Progression Of Overt Diabetic Nephropathy Research Articles

Screening for Microalbuminuria in Newly Detected Type 2Diabetes Mellitus Patients


 Microalbuminuria is a major risk factor for various renal and cardiovascular events. The need for early detection and treatment of patients at risk for microalbuminuria is important to limit the excess renal and cardiovascular disease associated with type 2 diabetes mellitus (T2DM). Therefore, this study aimed to screen newly detected T2DM patients for the presence of microalbuminuria. A total of 120 patients diagnosed with T2DM were included in this prospective observational study. After collecting history, physical examination, and various biochemical investigations such as kidney function test, plasma blood sugars, lipid profile and glycosylated hemoglobin (HbA1c) were conducted. The detection of microalbuminuria was done by Micral test. Data were analyzed by the Chi-square test for significance of qualitative variables. A p-value of < 0.05 was considered significant. Prevalence of microalbuminuria among T2DM patients was observed to be 40%. HbA1c levels of females showed a significant association (p=0.007). Patients with BMI>25 kg/m2 had a significant incidence of microalbuminuria (p<0.001). Urinary glucose was significantly higher (p=0.024) in 83.3% of patients with microalbuminuria. The mean fasting and postprandial blood glucose levels were considerably higher in patients with microalbuminuria (p=0.004, p=0.002). Blood urea and serum creatinine levels, too, were noted to be slightly higher in patients with microalbuminuria (p=018, p=0.001). Prevalence of microalbuminuria was slightly less in newly diagnosed T2DM patients. Early diagnosis and management of microalbuminuria in asymptomatic individuals could help in preventing worsening in renal function and progression of overt diabetic nephropathy.

The Glucagon-Like Peptide-1 Receptor Agonist, Liraglutide, Attenuates the Progression of Overt Diabetic Nephropathy in Type 2 Diabetic Patients

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Glucagon-like peptide-1 (GLP-1) is one of the incretins, gut hormones released from the intestine in response to food intake. GLP-1 receptor (GLP-1R) agonists have been used to treat type 2 diabetes. Here, we studied the effect of the administration of a GLP-1R agonist, liraglutide, on proteinuria and the progression of overt DN in type 2 diabetic patients. Twenty-three type 2 diabetic patients with overt DN, who had already been treated with blockade of renin-angiotensin system under dietary sodium restriction, were given liraglutide for a period of 12 months. Treatment with liraglutide caused a significant decrease in HbA1c from 7.4 ± 0.2% to 6.9 ± 0.3% (p = 0.04), and in body mass index (BMI) from 27.6 ± 0.9 kg/m² to 26.5 ± 0.8 kg/m² after 12 months (p < 0.001), while systolic blood pressure did not change. The progression of DN was determined as the rate of decline in estimated glomerular filtration rate (eGFR). The 12-month administration of liraglutide caused a significant decrease in proteinuria from 2.53 ± 0.48 g/g creatinine to 1.47 ± 0.28 g/g creatinine (p = 0.002). The administration of liraglutide also substantially diminished the rate of decline in eGFR from 6.6 ± 1.5 mL/min/1.73 m²/year to 0.3 ± 1.9 mL/min/1.73 m²/year (p = 0.003). Liraglutide can be used not only for reducing HbA1c and BMI, but also for attenuating the progression of nephropathy in type 2 diabetic patients.

糖尿病性腎症に対する低用量アンジオテンシンII受容体拮抗薬/低用量利尿薬/カルシウム拮抗薬の三剤併用療法の腎保護作用

Combination therapy with angiotensin receptor antagonist(ARB) plus angiotensin converting enzyme inhibitor(ACE-I) (ARB/ACE-I) was efficacious in reducing proteinuria in patients with progressive renal disease. However, this therapy may be associated with the worsening of anemia and hyperkalemia. The present study addressed whether or not triple therapy with low-dose ARB, low-dose diuretic (D) and calcium channel blocker(CCB) (ARB/D/CCB) is as effective as therapy with low-dose ARB/ACE-I in retarding the progression of overt diabetic nephropathy. In the triple therapy, the patients were initially subjected to monotherapy with CCB for 24 weeks. Low-dose ARB and low-dose D were added to the treatment for an additional 24-week period. In parallel, patients undergoing double therapy were initially treated with low-dose ACE-I alone for 24 weeks, and then low-dose ARB was added for an additional 24-week period. The results were as follows: 1) In the triple therapy, blood pressure was reduced by 9 mmHg in systole and 5 mmHg in diastole (not significant) compared to monotherapy with CCB. There was a significant decline in proteinuria (3.3 +/- 1.2 g/day in the CCB-treated period vs. 2.1 +/- 1.0 g/day in the ARB/D/CCB-treated period, n = 12, p = 0.0143). Furthermore, a significant improvement in the slope of reciprocal serum creatinine concentration(1/Cr) was found in response to triple therapy(1/Cr: -0.0118 +/- 0.0009 in the CCB-treated vs. -0.0035 +/- 0.0028(I/mg/dl/month) in the ARB/D/CCB-treated period, n = 12, p < 0.001). There was neither a worsening of anemia nor an increase in the serum potassium(K) concentration. 2) In the double therapy, blood pressure was reduced by 12 mmHg in systole(p = 0.0079, n = 11) and 6 mmHg in diastole(n = 11, p = 0.0037) compared to the monotherapy with ACE-I. A significant improvement in the slope of 1/Cr was found in the double therapy(1/Cr: -0.0095 +/- 0.0052 in the ACE-I treated period vs. -0.0029 +/- 0.0028(I/mg/dl/month) in the ARB/ACE-I, n = 11, p < 0.001). In addition, there was a substantial reduction in hematocrit and increase in serum K concentration. The present result suggests that triple therapy consisting of ARB/D/CCB is as efficacious as double therapy with ARB/ACE-I in protecting the kidney from the progression in patients with diabetic overt nephropathy. The former may be expected to have less adverse effects.

Avosentan for Overt Diabetic Nephropathy

In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P = 0.225), 17 (3.6%; P = 0.194), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure.

Redistribution of connexin43 expression in glomerular podocytes predicts poor renal prognosis in patients with type 2 diabetes and overt nephropathy

Significance of podocyte injury in the progression of diabetic nephropathy is not well-understood. In this study, we examined whether alteration of gap junction protein connexin43 (Cx43) expression in podocytes is associated with the progression of overt diabetic nephropathy. We recruited 29 type 2 diabetic patients with overt nephropathy who underwent renal biopsy. Nephrectomized kidney samples obtained from seven subjects with localized neoplasm and biopsy specimens from five patients diagnosed as minor glomerular abnormalities were used as controls. Cx43 staining on paraffin-embedded kidney sections were studied by immunohistochemistry. In controls, Cx43 was expressed at podocytes in a linear pattern along the glomerular basement membrane. In contrast, downregulation and loss of uniformly linear staining of Cx43 (Cx43 heterogeneity) in podocytes were observed in diabetic nephropathy. Cx43 intensity correlated with current renal function (R = 0.647, P < 0.005), whereas the magnitude of Cx43 heterogeneity correlated well with the degree of future decline in renal function (R = -0.705, P < 0.001). Alteration of Cx43 expression in podocytes was closely associated with the progression of overt diabetic nephropathy. These results indicate that change in Cx43 expression at podocytes represents a progressive stage in overt diabetic nephropathy and that it may be a convenient way to predict future decline in renal function.

Chronic intermittent intravenous insulin therapy: a new frontier in diabetes therapy.

The limited success achieved in controlling diabetes and its complications with conventional insulin therapy suggests the need for reevaluation of the appropriateness of insulin administration protocols. Indeed, conventional subcutaneous insulin administration produces slowly changing blood insulin levels and suboptimal hepatocyte insulinization resulting in impaired hepatic capacity for processing incoming dietary glucose. The novel approach to insulin administration known as chronic intermittent intravenous insulin therapy (CIIIT) delivers insulin in a pulsatile fashion and achieves physiological insulin concentration in the portal vein. Done as a weekly outpatient procedure combined with daily intensive subcutaneous insulin therapy, this procedure has been shown to (1) significantly improve glycemic control while decreasing the incidence of hypoglycemic events, (2) improve hypertension control, (3) slow the progression of overt diabetic nephropathy, and (4) reverse some manifestations of diabetic autonomic neuropathy (e.g., abnormal circadian blood pressure pattern, severe postural hypotension, and hypoglycemia unawareness).

Effect Of Intensive Insulin Therapy On Progression Of Overt Nephropathy In Patients With Type 1 Diabetes Mellitus

To assess the effects of chronic (long-term) intermittent intravenous insulin therapy (CIIIT) on the progression of overt nephropathy in patients with type 1 diabetes mellitus. We undertook a retrospective longitudinal three-center study of 31 patients with type 1 diabetes mellitus and overt nephropathy, who were receiving intensive subcutaneous insulin therapy (four insulin injections daily) and weekly CIIIT. All study patients had follow-up consultations weekly for at least 12 months (mean duration, 37.0 +/- 4.6 months). Each patient had monthly hemoglobin A(1c) (by high-performance liquid chromatography) and semiannual creatinine clearance determinations. The hemoglobin A(1c) levels declined significantly from 8.6 +/- 0.6% to 7.6 +/- 0.3% (P = 0.0062) during the study period. The creatinine clearance remained essentially unchanged (from 46.1 +/- 3.0 mL/min per 1.73 m 2 at baseline to 46.0 +/- 3.9 mL/min per 1.73 m 2 at the end of the observation period, with an average annualized slope increase of 3.39 +/- 1.5 mL/min per year--no significant difference). The addition of CIIIT to intensive subcutaneous insulin therapy in patients with type 1 diabetes mellitus seems to arrest or appreciably reduce the progression of overt diabetic nephropathy, as well as substantially improve their glycemic control.

Effect of moderate dietary protein restriction on the progression of overt diabetic nephropathy: a 6-mo prospective study

To assess whether moderate dietary protein restriction can delay the progression of overt diabetic nephropathy, 22 subjects with insulin-dependent diabetes mellitus were randomly assigned to an unrestricted protein diet (> 1.6 g.kg body wt-1.d-1) or a moderately protein-restricted diet (0.8 g.kg body wt-1.d-1) and followed prospectively for six mo. Direct isotope methods were used to assess renal function. Protein intake was assessed by measurement of urinary urea nitrogen. The two groups were well-matched for age, sex, duration of diabetes, glycemic control, blood pressure, and degree of renal insufficiency. Patients consuming the unrestricted protein diet (n = 11) showed a progressive decline in glomerular filtration rate of 1.3 mL.min-1.mo-1 with no change in proteinuria. Patients consuming the moderately protein-restricted diet showed a marked decrease in the degree of proteinuria (2.15-1.13 g/d, P = 0.036) and a stabilization of glomerular filtration rate. This occurred independently of changes in blood pressure or glycemic control. Moderate dietary protein restriction can ameliorate progression of overt diabetic nephropathy.