The relationship of pathologic classification and prognosis in diabetic nephropathy

Objective To explore the relationship between clinical manifestations and pathological changes in diabetic nephropathy (DN) and to assess the predictive power of the pathologic classification for DN established by the Renal Pathology Society in 2010. Methods Patients with type 1 or type 2 diabetes and biopsy-proven DN in the Third Affiliated Hospital of Sun Yat-sen University between January 2004 to June 2014 were enrolled in the present study and were followed-up until 31 December 2014. The outcome was defined as renal end-points including renal replacement therapy and doubling of serum creatinine as well as all-cause mortality. The laboratory and histologic data were analyzed and outcomes were assessed using survival analysis. Results Fifty-seven people enrolled in this study were categorized into Class IIa (n=9), Class IIb (n=9), Class III (n=25) and Class IV (n=14) while no participants belonged to Class I. The changes of Class IIa were slight and those of Class IV were severe both in the clinical data (diabetic duration, blood pressure, estimated glomerular filtration rate, urine protein excretion rate, albumin and hemoglobin) and the pathological data (percentage of global glomerulosclerosis, percentage and scoring of interstitial fibrosis and tubular atrophy, scoring of interstitial inflammation and incidence of large vessel lesions). There were no significant differences between Class IIb and III in the above variables except for the scoring of arteriosclerosis. The mean follow-up duration was 25.9 months. Twenty-five patients (43.9%) reached the renal outcomes and six people (10.5%) reached all-cause mortality. The survival analysis showed that there were significant differences among the renal survival curves of different glomerular classes and of different interstitial and vascular scorings, but not in the survival curves related to all-cause mortality. Conclusions The glomerular classes are not completely associated with renal prognosis. The clinical manifestations and renal outcomes are benign in Class IIa, moderate but similar in Class IIb and III and severe in Class IV. The glomerular classification and interstitial and vascular scorings are associated to renal prognosis while their associations with mortality remain to be verified.     

Roles of AKAP1 in high-glucose induced mitochondrial fission in podocytes

Objective To investigate the roles of A kinase anchoring protein1(AKAP1)in high-glucose induced mitochondrial fission in podocytes. Methods Conditionally immortalized human podocytes were cultured in serum-free medium for 24 hours, and then exposed to different glucose concentration conditions in different time periods. The protein expressions of AKAP1 were observed by immunofluorescence, and AKAP1, dynamin related protein1 (Drp1) and phospho Ser 637-Drp1 (p-Drp1) were analyzed by Western blotting. AKAP1 siRNA was transfected to block AKAP1 expression.Podocytes were then divided into normal control group (5 mmol/L glucose), hypertonic group (30 mmol/L mannitol+5 mmol/L glucose), high glucose group (35 mmol/L glucose), and high glucose+AKAP1 siRNA group. Mitochondrial morphological changes were assessed by mitotracker red staining. Podocyte apoptosis was assessed by flow cytometry. Results Compared with normal group, high-glucose induced more podocytes apoptosis (P＜0.05), more mitochondrial fission with decreased aspect ratio and form factor (all P＜0.05). Upregulated AKAP1 protein level, and increased ratio of p-Drp1/Drp1 (all P＜0.05) in time and concentration dependent manners were also observed. Compared with high glucose group, transfection of AKAP1 siRNA showed less apoptosis (P＜0.05), less mitochondrial fission with increased aspect ratio and form factor (all P＜0.05), and down-regulated AKAP1 protein level as well as p-Drp1/Drp1 ratio (all P＜0.05). Conclusion High glucose induced mitochondrial fission might be induced through AKAP1-Drp1 pathway.     

Osteoinductive factor is a novel biomarker for the diagnosis of early diabetic nephropathy

Background: Microalbuminuria is the earliest clinical sign of diabetic nephropathy (DN). However, earlier markers as a diagnostic tool for DN was required for the invalid of microalbuminuria in some cases. Osteoinductive factor (OIF) was known to be an essential component of the normal vascular matrix. We aimed to research the relationship between DN and OIF, and discussed the availability of the serological markers for earlier stage of DN. Method: One hundred twenty Chinese subjects, who included patients with type 2 diabetes mellitus (T2DM), DN with microalbuminuria, and DN with macroalbuminuria, as well as healthy controls, were enrolled in this study. Serum OIF levels were examined by ELISA and other clinical biochemical parameters were tested based on standard methods. Results: Our results indicated that, serum OIF levels were significantly increased in DN subjects compared with healthy and T2DM subjects (P < 0.05 respectively). However, no significant changes in serum OIF levels were found between T2DM and healthy subjects. Furthermore, serum OIF had negative correlation with estimated glomerular filtration rate (eGFR) and positive correlation with blood urea nitrogen(BUN) and creatinine. ROC curve analysis showed that serum OIF level was a good sensitive and specificity marker for microalbuminuria and early renal damage with sensitivity of 86.7% and specificity of 95%, as well as for macroalbuminuria and damage progress with sensitivity of 90% and specificity of 95%. Conclusion: OIF may be an indicator of the earlier-stage DN in subjects with T2DM. Understanding the exact mechanism of up-regulated OIF in subjects with DN requires further study.     

Utility Values Associated with Diabetic Retinopathy in Chennai,India

Abstract

Purpose: The aim of this study was to estimate utility values associated with different severity stages of diabetic retinopathy (DR) in India by a direct elicitation method (time-trade off, TTO) and indirectly by questionnaire.

Methods: People with diabetes aged 40 years and over were recruited from an on-going DR epidemiology study and a laser clinic in Chennai, India. Utility values were elicited using the direct TTO method and indirectly through a validated questionnaire (EQ-5D).

Results: Of 249 participants, 30 had no DR, 73 had non-proliferative DR, 114 had sight-threatening DR, and 32 were blind from DR (bilateral visual acuity <6/60). The mean TTO utility value was 0.73 (standard deviation, SD, 0.31). TTO utility values decreased with increasing severity of DR (p?<?0.001) and were significantly lower among participants with sight threatening DR (0.70, SD 0.33) and blindness (0.55, SD 0.24) compared to those with no DR (0.89, SD 0.25) after adjustment for sociodemographic and clinical factors. Blindness from DR was independently associated with a lower EQ-5D utility value. The utility value derived from EQ-5D (0.06) associated with being blind from DR was substantially lower than that of the TTO utility value (0.55).

Conclusions: This study provides estimates of utility values that can be used in economic evaluations of DR screening strategies in India. The relatively low utility values associated with blindness highlights the importance of screening programs for early detection of the sight-threatening stages to prevent vision loss from DR in this setting.     

Ambulatory blood pressure recording in diabetic patients with abnormal responses to cardiovascular autonomic function tests

The aim of our study was to analyse the 24-h periodic pattern of blood pressure (BP) in diabetic patients with abnormal responses to cardiovascular reflexes, in order to evaluate the extent of the initial autonomic damage. We studied 44 patients with diabetes mellitus (14 insulin-dependent, 30 non-insulin-dependent; mean duration of disease 6.5±1.8 years) in good metabolic control (fasting glycaemia <140 mg/dl, postprandial glycaemia <180 mg/dl, fructosamine <285 mg/dl), divided into two subgroups, containing 21 normotensives (13 males and 8 females aged 28–72 years) and 23 hypertensives (13 males and 10 females aged 32–70 years) respectively. All patients showed abnormal responses to at least two out of four tests: deep breathing, lying to standing, Valsalva manuvre and postural hypotension. Two sex-and age-matched control groups were recruited, comprising 20 normotensive and 20 hypertensive diabetic patients without dysautonomia, respectively. The reference group consisted of 248 normotensives (135 males and 113 females, aged 18–76 years) and 212 mild-moderate hypertensives (130 males and 82 females, aged 27–66 years). Each patient underwent ambulatory BP monitoring for at least 24 h, using an auscultatory automatic device. Data concerning biological rhythms were analysed by means of periodic functions. We limited the Fourier partial sums to the first three harmonics. In the diabetic normotensive groups, we observed that the absolute systolic and diastolic BP minima during the night occurred very rapidly and that the increase to the morning maximum was markedly slowed in patients with abnormal responses to cardiovascular tests in comparison with the controls (nocturnal BP decrease –5.8/–4.7 vs –3.8/–4.0 mm Hg/h; increase 4.7/3.6 vs 5.9/6.1 mm Hg/h). The same phenomenon was observed in both hypertensive groups but the differences were more marked (nocturnal BP decrase –7.7/–7.1 vs –4.3/–3.9 mm Hg/h; increase 3.2/2.1 vs 5.8/4.3 mm Hg/h). Diabetic patients without dysautonomia had similar patterns to those in the normotensive and hypertensive reference groups. Since alterations in circadian rhythm are preceded by an intermediate smoothed BP curve during the early morning, which is well defined by Fourier analysis and related speeds, this method makes it possible to quantify the extent of the initial autonomic damage.     

Posterior sub-tenon’s bevacizumab injection in diabetic macular edema; a pilot study

Purpose

To evaluate the short-term results of sub-tenon’s injection of bevacizumab in patients with clinically significant macular edema (CSME).

Methods

In this prospective non-comparative interventional case series, sub-tenon’s injection of 2.5 mg/0.1 ml bevacizumab was performed for eyes with CSME. Macular thickness and best corrected visual acuity measurements were performed before and one month after injections.

Results

Nineteen eyes of twelve patients with a mean age of 59.8 ± 5.7 years were evaluated. Thirteen eyes (68.4%) had center-involving macular edema. No significant difference was observed between pre- and post-injection central subfield retinal thickness measurements (P = 0.3). Central subfield thickness measurements improved or remained unchanged in 13 eyes (68.4%). Baseline BCVA of 0.48 ± 0.35 LogMAR improved to 0.36 ± 0.26 LogMAR after injection (P = 0.01). Improvement of >2 lines in BCVA was found in 5 eyes (26.3%), and no eye lost >2 lines of BCVA. No complication associated with sub-tenon’s injection was observed.

Conclusion

Sub-tenon’s injection of bevacizumab resulted in significant short-term visual improvement in eyes with CSME. Retinal thickness changes were not significant.