Development Of Overt Diabetic Nephropathy Research Articles

DIABETES & MICROALBUMINURIA- A MULTI-SYSTEM DISEASE

In diabetic patients, the presence of microalbumin in the urine is perhaps the most significant early signal for the onset of systemic vasculopathy and associated target organ damage viz., brain, heart, and kidneys1. Microalbuminuria is considered to be a predictor of the development of overt diabetic nephropathy in type 1 and 2 diabetes2. Diabetic patients are at considerable risk of either having or developing the renal disease and/or related cardiovascular diseases, usually starting with microalbuminuria often related to insulin resistance (or metabolic syndrome)1. Thus, microalbuminuria is a relatively common accompaniment of metabolic syndrome and the foremost predictor of renal disease as well as cardiovascular disease3,4. Hypertension and microalbuminuria often coexist in diabetic patients, and reducing blood pressure reduces microalbuminuria in type 1 diabetes2. However, the relationship between hypertension and microalbuminuria in diabetes is complex. Furthermore, microalbuminuria is also associated with other inflammatory states, including rheumatoid arthritis and inflammatory bowel disease. Also, male sex and hormone replacement therapy in women seems to increase the susceptibility of a person to microalbuminuria, although the basis for this is yet not clear2.

Microalbuminuria among Newly Diagnosed Diabetic Patients at Mulago National Referral Hospital in Uganda: A Cross Sectional Study.

BackgroundMicroalbuminuria is an early marker of nephropathy, cardiovascular diseases and severe ocular morbidity in adults with diabetes mellitus. This subclinical condition is associated with high morbidity and mortality. Microalbuminuria precedes the development of overt diabetic nephropathy by 10–14 years. At this stage, one can reverse diabetic nephropathy or prevent its progression. Unfortunately, tests to detect microalbuminuria in diabetics are not routinely done in Uganda. This study sought to determine the prevalence and factors associated with microalbuminuria among newly diagnosed diabetic patients in the National Referral Hospital in Uganda.MethodsIn this cross-sectional study conducted between June 2014 and January 2015, we recruited 175 newly diagnosed adult diabetic patients. Information on patients’ socio-demographics, biophysical profile, blood pressure measurement, biochemical testing and echocardiographic findings was obtained for all the participants using a pre-tested questionnaire. Microalbuminuria was defined as Albumin to Creatinine Ratio (ACR) between 30 and 299 mg/g. Bivariate and multivariate logistic regression analyses were used to investigate the association of several factors with microalbuminuria.ResultsOf the 175 patients recruited, males were 90 (51.4%) and the mean age was 46 ± 15 years. Majority of patients had type 2 DM 140 (80.0%) and the rest had type 1 DM 35 (20.0%). The mean HbA1C was 13.9 ± 5.3%. Mean duration of diabetes was 2 months. Prevalence of microalbuminuria was 47.4% (95% CI: 40.0%−54.9%) among all the patients that were assessed in the study. The independent factor associated with microalbuminuria was pregnancy (OR7.74[95% CI: 1.01–76.47] P = 0.050) while mild and moderate physical activity at work were inversely associated with microalbuminuria respectively (OR0.08[95% CI: 0.01–0.95] P = 0.046) and (OR0.07[95% CI: 0.01–0.77] P = 0.030).ConclusionsPrevalence of microalbuminuria was high in this patient population of newly diagnosed diabetes mellitus. Pregnancy was positively associated with significant microalbuminuria while physical activity at work was inversely associated with microalbuminuria. Early detection and management of microalbuminuria in asymptomatic individuals may help in preventing deterioration in renal function and development of overt diabetic nephropathy and progression to ESRD.

The prevalence of microalbuminuria and associated factors among patients with type 2 diabetes mellitus in Botswana

Microalbuminuria (MA) has been established as an early marker of both diabetic nephropathy and vascular disease in patients with diabetes mellitus (DM). This study was conducted to determine the prevalence of MA and associated factors among patients with type 2 DM in Botswana. Outpatient tertiary clinic. A cross-sectional descriptive study involving 289 patients with type 2DM was conducted from January 2013 to June 2013 in Block 6 Reference Clinic, a tertiary clinic in Gaborone, Botswana. A random spot urine sample was collected from each patient with MA defined as urine albumin-to-creatinine ratio (ACR) between 3.0 and 30.0 mg/mmol. Data analysis was done using STATA version 12 (College Station, TX, USA). Unpaired Student's t-test was used for compairing means and Chi-squared test was used for comparison of proportions between groups. A P value of <0.05 was considered statistically significant. The majority of recruited patients (191, 66.1%) were females, and the median age (interquartile range) of the patients was 52 (42-53) years. The mean glycosylated hemoglobin (HbA1c) for the study population was 8.43% with 70.6% of the population having HbA1c over 7%. MA was found in 129 (44.6%) of study participants. The duration of diabetes of 6-10 years, estimated glomerular filtration rate, HbA1c, and higher serum trigerycides levels were significantly associated with presence of MA. High prevalence of MA raises an urgent need for changes in the management of patients with type 2 DM in Botswana, with emphasis on prevention and reduction of MA to avoid development of overt diabetic nephropathy and ensuing cardiovascular morbidity and mortality.

Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials

Intensive glucose control is understood to prevent complications in adults with type 2 diabetes. We aimed to more precisely estimate the effects of more intensive glucose control, compared with less intensive glucose control, on the risk of microvascular events. In this meta-analysis, we obtained de-identified individual participant data from large-scale randomised controlled trials assessing the effects of more intensive glucose control versus less intensive glucose control in adults with type 2 diabetes, with at least 1000 patient-years of follow-up in each treatment group and a minimum of 2 years average follow-up on randomised treatment. The prespecified and standardised primary outcomes were kidney events (a composite of end-stage kidney disease, renal death, development of an estimated glomerular filtration rate <30 mL/min per 1·73m2, or development of overt diabetic nephropathy), eye events (a composite of requirement for retinal photocoagulation therapy or vitrectomy, development of proliferative retinopathy, or progression of diabetic retinopathy), and nerve events (a composite of new loss of vibratory sensation, ankle reflexes, or light touch). We used a random-effects model to calculate overall estimates of effect. We included four trials (ACCORD, ADVANCE, UKPDS, and VADT) with 27 049 participants. 1626 kidney events, 795 eye events, and 7598 nerve events were recorded during the follow-up period (median 5·0 years, IQR 4·5-5·0). Compared with less intensive glucose control, more intensive glucose control resulted in an absolute difference of -0·90% (95% CI -1·22 to -0·58) in mean HbA1c at completion of follow-up. The relative risk was reduced by 20% for kidney events (hazard ratio 0·80, 95% CI 0·72 to 0·88; p<0·0001) and by 13% for eye events (0·87, 0·76 to 1·00; p=0·04), but was not reduced for nerve events (0·98, 0·87 to 1·09; p=0·68). More intensive glucose control over 5 years reduced both kidney and eye events. Glucose lowering remains important for the prevention of long-term microvascular complications in adults with type 2 diabetes. None.

Importance of reno-protection in adolescents with diabetes and microalbuminuria

SUMMARY Increases in urinary albumin excretion (microalbuminuria) can be detected in young people with Type 1 diabetes (T1D) during puberty, and they may indicate a risk for the development of overt diabetic nephropathy (DN) and cardiovascular disease. During adolescence, poor glycemic control, dyslipidemia, increases in blood pressure and inflammatory markers, female gender, and hormonal changes all contribute to the risk of microalbuminuria. Currently, interventions to reduce the long-term risk for DN in adolescents with T1D are mainly based on improving glycemic control, while there is no clear guidance on other potential cardio–renal protection strategies. The efficacy of angiotensin-converting enzyme inhibitors and statins is currently being investigated in adolescents with T1D at high risk of developing DN. In addition, there is growing interest in the development of new interventions targeting specific pathways implicated in DN.

Effects of different ACE inhibitor combinations on albuminuria: results of the GUARD study

Clinical practice guidelines recommend blockers of the renin-angiotensin system alone or in combination with other agents to reduce blood pressure and albuminuria in patients with type 2 diabetes. Dihydropyridine calcium channel blockers, however, may lower blood pressure but not albuminuria in these patients. Here we tested the hypothesis that combining an ACE inhibitor with either a thiazide diuretic or a calcium channel blocker will cause similar reductions in blood pressure and albuminuria in hypertensive type 2 diabetics. We conducted a double blind randomized controlled trial on 332 hypertensive, albuminuric type 2 diabetic patients treated with benazepril with either amlodipine or hydrochlorothiazide for 1 year. The trial employed a non-inferiority design. Both combinations significantly reduced the urinary albumin to creatinine ratio and sitting blood pressure of the entire cohort. The percentage of patients progressing to overt proteinuria was similar for both groups. When we examined patients who had only microalbuminuria and hypertension we found that a larger percentage of the diuretic and ACE inhibitor normalized their albuminuria. We conclude that initial treatment using benzaepril with a diuretic resulted in a greater reduction in albuminuria compared to the group of ACE inhibitor and calcium channel blocker. In contrast, blood pressure reduction, particularly the diastolic component, favored the combination with amilodipine. The dissociation between reductions in blood pressure and albuminuria may be related to factors other than blood pressure.

Effects of Aerobic Exercise on Microalbuminuria and Enzymuria in Type 2 Diabetic Patients

Increased urinary albumin excretion is a strong predictor for the development of overt diabetic nephropathy and overall cardiovascular morbidity and mortality in patients with type 2 diabetes. In a previous study, regular aerobic physical activity in overweight/obese patients with type 2 diabetes mellitus was found to have significant beneficial effects on glycemic control, insulin resistance, cardiovascular risk factors, and oxidative stress. The aim of the present study was to investigate the effects of aerobic exercise in the same cohort of type 2 diabetic patients on urinary albumin excretion, serum levels and urinary excretion of enzymes, tubular damage, and metabolic control markers in type 2 diabetic patients. Changes from baseline to 3 and 6 months of aerobic exercise were assessed for urinary albumin excretion, serum activities, and urinary excretion of N-acetyl-β-D-glucosaminidase (NAGA), plasma cell glycoprotein 1 (PC-1) and aminopeptidase N (APN), as well as their association with insulin resistance, cardiovascular risk factors, and oxidative stress parameters in 30 male type 2 diabetic patients (aged 54.8 ± 7.3 years, with a mean BMI of 30.8 ± 3.0 kg/m2). Microalbuminuria was found in six (20%) diabetic patients at baseline, three of them (10%) after three months, and only one patient (3.33%) at the end of the study period. A significant correlation was found for urinary albumin excretion at baseline both with sulfhydryl-groups and catalase, but not for urinary albumin excretion with MDA and glutathione. The prevalence of microalbuminuria tended to decrease after six months of aerobic exercise in type 2 diabetic patients, independently of any improvement in insulin resistance and oxidative stress parameters. Neither between-group nor within-group changes were found for urinary PC-1, APN, and NAGA activity. Serum NAGA was significantly increased (p < 0.05) over the control level in diabetic patients at baseline, but it decreased to the normal level after six months of exercise. This study has shown that a six-month aerobic exercise, without any change in the medication, tended to decrease microalbuminuria without changing enzymuria. However, further studies are needed not only to confirm those findings, but to elucidate potential mechanisms that would clarify the beneficial effects of exercise.

Progression of microalbuminuria in type 1 diabetes: Ten-year prospective observational study

In patients with diabetes, the presence of persistent microalbuminuria is an established predictor of development of overt diabetic nephropathy, progressive renal insufficiency and increased risk of cardiovascular disease, in both type 1 and 2 diabetes [1‐4]. Approximately 30% of type 1 diabetic patients may develop diabetic nephropathy within 25 years of diabetes, although recent data suggest a declining incidence [5, 6]. In the original studies demonstrating the predictive value of microalbuminuria, up to 80% of patients with microalbuminuria progressed to overt diabetic nephropathy. Recently, it has been suggested that microalbuminuria may not be as sensitive and specific as predictor of diabetic nephropathy as originally suggested [7]. Observational studies have found regression from microalbuminuria to normoalbuminuria in a substantial fraction of patients with type 1 diabetes and microalbuminuria [8]. Furthermore, it has been suggested from uncontrolled studies of patients with long duration of diabetes that microalbuminuria is not a good predictor of progression to overt nephropathy in longstanding type 1 diabetic patients [9]. We conducted a 10-year observational follow-up study of a large cohort of type 1 diabetic patients to elucidate putative risk markers for the progression from microalbuminuria to overt diabetic nephropathy. We have previously demonstrated the presence of poor glycemic control, retinopathy, smoking, and elevated urinary albumin excretion within normal range to be predictors of development of microalbuminuria [10]. In the present study, the factors involved in progression from microalbuminuria to overt nephropathy are evaluated, as well as the predictive value of microalbuminuria in longstanding type 1 diabetes for the development of overt diabetic nephropathy. In addition, we wanted to determine the annual rate of progression in urinary albumin excretion rate in microalbuminuric patients.

Angiotensin blockade in type 2 diabetic renal disease

The available evidence on renal protection in type 2 diabetes mellitus favors the administration of an angiotensin receptor blocker (ARB) more than that of an angiotensin converting enzyme inhibitor (ACEi). This evidence is based on recent studies showing that losartan and irbesartan can prevent the development of overt diabetic nephropathy in microalbuminuric type 2 diabetic patients as well as slow the velocity of progression to end-stage renal disease in patients with overt type 2 diabetic nephropathy. These studies do not deny the possibility that ACEi are equally effective, but studies of an adequate magnitude are lacking. These findings on ARB administration do not preclude the importance of strict control of blood pressure and proteinuria and/or albuminuria to avoid or retard renal damage in type 2 diabetic patients.

Diabetic microalbuminuria delayed by ACE inhibitor

Angiotensin-converting enzyme (ACE) inhibitors are already known to slow the development of overt diabetic nephropathy in patients with type 2 diabetes mellitus (T2DM) with hypertension or in normotensive patients with T1DM. However, the effectiveness of other antihypertensive drugs has not been fully clarified. A recent comparison of perindopril, an ACE inhibitor, with nifedipine, a calcium-channel blocker, has shown that perindopril was more effective at slowing the progression of this condition in normotensive diabetics.Writing in the American Journal of Kidney Disease (May issue), George Jerums (University of Melbourne, VIC, Australia) and colleagues compared the results of 36 months of treatment with either perindopril or nifedipine of 33 normotensive patients with T1DM. Whereas there was no difference in mean arterial pressure, or changes in the levels of cholesterol, triglyceride or glycosylated hemoglobin between the two groups, albumin excretion rates (AER) progressively increased in both the nifedipine and placebo groups (reaching a median of 122 μg min−1 and 112 μg min−1 respectively) and declined in most of the patients receiving perindopril (a median of 23 μg min−1 was recorded).Compared with the four nifedipine-treated and three placebo-treated patients, only one perindopril-treated patient developed macroalbuminuria. Seven perindopril-treated patients regressed to normoalbuminuria compared with none of the other patients.That the use of an ACE inhibitor was more effective than were dihydropyridine calcium-channel blockers in slowing the long-term progression of albuminuria suggests that ACE inhibitors should be used as treatment for normotensive microalbuminuric patients with T1DM. However, Jerums et al. are quick to caution whether such functional effects of ACE inhibition are associated with protective effects on renal structure. LS

The Importance of Microalbuminuria as an Indicator of Incipient Diabetic Nephropathy: Therapeutic Implications

Nephropathy is the major life-threatening complication of insulin-dependent diabetes mellitus (IDDM). The clinical syndrome is characterized by persistent albuminuria (greater than 300 mg day), a rise in arterial blood pressure, and a relentless decline in glomerular filtration rate leading to end-stage renal failure. The availability of a radioimmunoassay for detecting albumin in low concentrations in urine has allowed the study of urinary albumin excretion rates in diabetics well before clinically persistent proteinuria develops. An albumin excretion rate greater than that in normal subjects and lower than that in macroalbuminuric subjects is called microalbuminuria (range 20–200 μg/min or 30–300 mg/24 h). Although recent studies have challenged the predictive value of microalbuminuria for later development of overt diabetic nephropathy, albumin excretion rate in the microalbuminuric range and its tracking (i.e. annual increase) are still considered reliable markers for prediction of later overt diabetic kidney disease. Overnight urinary collection is preferred for calculation of the rate of albumin excretion, but may be difficult to perform precisely. The albumin:creatinine ratio of the first morning urine sample is a reliable screening method: the microalbuminuric range is considered to be 2.5–25 mg/mmol or 30–300 mg/g (3.5 mg/mol has been proposed as lower limit in females because of their lower creatinine excretion). Irrespective of the procedure used, at least two samples over a 3–6-month period should test positive before microalbuminuria is confirmed and ‘persistent microalbuminuria’ defined. If the albumin excretion rate is persistently in the microalbuminuric range it is of crucial importance to define strategies and carry out interventions for prevention of decline in kidney function. The goal of achieving the best glycaemic control as early as possible in as many IDDM patients as is safely possible is particularly important in microalbuminuric patients. Although it is unsafe to reduce dietary protein intake drastically, particularly in children and adolescents, moderate decrease of protein intake (i.e. 0.9–1.1/g/kg day) is advisable in diabetic patients from the very beginning of the disease. Timely treatment with an angiotensin-converting enzyme inhibitor, independently of rise in arterial blood pressure, should be considered if improvement of glycaemic control and moderate decrease of dietary protein intake for 6–12 months have failed to reduce the albumin excretion rate. Screening programmes for microalbuminuria and early intervention can substantially modify the natural history of diabetic renal involvement and disease and possibly reduce the incidence of end-stage renal failure.

Nephroprotective effects of nitrendipine in hypertensive type I and type II diabetic patients.

Hypertension is significantly involved in the progression of diabetic nephropathy and in the development of end stage renal disease in both type I and type II diabetes mellitus. We have investigated whether long-term monotherapy with a calcium antagonist, nitrendipine, prevents the development of overt diabetic nephropathy in type I and type II diabetic patients with mild to moderate hypertension and persistent microalbuminuria (ie, incipient nephropathy). After a 4-week run-in and washout period, respectively, 25 patients met the inclusion criteria. Twenty-two patients (six with type I and 16 with type II diabetes) completed the 12-month study. Twelve months of treatment with nitrendipine resulted in a significant reduction in systolic blood pressure in patients with type I (157.5 +/- 8.1 mm Hg v 135.8 +/- 4.2 mm Hg, P < 0.05) and type II (163.1 +/- 4.3 mm Hg v 135.9 +/- 3.6 mm Hg, P < 0.001) diabetes. A significant reduction also was seen in diastolic blood pressure (91.7 +/- 1.7 mm Hg v 79.2 +/- 3.5 mm Hg in type I diabetic patients, P < 0.01; 94.7 +/- 1.4 mm Hg v 78.1 +/- 1.5 mm Hg in type II diabetic patients, P < 0.001). A significant reduction in albuminuria was associated with the blood pressure reduction in both type I (57.8 +/- 11.9 mg/24 hr v 24.9 +/- 5.9 mg/24 hr, -57%) and type II (134.6 +/- 20.7 mg/24 hr v 70.3 +/- 16.8 mg/24 hr, -48%) diabetic patients. The mean glomerular filtration rate increased by 21% (112 +/- 12 mL/min v 135 +/- 14 mL/min) and by 23% (106 +/- 12 mL/min v 130 +/- 14 mL/min) in type I and type II diabetic patients, respectively. No significant changes were found in renal plasma flow rates or in serum concentrations of beta 2-microglobulin. With the exception of a significant (P < 0.05) reduction in hemoglobin A1 concentration in type II diabetic patients after 3 months of treatment with nitrendipine, fasting blood glucose, hemoglobin A1, residual beta-cell function (C-peptide levels), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and body mass index remained essentially unchanged during follow-up. These findings suggest that 12 months of monotherapy with the dihydropyridine-type calcium antagonist nitrendipine reduced albuminuria and increased the lowered glomerular filtration rate without adverse effects on glucose and lipid control.(ABSTRACT TRUNCATED AT 400 WORDS)

Global glomerular sclerosis and glomerular arteriolar hyalinosis in insulin dependent diabetes

We studied the lesions of global glomerular sclerosis and arteriolar hyalinosis in 43 (29 females) insulin-dependent diabetes mellitus (IDDM) patients whose creatinine clearance (CCr) was greater than or equal to 45 ml/min/1.73 m2 and whose renal biopsies had at least 20 glomeruli available for study. These patients, ages 17 to 55 years, had IDDM for 7 to 32 (20 +/- 6, means +/- SD) years. CCr ranged from 47 to 139 (91 +/- 25) ml/min/1.73 m2 and urinary albumin excretion (UAE) from 5 to 3386 (median = 127) mg/24 hrs. Eighteen patients were hypertensive. Thus, these patients represented a broad clinical range from normal renal function through overt diabetic nephropathy. The percent of glomeruli which were globally sclerosed was strongly correlated with CCr (r = -0.64, P less than 0.0001) and log UAE (r = +0.67, P less than 0.001). Hypertension was more common in patients with more than 10% sclerosed glomeruli (chi square = 9.5, P less than 0.002). Percent sclerosed glomeruli was highly significantly correlated with the index of severity of the arteriolar hyalinosis lesion (r = +0.66, P less than 0.0001) and mesangial volume fraction (r = +0.61, P less than 0.0001). We hypothesize that arteriolar hyalinosis could contribute to global glomerular sclerosis through severe compromise of glomerular blood flow. Alternately, global glomerular sclerosis may result from marked mesangial expansion and capillary occlusion. However, in this broad range of patients it appeared that global glomerular sclerosis and mesangial expansion were not infrequently independent diabetic renal lesions which could contribute separately to the ultimate development of overt diabetic nephropathy.

Global glomerular sclerosis and glomerular arteriolar hyalinosis in insulin dependent diabetes

We studied the lesions of global glomerular sclerosis and arteriolar hyalinosis in 43 (29 females) insulin-dependent diabetes mellitus (IDDM) patients whose creatinine clearance (CCr) was greater than or equal to 45 ml/min/1.73 m2 and whose renal biopsies had at least 20 glomeruli available for study. These patients, ages 17 to 55 years, had IDDM for 7 to 32 (20 +/- 6, means +/- SD) years. CCr ranged from 47 to 139 (91 +/- 25) ml/min/1.73 m2 and urinary albumin excretion (UAE) from 5 to 3386 (median = 127) mg/24 hrs. Eighteen patients were hypertensive. Thus, these patients represented a broad clinical range from normal renal function through overt diabetic nephropathy. The percent of glomeruli which were globally sclerosed was strongly correlated with CCr (r = -0.64, P less than 0.0001) and log UAE (r = +0.67, P less than 0.001). Hypertension was more common in patients with more than 10% sclerosed glomeruli (chi square = 9.5, P less than 0.002). Percent sclerosed glomeruli was highly significantly correlated with the index of severity of the arteriolar hyalinosis lesion (r = +0.66, P less than 0.0001) and mesangial volume fraction (r = +0.61, P less than 0.0001). We hypothesize that arteriolar hyalinosis could contribute to global glomerular sclerosis through severe compromise of glomerular blood flow. Alternately, global glomerular sclerosis may result from marked mesangial expansion and capillary occlusion. However, in this broad range of patients it appeared that global glomerular sclerosis and mesangial expansion were not infrequently independent diabetic renal lesions which could contribute separately to the ultimate development of overt diabetic nephropathy.

Diabetic nephropathy in normotensive patients

Arterial pressure is within 'normal' limits in most diabetic patients with or without microalbuminuria and elevated in 70% of patients with overt diabetic nephropathy. An abnormal increase in the level of urinary excretion is a strong predictor of the subsequent development of overt diabetic nephropathy and ultimately renal insufficiency. Correction of hypertension is associated with a reduction in the rate of decline of the glomerular filtration rate in overt diabetic nephropathy. In patients with microalbuminuria, short-term studies have shown that angiotensin converting enzyme (ACE) inhibitors, in contrast with calcium antagonists, decrease urinary albumin excretion. Additional studies assessing the long-term effect of antihypertensive agents on the evolution of early diabetic nephropathy are needed. The superiority of ACE inhibitors over other antihypertensive agents in the treatment of overt or early diabetic nephropathy remains to be demonstrated. In addition to arterial pressure control, it is possible that optimal glycaemic control in addition to the modification of protein intake, dietary sodium and serum lipid profile may alter the course of diabetic nephropathy.