Multicentre prospective validation of a urinary peptidome-based classifier for the diagnosis of type 2 diabetic nephropathy

Background Diabetic nephropathy (DN) is one of the major late complications of diabetes. Treatment aimed at slowing down the progression of DN is available but methods for early and definitive detection of DN progression are currently lacking. The ‘Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria trial' (PRIORITY) aims to evaluate the early detection of DN in patients with type 2 diabetes (T2D) using a urinary proteome-based classifier (CKD273). Methods In this ancillary study of the recently initiated PRIORITY trial we aimed to validate for the first time the CKD273 classifier in a multicentre (9 different institutions providing samples from 165 T2D patients) prospective setting. In addition we also investigated the influence of sample containers, age and gender on the CKD273 classifier. Results We observed a high consistency of the CKD273 classification scores across the different centres with areas under the curves ranging from 0.95 to 1.00. The classifier was independent of age (range tested 16-89 years) and gender. Furthermore, the use of different urine storage containers did not affect the classification scores. Analysis of the distribution of the individual peptides of the classifier over the nine different centres showed that fragments of blood-derived and extracellular matrix proteins were the most consistently found. Conclusion We provide for the first time validation of this urinary proteome-based classifier in a multicentre prospective setting and show the suitability of the CKD273 classifier to be used in the PRIORITY tria

Advanced Diabetic Neuropathy: A Point of no Return?

Diabetic peripheral neuropathy is the most common complication of long-standing diabetes mellitus which frequently results in clinically significant morbidities e.g. pain, foot ulcers and amputations. During its natural course it progresses from initial functional changes to late, poorly reversible, structural changes. Various interconnected pathogenetic concepts of diabetic neuropathy have been proposed based on metabolic and vascular factors, mostly derived from long-term hyperglycemia. These pathogenetic mechanisms have been targeted in several experimental and clinical trials. This review summarizes available, mainly morphological data from interventions designed to halt the progression or achieve the reversal of established diabetic neuropathy, which include the recovery of normoglycemia by pancreas or islet transplantation, polyol pathway blockade by aldose reductase inhibitors, mitigation of oxidative stress by the use of antioxidants or correction of abnormalities in essential fatty acid metabolism. Unfortunately, to date, no treatment based on pathogenic considerations has shown clear positive effects and thus early institution of optimal glycemic control remains the only available measure with proven efficacy in preventing or halting progression of diabetic neuropathy. Further experimental and clinical research employing objective reproducible parameters is clearly needed. Novel non-invasive or minimally invasive methods e.g. corneal confocal microscopy or epidermal nerve fiber counts may represent potentially useful instruments for the objective assessment of nerve damage and monitoring of treatment effects

The Role of Narrow Band Imaging in the Detection of Recurrent Laryngeal and Hypopharyngeal Cancer after Curative Radiotherapy

Narrow band imaging is considered a significant improvement in the possibility of detecting early mucosal lesion of the upper aerodigestive tract. Early detection of mucosal neoplastic lesions is of utmost importance for patients survival. There is evidence that, especially in patients previously treated by means of curative radiotherapy or chemoradiotherapy, the early detection rate of recurrent disease is quite low. The aim of this study was to prove whether the videoendoscopy coupled with NBI might help detect recurrent or secondary tumors of the upper aerodigestive tract. 66 patients previously treated by means of RT or CRT with curative intent were enrolled in the study. All patients underwent transnasal flexible videoendoscopy with NBI mode under local anesthesia. When a suspicious lesion was identified in an ambulatory setting, its nature was proved histologically. Many of these changes were not identifiable by means of conventional white light (WL) endoscopy. The accuracy, sensitivity, specificity, and positive and negative predictive value of the method are very high (88%, 92%, 76%, 96%, and 91%, resp.). Results demonstrate that outpatient transnasal endoscopy with NBI is an excellent method for the follow-up of patients with carcinomas of the larynx and the hypopharynx primarily treated with radiotherapy

Polyclonal Anti-T-Cell Therapy for Type 1 Diabetes Mellitus of Recent Onset

The destruction of pancreatic β-cells in type 1 diabetes mellitus is mediated by autoreactive T-lymphocyte clones. We initiated a prospective randomized controlled trial of polyclonal rabbit anti-T-cell globulin (ATG) in patients with type 1 diabetes within 4 weeks of diagnosis and with residual post-glucagon C-peptide levels still over 0.3 nmol/l. ATG was administered as an initial bolus of 9 mg/kg followed by 3 consecutive doses of 3 mg/kg. An interim analysis was performed to establish whether any significant changes in C-peptide production and insulin requirement had occurred that would justify the continuation of this pilot study. By May 2004, 11 subjects were assigned to treatment with ATG along with intensified insulin therapy and 6 to intensified insulin therapy with placebo, and were followed for a period of at least 6 months. During the first 12 months a significant difference in the insulin dose trends was found between the groups (p = 0.010) with a lower insulin dosage in the ATG group. There was also a difference in the glucagon stimulated C-peptide level trends of marginal significance (p = 0.068). Compared to values at screening, stimulated C-peptide levels significantly improved in the ATG group (p = 0.012) but not in the placebo group. Complete diabetes remission occurred in 2 patients in the ATG and in none of the placebo group. Glycosylated hemoglobin at 12 months tended to be lower in the ATG group (p = 0.088). Significant adverse effects of ATG treatment, mainly transient fever and moderate symptoms of serum sickness (7 and 6 subjects, respectively) were observed during the first month only. The interim analysis of this ongoing study suggests that short-term ATG therapy in type 1 diabetes of recent onset contributes to the preservation of residual C-peptide production and to lower insulin requirements in the first year following diagnosis

Power Spectral Analysis of Heart Rate Variability in Patients with Charcot’s Neuroarthropathy

Charcot’s or neuropathic osteoarthropathy is one of the most debilitating orthopedic sequelae of diabetes mellitus. Distinguishing Charcot’s neuroarthropathy from clinically similar conditions may be challenging. The neurovascular theory postulates that Charcot’s neuroarthropathy may be secondary to sympathetic denervation of the lower-extremity vasculature. A convenient method for assessing autonomic neuropathy in patients with Charcot’s neuroarthropathy is needed. Short-term power spectral analysis (PSA) of heart rate variability (HRV), a noninvasive and quantitative method for assessing autonomic neuropathy, may be advantageous compared with the traditionally used Ewing’s cardiovascular reflex tests. However, there are limitations to the clinical use of PSA of HRV because of poor standardization. We standardized PSA of HRV and assessed autonomic neuropathy in 17 people with acute Charcot’s neuroarthropathy using PSA of HRV versus Ewing’s tests. More patients with Charcot’s neuroarthropathy were diagnosed as having autonomic neuropathy with PSA of HRV than with Ewing’s tests (94% versus 82%); however, no significant difference between the two methods was found. The results of this study suggest that PSA of HRV requires minimal patient collaboration and time expenditure compared with Ewing’s tests and may be useful in detecting autonomic neuropathy in patients with Charcot’s neuroarthropathy. (J Am Podiatr Med Assoc 96(1): 1–8, 2006)</jats:p