Effect of Concentration/Dose Ratio in De Novo Kidney Transplant Recipients Receiving LCP-Tacrolimus or Immediate-Release Tacrolimus: Post Hoc Analysis of a Phase 3 Clinical Trial.

BACKGROUND A previous phase 3 clinical trial in de novo adult kidney transplant recipients (NCT01187953) compared the efficacy and safety of once-daily LCP-tacrolimus (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). However, whether the rate of tacrolimus metabolism affects outcomes between LCPT and IR-Tac was not examined. MATERIAL AND METHODS Patients were initiated on 0.17 mg/kg/day LCPT or 0.1 mg/kg/day IR-Tac, with doses adjusted over time to maintain target therapeutic trough concentrations. This post hoc analysis examined dosing trends, relative efficacy, and safety of LCPT (n=247) and IR-Tac (n=249) in slow, intermediate, and rapid metabolizers as defined by concentration/dose ratios at day 30. RESULTS For all metabolizer subgroups, minimum target tacrolimus trough concentrations were obtained more rapidly with LCPT than with IR-Tac. Slow metabolizers were more likely to exceed target trough concentrations with LCPT, while rapid metabolizers were more likely to fall below target trough concentrations with IR-Tac. Regardless of metabolizer status, significant differences were not detected between LCPT and IR-Tac for treatment failure, death, graft failure, biopsy-proven acute rejection, estimated glomerular filtration rate, or other clinical outcomes. CONCLUSIONS Although within metabolizer subgroups, attainment of target trough concentrations in the first week differed between LCPT and IR-Tac, these results suggest that, regardless of metabolizer phenotype, clinical outcomes do not differ between these formulations when dose adjustments are made.

Morning blood pressure surge is associated with autonomic neuropathy and peripheral vascular disease in patients with diabetes.

Although vascular and autonomic nervous system have been involved in the regulation of morning surge in blood pressure (MBPS), data on clinical correlates of MBPS in diabetic population are scarce, in particular with regard to diabetic complications. This study was aimed at investigating predictors and correlates of MBPS in diabetes. In a cross-sectional study including 167 patients with diabetes (age 58.5 ± 11.1 years, duration 15.9 ± 12.1 years), clinical variables, diabetic and neuropathic complications, and MBPS (using 24-h ambulatory blood pressure monitoring) were measured. The upper quartile of MBPS (>30.5 mmHg) was associated with higher values of waist circumference (P = 0.027), triglycerides (P = 0.021), and Michigan Diabetic Neuropathy Score (P = 0.042), with lower HDL cholesterol (P = 0.030), and with the presence of cardiovascular autonomic neuropathy (CAN) (P = 0.016) and peripheral vascular disease (PVD) (P < 0.0001). In a logistic regression analysis, PVD (odds ratio: 10.2, P = 0.001), CAN (odds ratio: 6.09, P = 0.016), and diastolic blood pressure (BP) (odds ratio: 1.06, P = 0.022) predicted MBPS upper quartile (r2 = 0.20, P = 0.0005). In a multiple regression analysis, PVD (P = 0.002) and diastolic BP (P = 0.003) were the only determinants of MBPS (r2 = 0.20). MBPS upper quartile was associated with BP dipping (systolic BP day-night reduction > 10%) (P = 0.012), and MBPS was positively related to systolic (rho = 0.41, P < 0.0001) and diastolic BP day-night reduction. In conclusion, metabolic syndrome stigmata, diastolic BP, CAN and PVD are the main predictors of MBPS in the diabetic population. Excessive MBPS and nondipping are not concurrent 24-h BP alterations. Autonomic dysfunction might exert an exacerbating effect on MBPS phenomenon.

A cross-sectional study investigating frequency and features of definitely diagnosed diabetic painful polyneuropathy.

This cross-sectional multicentre study aimed at investigating frequency and features of painful diabetic polyneuropathy. We consecutively enrolled 816 patients attending hospital diabetic outpatient clinics. We first definitely diagnosed diabetic polyneuropathy and pure small-fibre polyneuropathy using clinical examination, nerve conduction study, and skin biopsy or quantitative sensory testing. Adhering to widely agreed criteria, we then identified neuropathic pain and diagnosed painful polyneuropathy using a combined approach of clinical examination and diagnostic tests. Of the 816 patients, 36% had a diabetic polyneuropathy associated with male sex, age, and diabetes severity; 2.5% of patients had a pure small-fibre polyneuropathy, unrelated to demographic variables and diabetes severity. Of the 816 patients, 115 (13%) suffered from a painful polyneuropathy, with female sex as the only risk factor for suffering from painful polyneuropathy. In this large study, providing a definite diagnosis of diabetic polyneuropathy and pure small-fibre polyneuropathy, we show the frequency of painful polyneuropathy and demonstrate that this difficult-to-treat complication is more common in women than in men.

Diabetic peripheral neuropathic pain is a stronger predictor of depression than other diabetic complications and comorbidities.

AIMS: To investigate the independent effect on depression of painless diabetic polyneuropathy, painful diabetic polyneuropathy, and general and diabetes-related comorbidities. METHODS: In 181 patients, the presence of painless diabetic polyneuropathy, painful diabetic polyneuropathy, comorbidities and depression was assessed using the Michigan Neuropathy Screening Instrument Questionnaire, the Michigan Diabetic Neuropathy Score, nerve conduction studies, the Douleur Neuropathique en 4 Questions, the Charlson Comorbidity Index and the Beck Depression Inventory-II. RESULTS: In all, 46 patients met the criteria of confirmed painless diabetic polyneuropathy and 25 of painful diabetic polyneuropathy. Beck Depression Inventory-II scores indicative of mild-moderate-severe depression were reached in 36 patients (19.7%). In a multiple logistic regression analysis (including age, sex, body mass index, being unemployed, duration, haemoglobin A1c, insulin treatment, systolic blood pressure, nephropathy, retinopathy, Charlson Comorbidity Index and painful diabetic polyneuropathy), female sex (odds ratio: 5.9, p = 0.005) and painful diabetic polyneuropathy (odds ratio: 4.6, p = 0.038) were the only independent predictors of depression. Multiple regression analysis, including Douleur Neuropathique en 4 Questions and Michigan Diabetic Neuropathy Score instead of painful diabetic polyneuropathy, showed that Douleur Neuropathique en 4 Questions, in addition to female sex, was a significant predictor of depressive symptoms severity (p =0.005). CONCLUSION: Painful diabetic polyneuropathy is a greater determinant of depression than other diabetes-related complications and comorbidities. Painful symptoms enhance depression severity more than objective insensitivity.

A novel association between nondipping and painful diabetic polyneuropathy.

OBJECTIVE: We hypothesized the meaningful coexistence of neuropathic pain and nondipping in painful diabetic polyneuropathy (PDPN). RESEARCH DESIGN AND METHODS: In 113 patients with PDPN, with painless diabetic polyneuropathy (DPN(+)) and without DPN (DPN(-)), neuropathic pain, sleep, risk for obstructive sleep apnea (OSA), autonomic function, and blood pressure (BP) circadian pattern were assessed using the Douleur Neuropathique en 4 Questions (DN4), the Medical Outcomes Study Sleep Scale, the Berlin Questionnaire, cardiovascular reflex tests, and ambulatory BP monitoring. RESULTS: Patients with PDPN showed higher nighttime systolic BP (130.4 ± 15.6 mmHg) than both DPN(-) (119.9 ± 10.6 mmHg; P < 0.0001) and DPN(+) patients (124.2 ± 12.3 mmHg; P < 0.05), and lower day-night difference (∆) in systolic BP (5.5 ± 6.5 vs. 8.6 ± 7.7%; P < 0.05) and diastolic BP than DPN(-) patients. In a stepwise regression analysis, orthostatic hypotension, high risk for OSA, and PDPN (DN4 interview) were independent determinants of ∆ in systolic BP (r = 0.46; P = 0.0001), ∆ in diastolic BP, and nighttime systolic BP. CONCLUSIONS: PDPN is associated with higher nocturnal systolic BP and impaired BP circadian pattern independent of pain-related comorbidities, suggesting a condition of high cardiovascular risk.

Common polymorphisms in MIR146a, MIR128a and MIR27a genes contribute to neuropathy susceptibility in type 2 diabetes.

Diabetic polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) are common type 2 diabetes complications with a large inter-individual variability in terms of clinical manifestations and severity. Our aim was to evaluate a possible involvement of genetic polymorphisms in miRNA regions in the susceptibility to DPN and CAN. Nine polymorphisms in miRNA genes were studied in a sample of 132 type 2 diabetes patients (T2D) analysed for DPN and 128 T2D patients analysed for CAN. A genotype-phenotype correlation analysis was performed. The T allele of rs11888095 single nucleotide polymorphism (SNP) in MIR128a was significantly associated with a higher risk (ORadj = 4.89, P adj = 0.02), whereas the C allele of rs2910164 SNP in MIR146a was associated with a lower risk to develop DPN (ORadj = 0.49, P adj = 0.09), respectively. A multivariate logistic regression analysis confirmed that both SNPs contribute to DPN (p < 0.001 and p = 0.01 for MIR128a and MIR146a, respectively). MIR128a SNP significantly contributed also to DPN score (p = 0.026). Rs895819 SNP in MIR27a was significantly associated with a higher risk to develop early CAN (P adj = 0.023 and ORadj = 3.43). The rs2910164 SNP in MIR146a showed a protective effect respect to early CAN (P adj = 0.052, ORadj = 0.32) and to confirmed CAN (P adj = 0.041, ORadj = 0.13). The same SNP resulted significantly associated with a lower CAN score and a higher E/I (p = 0.002 and p = 0.003, respectively). In conclusion, we described associations of MIR128a and MIR146a SNPs with DPN susceptibility and of MIR146a and MIR27a SNPs with CAN susceptibility. This is the first study showing that genetic variability in miRNA genes could be involved in diabetic neuropathies susceptibility.

MicroRNA genetic variations: association with type 2 diabetes.

MicroRNAs are small single-stranded molecules that have emerged as important genomic regulators in different pathways. Different studies have shown that they are implicated in the metabolism and glucose homeostasis, and therefore, they could also be involved in the pathogenesis of metabolic disorders such as type 2 diabetes (T2DM). The aim of this study was to verify whether genetic variations in candidate microRNA (miRNA or miR) genes could contribute to T2DM susceptibility. We have selected 13 miRNAs as candidate loci according to literature data and to a computational analysis. MicroRNA genes were analyzed by direct sequencing in a cohort of 163 Italian T2DM patients and 185 healthy controls. We identified 6 novel variants never described before and 9 SNPs already described in databases. Five newly identified variants were found only in the cases group. We performed a case/control association study to test the associations of particular alleles/genotypes of identified SNPs with the disease. Two polymorphisms were associated with T2DM susceptibility: in particular, the G allele of rs895819 in hsa-mir-27a has shown a significantly protective effect (OR = 0.58 and P = 0.008), while the G allele of rs531564 in hsa-mir-124a appears to be a risk allele (OR = 2.15, P = 0.008). This is the first report indicating that genetic polymorphisms in miRNA regions could contribute to T2DM susceptibility.

TCF7L2 gene polymorphisms and type 2 diabetes: association with diabetic retinopathy and cardiovascular autonomic neuropathy.

Type 2 diabetes (T2DM) is a complex disease resulting from the contribution of both environmental and genetic factors. Recently, the list of genes implicated in the susceptibility to T2DM has substantially grown, also as a consequence of the great development of the genome-wide association studies in the last decade. Common polymorphisms in TCF7L2 gene have shown to have a strong effect with respect to many other involved genes. The aims of our study were to confirm the role of TCF7L2 in the susceptibility to T2DM in the Italian population and to investigate whether TCF7L2 genotypes also contribute to the clinical phenotypes variability and to diabetic complications development. Three TCF7L2 polymorphisms (rs7903146, rs7901695 and rs12255372) have been analyzed by allelic discrimination assays in a cohort of 154 Italian patients with T2DM and 171 healthy controls. A case-control association study and a genotype-phenotype correlation study have been carried out. Consistent with previous studies, all three SNPs showed a strong association with susceptibility to T2DM, both at genotypic (P = 0.003, P = 0.004 and P = 0.012) and at allelic level (P = 0.0004, P = 0.0004 and P = 0.003). Moreover, we observed associations between TCF7L2 variants and the following diabetic complications: diabetic retinopathy, cardiovascular disease and coronary artery disease. We also found a strong correlation between the rs7903146 and the presence of cardiovascular autonomic neuropathy (P = 0.02 with a high OR = 8.28). In conclusion, our study, in addition to confirming the involvement of TCF7L2 gene in the T2DM susceptibility, has shown that TCF7L2 genetic variability also contributes to the development of diabetic complications such as retinopathy and cardiovascular autonomic neuropathy.

Clinical correlates of painful diabetic neuropathy and relationship of neuropathic pain with sensorimotor and autonomic nerve function.

BACKGROUND: This study investigated the clinical correlates of painful diabetic polyneuropathy (PDPN) and the relationship of neuropathic pain with sensorimotor and autonomic nerve function. METHODS: Seventy-eight diabetic patients with PDPN (PDPN(+)), 57 with non-painful diabetic polyneuropathy (DPN(+)), and 56 without diabetic polyneuropathy (DPN(-)) were prospectively studied. Autonomic neuropathy, neuropathic symptoms and signs, vibration perception threshold, and neuropathic pain were assessed using 4 cardiovascular tests, scoring systems for symptoms and signs (Michigan Diabetic Neuropathy Score, MDNS), Biothesiometer, and a numerical rating scale. RESULTS: Compared to DPN(+), PDPN(+) patients displayed higher BMI (P=0.0043), waist circumference (P=0.0057), neuropathy symptom score (P<0.0001), MDNS (P<0.0001), and lower Valsalva ratio (P=0.037). In a multiple logistic regression analysis including PDPN as the dependent variable and age, sex, body mass index (BMI), abdominal obesity, diabetes type, diabetes duration, HbA1c, blood pressure, triglycerides, smoking, peripheral arterial disease, Valsalva ratio and MDNS as the independent variables, BMI (OR 1.22, P=0.0012) and MDNS (OR 1.27, P=0.0005) were significantly and independently associated with PDPN. In a multivariate regression analysis including as independent variables also sex, age, diabetes type, diabetes duration and Valsalva ratio, 24-h pain score was significantly related to neuropathy symptom score (P=0.0011), MDNS (P=0.0158), and 10g monofilament (P=0.018). DISCUSSION: BMI and sensorimotor deficits were the main determinants of PDPN and, as a novel finding, neuropathic pain intensity was related to the degree of neuropathy deficits. Thus, some peculiarity exists in metabolic correlates of diabetic neuropathic pain compared to insensate neuropathy but painfulness can still coexist with insensitivity.

Reappraisal of the diagnostic role of orthostatic hypotension in diabetes.

OBJECTIVE: Given the controversial aspects of orthostatic hypotension (OH) testing in diabetes, we evaluated the diagnostic role for cardiac autonomic neuropathy (CAN) and for nondipping of OH, defined according to a fall in systolic blood pressure (BP) > or = 30 (30-OH) or > or = 20 mmHg (20-OH). METHODS: 164 diabetic patients underwent 24 hours BP monitoring, three heart rate cardiovascular tests, and OH test. RESULTS: Compared to 30 mmHg, the 20 mmHg criterion increased the frequency of OH from 11 to 19.5%. Both 30-OH and 20-OH were associated with CAN (chi (2) = 30.5, P < 0.0001, and chi (2) = 45.1, P < 0.0001, respectively) and nondipping (chi (2) = 31.7, P < 0.0001, and chi (2) = 17.2, P = 0.0001, respectively). ROC curve for orthostatic systolic BP fall provided an AUC of 0.79 +/- 0.04 (95% CI 0.70-0.86) for diagnosing CAN and of 0.77 +/- 0.05 (95% CI 0.66-0.86) for diagnosing nondipping. Both 30-OH and 20-OH showed a low sensitivity and high specificity for CAN [sensitivity 31%, specificity 98%, Likelihood Ratio for a positive result (LR(+)) 17.1; and sensitivity 50%, specificity 95%, LR(+) 9.3, respectively], and for nondipping (sensitivity 40%, specificity 96%, LR(+) 8.9, and sensitivity 47%, specificity 87%, LR(+) 3.5, respectively), having 30-OH a higher LR(+) in both cases. INTERPRETATION: OH had only moderate diagnostic accuracy, with high specificity and low sensitivity, for CAN, diagnosed on the basis of heart rate cardiovascular tests, and-as a novel finding-also for nondipping. A different definition of OH did not substantially affect its diagnostic characteristics, with just a slightly greater ability of the 30 mmHg criterion to estimate the probability of CAN and nondipping.