 for all comparisons) and the optimal threshold value of ≤12 µV defined SFSN cases with 80% sensitivity and 72% specificity. CONCLUSION: In patients presenting with polyneuropathy manifestations and normal NCS, though small fiber function tests were intuitively considered the best alternative measures to predict reduced IENFD, their diagnostic performance was poor. Instead, novel threshold values within the normal range for large fiber tests should be considered as an alternative strategy to select subjects for skin biopsy in diagnostic protocols for SFSN.