The Natural Course of Microalbuminuria in Insulin-dependent Diabetes: A 10-year Prospective Study

The purpose of this study was to describe the clinical course in patients followed right from the onset of microalbuminuria to the development of diabetic nephropathy. A 10-year prospective follow-up of 209 consecutive normotensive insulin-dependent diabetic patients with normal urinary albumin excretion (UAE <30 mg 24 h^?1), age 34 (18–50) years and duration of diabetes 17 (10–30) years was performed. Twenty-four-hour urinary albumin excretion was measured every 4 months, glycated haemoglobin and supine blood pressure was measured annually. Two-hundred (96%) patients completed 10 (range 5–10) years follow-up. Twenty-nine (15%) patients developed persistent microalbuminuria (UAE 30–300 mg 24 h^?1). Eight of these have progressed to nephropathy and one had died of diabetic nephropathy. Multiple stepwise logistic regression analysis demonstrated baseline urinary albumin excretion (p = 0.0016) and glycated haemoglobin (p = 0.0014) but not blood pressure as predictors of development of microalbuminuria within the following 10 years. The median annual increase in urinary albumin excretion was 27 (range 17–65)% in the 29 patients developing microalbuminuria. The median duration from onset of microalbuminuria to development of nephropathy was 7 years. The prevalence of patients receiving antihypertensive treatment (BP > 140/90 mmHg) increased from 10% at onset of microalbuminuria to 45% 4 years after onset of microalbuminuria. The prevalence of patients with proliferative retinopathy increased from 7% at onset of microalbuminuria to 28% 4 years after onset of microalbuminuria. The incidence of persistent microalbuminuria in normotensive insulin-dependent diabetic patients is 2% per year, and development of persistent microalbuminuria is a strong predictor of overt nephropathy. Development of hypertension is frequent in the early course of microalbuminuria and treatment modalities for normotensive patients with microalbuminuria are urgently needed.     

Urinary albumin excretion and 24-hour blood pressure as predictors of pre-eclampsia in Type I diabetes

Aims/hypothesis. To evaluate the value of 24-h blood pressure monitoring compared to office blood pressure and urinary albumin excretion in predicting pre-eclampsia in Type I (insulin-dependent) diabetes mellitus.¶Methods. The study included 136 consecutive pregnancies in Caucasian women with Type I diabetes before gestation without diabetic nephropathy, anamnestic hypertension or early abortion. Values of urinary albumin excretion and office blood pressure before pregnancy and the HbA_1C value at the time of conception were obtained. Microalbuminuria was defined as urinary albumin excretion of 30–300 mg/24 h in two out of three consecutive urine samples. Single measurements of 24-h urinary albumin excretion, office blood pressure and HbA_1C were done five 5 times during pregnancy. In a subgroup of 74 women 24-h blood pressure measurements were done at 10 and 28 weeks of gestation. Pre-eclampsia was defined as office blood pressure higher than 140/90 mm Hg accompanied by proteinuria above 0.3 g/24 h later than 20 weeks of gestation.¶Results. Urinary albumin excretion and systolic blood pressure were higher before and throughout pregnancy in 14 women developing pre-eclampsia compared with women remaining normotensive (p < 0.001; p < 0.05, respectively). By logistic regression analysis the best predictor for pre-eclampsia was microalbuminuria before pregnancy (p < 0.05) with no additive predictive effect of 24-h blood pressure or office blood pressure measurement. The night:day ratio of blood pressure was similar in the two groups.¶Conclusion/interpretation. Microalbuminuria before pregnancy is the strongest predictor of pre-eclampsia in Type I diabetes. Measuring 24-h blood pressure early in pregnancy did not improve the ability to identify women at risk. [Diabetologia (2000) 43: 927–931]     

Efficacy of urinary N-acetyl-β-D-glucosaminidase to evaluate early renal tubular damage as a consequence of type 2 diabetes mellitus: a cross-sectional study

We assessed the prognostic accuracy of urinary N-acetyl-β-D-glucosaminidase (NAG), an early proximal tubular damage marker for the onset of diabetic nephropathy. The study included 491 eligible participants with 76 healthy controls, 194 type 2 diabetes mellitus (T2DM) patients with 0–5, 5–10, 10–15, and 15–20 years of T2DM duration, 71 microalbuminuric patients, 100 diabetic nephropathy patients, and 50 non-diabetic nephropathy patients. Fasting glucose, serum fructosamine, HbA1C, urinary microalbumin, serum creatinine, estimated glomerular filtration rate (eGFR), serum NAG, and urinary NAG were estimated. We compared urinary NAG activity with other well-established markers of diabetic nephropathy like microalbuminuria, eGFR, and serum creatinine. Urinary NAG excretion was increased by 8 and 12 folds in T2DM patients of 10–15 and 15–20 years of diabetes duration (p < 0.0001), respectively, without the appearance of microalbuminuria. The urinary NAG activity increased 16 and 18 fold in moderately increased albuminuria and diabetic nephropathy patients, respectively (p < 0.0001), without any change in non-diabetic nephropathy patients. A cutoff value of 3 U/L of urinary NAG has demonstrated a sensitivity of 96.1 % and a specificity of 100 % discriminating healthy controls from patients with T2DM duration of 10–15 years (AUC 1.000) and 15–20 years (AUC 0.999); microalbuminuria (AUC 0.999), and diabetic nephropathy (AUC 1.000). Urinary NAG excretion gradually increases with the increase in duration of diabetes and appeared much before the microalbuminuria, decreased eGFR, and increased serum creatinine. Thus, the urinary NAG may be considered as a potential site-specific early tubular damage marker leading to diabetic nephropathy.

     

Microalbuminuria as Identified by a Spot Morning Urine Specimen in Non-insulin-treated Diabetes: an Eight-year Follow-up Study

This study followed up a cohort of patients with microalbuminuria identified on a spot morning urine sample 8 years earlier and aimed to determine if a spot morning urinary albumin concentration was able to identify patients with non-insulin treated diabetes at increased risk of mortality and progression to nephropathy. In 1984, 47 of 216 patients chosen by random selection from our teaching hospital-based diabetes clinic were identified as having microalbuminuria (urinary albumin concentration 35–300 μg ml^?1). Subjects were compared with an age-matched control group from the 1984 cohort who did not have microalbuminuria. Eight years later, 22 of 47 (46.8 %) patients with microalbuminuria had died compared to 10 of 47 (21.3 %) patients without albuminuria (p < 0.05). The majority of deaths were from cardiovascular disease (53.1 %). Logistic regression showed microalbuminuria to be an independent predictor of mortality, not influenced by age, duration of diabetes, blood pressure, glycosylated haemoglobin or creatinine at the initial examination. Eight years later, in the group with initial microalbuminuria, eight still had microalbuminuria and five patients had developed nephropathy. In the group without albuminuria in 1984, only one patient had progressed to microalbuminuria and no patients to nephropathy. In conclusion, a spot urinary albumin concentration is of value in identifying patients with an increased risk of mortality or progression to nephropathy, and is simple to obtain at a clinic.     

Urinary excretion of albumin, α-1-microglobulin,and N-acetyl-B-D-glucosaminidase in relation to smoking habits in diabetic and nondiabetic subjects

Smoking may be a risk factor for the development of diabetic nephropathy. Therefore, the urinary excretion of albumin, α-1-microglobulin, and N-acetyl-BD glucosaminidase was studied in 24 young adult diabetic patients who smoked. None of these patients had urine samples positive for albumin as determined by the Albustix method (i.e., a urinary concentration of albumin of < 0.5 g in 24 hr). Control groups were nonsmoking diabetic patients (matched for age and duration of diabetes) and nondiabetic subjects (smokers and nonsmokers). Explred breath carbon monoxide and the urinary nicotine metabolite continine were measured as objective markers of smoking load. No significant differences in concentrations of urinary proteins were found among any of the four groups. Therefore, smoking is not associated with the development of an increased urinary excretion of albumin within the “microalbuminuria” range. However, further studies are required to determine whether smoking is a risk factor for the progression of established microalbuminuria to Albustix positive proteinuria in diabetic patients.     

Albuminuria and associated medical risk factors: A cross-sectional study in 476 type I (insulin-dependent) diabetic patients. Part 1

Albumin concentration in a morning urine sample was analyzed in a cross-sectional study in 476 insulin-dependent diabetic patients. The following groups of patients were defined: A) normal urinary albumin (urine albumin <12.5 mg/L); B) high normal albuminuria (12.5–30 mg/L); C) microalbuminuria, ie, incipient nephropathy (31–299 mg/L); and D) clinical nephropathy (≥300 mg/L). The prevalences of incipient and clinical diabetic nephropathy were 24.8 and 14.4%, respectively. There were no differences in clinical parameters such as age, age at onset or duration of diabetes, blood pressure, serum creatinine, or HbA_1c levels between groups A and B. The frequency of retinopathy in these groups was 55 and 50%, respectively. In group C, there were increases in age, duration of diabetes, blood pressure, serum creatinine, and HbA_1c levels. The frequency of retinopathy was higher (80%), and more patients had severe forms (47%). In group D, there were further increases in all parameters and, in addition, younger age at onset of diabetes. The frequency of retinopathy was 97%, and severe forms of retinopathy were more common (86%). Seventeen percent of the patients were treated for hypertension. These patients were older, had longer duration of diabetes, and had higher levels of blood pressure, serum creatinine, and urinary albumin, as well as a younger age at onset of diabetes than patients not requiring antihypertensive treatment.     

Glycosaminoglycans urinary excretion as a marker of the early stages of diabetic nephropathy and the disease progression

BACKGROUND: Diabetes mellitus affects the metabolism of several components of extra-cellular matrix, including glycosaminoglycans (GAG). Alterations in the metabolism of GAG may play an important role in the development of diabetic complications. METHODS: Consequently, the relationship between diabetic nephropathy and urinary GAG excretion has been estimated in 86 diabetic patients (33 type 1 diabetes mellitus (DM), 53 type 2 DM) in comparison to 30 healthy controls (Figure 1). GAG concentration in 24-h urine samples has been determined by precipitation with cetylpyridinum chloride and potassium acetate in ethanol followed by a fluorometric test with 2-Hexadecyl-9H-pyrido(4,3b)indolium Bromide. RESULTS: Diabetic subjects excrete significantly more GAG than the control group (66.47 mg/24 h vs 50.11 mg/24 h). A marked difference in urinary GAG excretion between diabetic patients with nephropathy (74.66 +/- 7.5 mg/24 h) and without nephropathy (50.13 +/- 5.37 mg/24 h) has been detected. With diabetic nephropathy, patients with a longer history of GAG excretion experience an increase. An increased urinary GAG excretion has been detected in patients with microalbuminuria or macroalbuminuria. CONCLUSIONS: In conclusion, it can be stated that all patients with DM compared to the control group show an increase in GAG excretion independent of diabetes duration. Urinary GAG excretion positively correlates with the duration of diabetic nephropathy. The assessment of GAG excretion values may be useful for determining the early stages of diabetic nephropathy and the progression of the disease.     

Lipid pattern,apolipoproteins A1 and B and lipoprotein (a) in type 1 diabetic patients with microalbuminuria

The plasma lipid changes commonly observed in patients with diabetic nephropathy may play a major role in determining the increased cardiovascular risk in these patients. Contrasting results have been reported on the patterns of lipids and lipoproteins in diabetic subjects with microalbuminuria. We examined 20 patients with type 1 (insulin-dependent) diabetes who had a urinary albumin excretion >30 mg/24 h (11 males and 9 females, age range 16–45 years, mean diabetes duration 11.7 years) and 20 type 1 diabetic patients without microalbuminuria matched for sex, age, diabetes duration, daily insulin requirement and degree of metabolic control. In all patients we measured plasma total cholesterol, highdensity lipoprotein (HDL)-cholesterol, triglycerides, apolipoproteins A₁ and B and lipoprotein (a) [Lp(a)]. No significant differences were found for any parameter between subjects with a urinary albumin excretion <20 mg/ 24 h and microalbuminuric patients. Moreover in nondiabetic controls the levels of plasma Lp(a) and of the other parameters measured were not significantly different from those of the two diabetic groups. Our results suggest that in type 1 diabetic patients with fairly good glycaemic control microalbuminuria is not associated with significant changes in the lipoprotein pattern.     

Microalbuminuria in patients with rheumatoid arthritis.

OBJECTIVES--To assess (a) the prevalence of microalbuminuria in patients with rheumatoid arthritis, (b) the association between urinary albumin excretion and disease activity as estimated by the erythrocyte sedimentation rate and C reactive protein (CRP), and (c) the association between urinary albumin excretion and treatment with antirheumatic drugs. METHODS--Sixty five patients with rheumatoid arthritis attending two rheumatology clinics were compared with 51 control subjects matched by age and sex. The controls consisted of 20 healthy subjects, 16 patients with osteoarthritis and 15 with non-articular rheumatism. Patients with hypertension, diabetes mellitus, or evidence of previous renal disease were not included. Urinary albumin was assayed by immunoturbidimetry in random urine samples on two occasions within seven months. The results were expressed as the ratio of urinary albumin to urinary creatinine ratio. Disease activity was assessed by the erythrocyte sedimentation rate and CRP. A drug history for the year before entry to the study was obtained for each patient. RESULTS--Urinary albumin to creatinine ratio in patients with rheumatoid arthritis was significantly greater than in controls (p < 0.01). Microalbuminuria (urinary albumin to creatinine ratio 3-30 mg/mmol in either or both urine samples) was present in 27.7% of patients with rheumatoid arthritis and 7.8% of the control subjects. A significant relation was noted between urinary albumin to creatinine ratio and CRP, and the duration of disease. The number of patients treated with either gold or penicillamine was significantly greater in patients with microalbuminuria than in patients with normoalbuminuria. CONCLUSIONS--Microalbuminuria is frequently present in patients with rheumatoid arthritis. Treatment with gold and penicillamine seems to increase the risk of developing microalbuminuria. Urinary albumin measured by immunochemical methods is a simple and sensitive test to detect early subclinical renal dysfunction and drug induced renal damage in rheumatoid arthritis. Urinary albumin excretion was found to be significantly correlated with CRP and may be a sensitive indicator of disease activity in patients with rheumatoid arthritis.     

Prevalence of microalbuminuria in maturity onset primarily non-insulin-requiring diabetes mellitus: Effect of disease duration,glycemic control,and mean systemic blood pressure

Because of the frequency of late cardiovascular complications in maturity onset non-insulin-dependent (Type II) diabetes mellitus, there have been few studies regarding nephropathy in this patients population. The authors have analyzed the prevalence of microalbuminuria and the nature of clinical manifestations associated with elevated albumin excretion rate (AER) in a large poputation presenting with Type II diabetes. Among 318 patients studied during 1986, pathologically elevated 24 h AERs were found in 59%. The rate of microalbuminuria among 205 Type I diabetic patients screened during the same interval was 43%. AER was found to be positively correlated with duration of disease (p<0.0008) and metabolic control as determined by measurement of glycosylated hemoglobin (HaA1_c) (p<0.002). There was only a modest agreement between AER and mean systemic blood pressure. The high prevalence of microalbuminuria in Type II diabetic patients and its known association with increased mortality emphasize the need for long-term follow up studies in order to clarify whether elevated AER in this patient populationsis predictive for overt diabetic nephropathy.     

First morning urinary albumin concentration is a good predictor of 24-hour urinary albumin excretion in children with Type I (insulin-dependent) diabetes

Summary Twenty-four hour urinary albumin excretion was measured in 97 children with Type 1 (insulin-dependent) diabetes and found to have a geometric mean of 6 mg/day (range 1–38 mg/d). The same geometric mean of 6 mg/day (range 1–45 mg/d) was found in 120 normal children. The relationship of 24-h urinary albumin excretion to the albumin concentration (mg/1) and to the ratio of albumin: creatinine (mg: mmol) on first morning urine samples in 64 patients was highly significant (r=0.93 and r=0.62 respectively, p < 0.001). In 41 patients, the relationship between 24-h urinary albumin excretion and albumin concentration upon urine samples at various times was assessed. The correlation was highest on the first morning sample (r=0.86); 09.00h to 13.00 h, 0.51; 13.00 h to 18.00 h, 0.68; 18.00 h to 23.00 h, 0.32. High sensitivity and moderate specificity was obtained using a first morning albumin concentration of greater than 20 mg/l to detect increased albumin excretion. These results show that the measurement of albumin concentration on the first morning urine sample can be used for a screening test for micro-albuminuria in children.     

Elevated urinary prostaglandin excretion and the effect of indomethacin on renal function in incipient diabetic nephropathy

We investigated whether the glomerular synthesis of prostaglandins modulates the glomerular filtration rate and urinary albumin excretion in incipient diabetic nephropathy (defined as urinary albumin excretion between 30 and 300 mg/24 h (microalbuminuria) in two out of three sterile ketone-free 24-h urine collections in patients having insulin-dependent diabetes mellitus (IDDM) without hypertension or other kidney disease). The urinary excretion of prostaglandin E2 was significantly elevated in 8 insulin-dependent diabetic patients with incipient nephropathy as compared with 9 normoalbuminuric IDDM patients and 11 healthy controls: 317 (182-1273); 95 (67-225); 132 (54-263) pg/min, respectively (2p less than 0.01). Glomerular filtration rate (single bolus 51Cr-EDTA technique) and albuminuria (radioimmunoassay) were measured twice within 2 weeks in 8 females having IDDM with incipient nephropathy. The study design was a randomized double-blind trial with the patients receiving either indomethacin (150 mg/day) or placebo for 3 days prior to the kidney function studies. Indomethacin treatment induced a significant reduction in urinary prostaglandin E2 excretion (73%) (2p less than 0.01), urinary albumin excretion rate diminished from 207 (63-253) to 87 (49-147) mg/24 h (2p less than 0.01), fractional clearance of albumin declined (70%) (2p less than 0.01). Glomerular filtration rate remained stable (108 (88-133) versus 110 (95-142) ml/min). Blood glucose and blood pressure were comparable during the placebo and indomethacin treatment (12.6 +/- 3 versus 13.4 +/- 5 mmol/l and 122/79 +/- 3/9 versus 122/82 +/- 4/10 mmHg, respectively). Our results suggest that enhanced glomerular synthesis of vasodilating prostaglandins may accelerate microalbuminuria in incipient diabetic nephropathy.     

Adjunctive treatment with moxonidine versus nitrendipine for hypertensive patients with advanced renal failure: a cost-effectiveness analysis

Background

The prevalences and risk factors of microalbuminuria are not full described among black African diabetic patients. This study aimed at determining the prevalence of microalbuminuria among African diabetes patients in Dar es Salaam, Tanzania, and relate to socio-demographic features as well as clinical parameters.

Methods

Cross sectional study on 91 Type 1 and 153 Type 2 diabetic patients. Two overnight urine samples per patient were analysed. Albumin concentration was measured by an automated immunoturbidity assay. Average albumin excretion rate (AER) was used and were categorised as normalbuminuria (AER < 20 ug/min), microalbuminuria (AER 20–200 ug/min), and macroalbuminuria (AER > 200 ug/min). Information obtained also included age, diabetes duration, sex, body mass index, blood pressure, serum total cholesterol, high-density and low-density lipoprotein cholesterol, triglycerides, serum creatinine, and glycated hemoglobin A_1c.

Results

Overall prevalence of microalbuminuria was 10.7% and macroalbuminuria 4.9%. In Type 1 patients microalbuminuria was 12% and macroalbuminuria 1%. Among Type 2 patients, 9.8% had microalbuminuria, and 7.2% had macroalbuminuria. Type 2 patients with abnormal albumin excretion rate had significantly longer diabetes duration 7.5 (0.2–24 yrs) than those with normal albumin excretion rate 3 (0–25 yrs), p < 0.001. Systolic and diastolic blood pressure among Type 2 patients with abnormal albumin excretion rate were significantly higher than in those with normal albumin excretion rate, (p < 0.001). No significant differences in body mass index, glycaemic control, and cholesterol levels was found among patients with normal compared with those with elevated albumin excretion rate either in Type 1 or Type 2 patients. A stepwise multiple linear regression analysis among Type 2 patients, revealed AER (natural log AER) as the dependent variable to be predicted by [odds ratio (95% confidence interval)] diabetes duration 0.090 (0.049, 0.131), p < 0.0001, systolic blood pressure 0.012 (0.003–0.021), p < 0.010 and serum creatinine 0.021 (0.012, 0.030).

Conclusion

The prevalence of micro and macroalbuminuria is higher among African Type 1 patients with relatively short diabetes duration compared with prevalences among Caucasians. In Type 2 patients, the prevalence is in accordance with findings in Caucasians. The present study detects, however, a much lower prevalence than previously demonstrated in studies from sub-Saharan Africa. Abnormal AER was significantly related to diabetes duration and systolic blood pressure.     

Haemostatic Measures in Type 2 Diabetic Patients with Microalbuminuria

The major cause of disability and early mortality in Type 2 diabetes is cardiovascular disease. An enhanced urinary albumin excretion is strongly predictive of increased mortality, but the causal relationship behind this association is unclear. Abnormalities in the haemostatic system may be involved in the vascular pathology. We therefore studied the level of von Willebrand factor (vWf:Ag), factor VIII (VIII:Ag), fibrinogen, and fibronectin in male diabetic patients 50–70 years of age, with normal albumin excretion (n = 14), microalbuminuria (n = 14), and frank albuminuria (n = 7). Fourteen healthy age-matched males served as a reference group. There were no significant differences between normo-and micro-albuminuric patients but vWf:Ag (p < 0.01), VIII:Ag (p < 0.01), and fibrinogen (p < 0.05) were increased in those with frank albuminuria. Urinary albumin excretion rate was significantly correlated to vWf:Ag (r = 0.46, p = 0.005), VIII:Ag (r = 0.45, p = 0.007), and fibrinogen (r = 0.49, p = 0.003). The known duration of diabetes was correlated to vWf and F VIII. The increased level of vWf:Ag in Type 2 diabetes and the significant association to the urinary albumin excretion rate may suggest a linkage between albuminuria and cardiovascular disease. However, the present study demonstrated no increase in haemostatic variables in patients with microalbuminuria as compared with those with normal albumin excretion.     

Relationship of Smoking and Albuminuria in Children with Insulin-dependent Diabetes

Recent evidence suggests the rise in urinary albumin excretion preceding diabetic nephropathy may represent a continuum. We therefore studied factors relating to albumin excretion rate in children with insulin-dependent diabetes. Normal overnight albumin excretion rate was determined in 690 healthy schoolchildren. The 95th centile was 7.2 μg min^?1. Patients included 169 children with IDDM aged 12.4 ± 3.1 years who performed 4.8 ± 0.4 overnight collections during 15 ± 0.5 months and were analysed cross sectionally. They were stratified accordingly to mean albumin excretion rate: normal < 7.2 μg min^?1, borderline 7.2–20 μg min^?1, microalbuminuria 20–200 μg min^?1; 96/169 patients performed 6.4 ± 0.2 overnight collections during 24 months follow-up and were analysed longitudinally. Cigarette smoking was determined by history and urine cotinine levels. Smoking correlated with albumin excretion rate, independent of age and other variables, in cross-sectional and longitudinal analysis (p < 0.003). Smoking was more prevalent in the borderline albuminuria and microalbuminuria groups (p < 0.004, p < 0.001). Mean HbA_1c during follow-up and mean HbA_1c since diagnosis were significantly higher in the microalbuminuric group, compared with the normal patient group. HbA_1c since diagnosis, mean blood pressure, lipoprotein(a), and apolipoprotein B did not correlate with albumin excretion rate, after controlling for other variables. Our findings highlight the continuing need for strategies to prevent smoking in this age group.     

Association of the pattern recognition molecule H-ficolin with incident microalbuminuria in an inception cohort of newly diagnosed type 1 diabetic patients: an 18 year follow-up study

Aims/hypothesis

Increasing evidence links complement activation through the lectin pathway to diabetic nephropathy. Adverse complement recognition of proteins modified by glycation has been suggested to trigger complement auto-attack in diabetes. H-ficolin (also known as ficolin-3) is a pattern recognition molecule that activates the complement cascade on binding to glycated surfaces, but the role of H-ficolin in diabetic nephropathy is unknown. We aimed to investigate the association between circulating H-ficolin levels and the incidence of microalbuminuria in type 1 diabetes.

Methods

We measured baseline H-ficolin levels and tracked the development of persistent micro- and macroalbuminuria in a prospective 18 year observational follow-up study of an inception cohort of 270 patients with newly diagnosed type 1 diabetes.

Results

Patients were followed for a median of 18 years (range 1–22 years). During follow-up, 75 patients developed microalbuminuria, defined as a persistent urinary albumin excretion rate (UAER) above 30 mg/24 h. When H-ficolin levels were divided into quartile groups an unadjusted Cox proportional hazards regression model showed a significant association with risk of incident microalbuminuria during follow-up (HR, fourth vs first quartile, 2.45; 95% CI 1.24, 4.85) (p?=?0.01). This remained significant after adjusting for HbA_1c, systolic blood pressure, smoking and baseline UAER (HR 2.09; 95% CI 1.03, 4.25) (p?=?0.04).

Conclusions/interpretation

Our data suggest that high levels of the complement activating molecule H-ficolin are associated with an increased risk of future progression to microalbuminuria in patients with newly diagnosed type 1 diabetes.     

Urinary excretion of retinol-binding protein in type 1 (insulin-dependent) diabetic patients with microalbuminuria and clinical diabetic nephropathy

The urinary excretion of retinol-binding protein (RBP) was studied in 101 insulin-dependent diabetic patients allocated to three groups according to 24-h urinary albumin excretion rate (UAE) (median of three urine collections): group 1 (n=45), normal UAE<30 mg/24h; group 2 (n=27), microalbuminuria (UAE 30–300 mg/24 h); and group 3 (n=29), clinical diabetic nephropathy (UAE>300 mg/24 h). We used 23 healthy subjects as controls. Fractional clearance of RBP (FC-RBP) and its 24-h urinary excretion rate (URBP) were higher in each diabetic group than in healthy subjects, the highest values being found in group 3. Groups 1 and 2 did not differ in URBP and FC-RBP. There was a correlation between FC-RBP and haemoglobin A1c in both the total diabetic cohort (P<0.001) and in diabetic patients in groups 1 and 2 with a glomerular filtration rate of more than 90 ml/min (P<0.05). No correlation was found between FC-RBP and UAE and/or duration of diabetes in any of the diabetic groups. We conclude that the increased urinary excretion of RBP, indicating proximal tubular dysfunction, is already present in normoalbuminuric insulindependent diabetic patients and correlates with metabolic control. Further deterioration in proximal tubular function was not observed in microalbuminuric patients, but is a late event in clinical diabetic nephropathy.     

Prevalence of microalbuminuria in children with Type 1 (insulin-dependent) diabetes mellitus

Summary The prevalence of microalbuminuria was determined in children aged 7 to 18 years with Type 1 (insulin-dependent) diabetes of more than 2 years' duration. All patients (n =102) attending 2 diabetes clinics were asked to collect 2 overnight timed urine samples for albumin analysis by radioimmunoassay. Complete urine collection was obtained in 97 patients (95%). Overnight urinary albumin excretion rates were also measured in 36 healthy children matched for age and sex. Nineteen of the 97 patients (20%) had microalbuminuria, i. e. overnight urinary albumin excretion rates above the upper normal level (14 g/min) in both urine collections. Microalbuminuria was only demonstrated in patients aged 15 years, prevalence 37% (19/52 patients). Arterial blood pressure was elevated, mean 122/84±11/9mmHg, in the microalbuminuric group (19 patients) compared to the age-matched normoalbuminuric diabetic group (33 patients), mean 117/74±10/10 mm Hg,p < 0.001. The prevalence of simplex retinopathy was identical in these two groups, i. e. 25%. Glycosylated haemoglobin was slightly higher in the microalbuminuric patients,p < 0.10. Our cross-sectional study reveals a high prevalence (37%) of persistent microalbuminuria, a stage highly predictive of later development of diabetic nephropathy, in Type 1 diabetic children aged 15 years.     

Transferrinuria in type 2 diabetic patients with early nephropathy and tubulointerstitial injury

BACKGROUND: Transferrinuria is thought to be a marker for early stages of diabetic nephropathy. Transferrin has also been proposed as a mediator of tubular toxicity because the reabsorption of transferrin results in the release of reactive iron in proximal tubular cells, promoting the formation of hydroxyl radicals. We evaluated the role of urinary transferrin excretion in diabetic patients with early nephropathy by comparing tubulointerstitial injury in renal biopsy specimens. PATIENTS AND METHODS: 45 type 2 diabetic patients with normoalbuminuria (urinary albumin excretion <30 mg/24 h) or microalbuminuria (30-300 mg/24 h) were studied. All patients with microalbuminuria underwent renal biopsy, and the severity of the tubulo-interstitial lesions was determined by a semiquantitative estimate of interstitial fibrosis, tubular atrophy, and interstitial inflammatory infiltrates. Subjects were classified into group A (normoalbuminuria, n=25), group B (microalbuminuria without tubulointerstitial changes, n=11) or group C (microalbuminuria with tubulointerstitial changes, n=9). RESULTS: Urinary transferrin excretion (UTf), as well as UTf/creatinine clearance (Ccr), and transferrin clearance (CTf/Ccr), was significantly higher in groups B and C than in group A, and it was significantly higher in group C than in group B. There were no significant differences in urinary albumin excretion or mesangial expansion rate (MR% estimated by quantitative morphometric studies) between groups B and C. Although urinary beta2-microglobulin excretion was significantly higher in group C than in groups A and B, urinary N-acetyl-beta-D-glucosaminidase activity was significantly higher in groups B and C than in group A. CONCLUSIONS: Increased transferrinuria in the microalbuminuric stage may lead to the development of tubulointerstitial injuries in type 2 diabetic patients.     

Efficacy of antihypertensive treatment with indapamide in patients with noninsulin-dependent diabetes and persistent microalbuminuria

In patients with insulin-dependent diabetes, antihypertensive treatment has a beneficial effect on the rate of progression toward uremia of overt diabetic nephropathy (albumin excretion rate [AER] greater than 300 mg/24 hour). The influence of hypertension on the progression of "incipient" nephropathy (AER ranging between 30 and 300 mg/24 hours) is not well defined, particularly in patients with noninsulin-dependent diabetes. In this study, 21 patients with noninsulin-dependent diabetes and hypertension (11 with normoalbuminuria and 10 with microalbuminuria), who were comparable for age, duration of diabetes and hypertension, were treated with indapamide, 2.5 mg once daily, and followed up for 24 months. Blood pressure, glomerular filtration rate (GFR), albumin excretion rate and subclass 4 of urinary immunoglobulin G (IgG4) were indicated. In normoalbuminuric patients, blood pressure was significantly reduced, whereas AER, IgG4 and GFR did not show any variation throughout the study. In microalbuminuric patients, blood pressure, AER and IgG4 were significantly reduced, and GFR remained unchanged. In patients with noninsulin-dependent diabetes, antihypertensive treatment, which is begun during incipient diabetic nephropathy, may have a beneficial effect on the progression of the disease, although a long-term follow-up study is needed to confirm this.