The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus

Aims/hypothesis

High intraglomerular pressure causes renal inflammation in experimental models of diabetes. Our objective was to determine whether renal hyperfiltration, a surrogate for intraglomerular hypertension, is associated with increased excretion of urinary cytokines/chemokines in patients with type 1 diabetes mellitus.

Methods

Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances for glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), respectively) and urine samples were obtained during clamped euglycaemia in individuals with type 1 diabetes with either hyperfiltration (GFR determined using inulin [GFR_INULIN] ≥135 ml? min^?1 1.73 m^?2, n?=?28) or normofiltration (n?=?21) and healthy control individuals (n?=?18).

Results

Baseline clinical characteristics, dietary sodium and protein intake and blood pressure levels were similar in the diabetic and healthy control groups. In addition, HbA_1c levels were similar in the two diabetic groups. As expected baseline GFR was higher in hyperfilterers than either normofiltering diabetic patients or healthy control patients (165?±?9 vs 113?±?2 and 116?±?4 ml min^?1 1.73 m^?2, respectively, p?<?0.01). ERPF and renal blood flow were also comparatively higher and renal vascular resistance was lower in hyperfiltering patients (p?<?0.01). Hyperfiltering diabetic patients had higher excretion rates for eotaxin, IFNα2, macrophage-derived chemokine, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB and granulocyte-macrophage colony-stimulating factor (p?≤?0.01). Urinary monocyte chemoattractant protein (MCP)-1 and RANTES (regulated on activation, normal T expressed and secreted) excretion was also higher in hyperfiltering vs normofiltering diabetic individuals (p?<?0.01) and fibroblast growth factor-2, MCP-3 and CD40K excretion was elevated in hyperfiltering diabetic individuals vs healthy controls (p?<?0.01).

Conclusions/interpretation

Renal hyperfiltration is associated with increased urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes.     

Renal and glycemic determinants of glomerular hyperfiltration in normoalbuminuric diabetics

Glomerular hyperfiltration is a characteristic feature of insulin-dependent diabetes. We examined the relative roles of renal size, as well as glycemic parameters (HbA_1c, glycosylated albumin, plasma glucose) in addition to growth hormone, somatomedin C, β-hydroxybutyrate, alanine, and glycerol in determining the glomerular filtration rate (GFR). Sixty-two insulin-dependent patients with normal urinary albumin excretion rates (AER <15 μg/min), who were <50 years of age, were included in the study. Data were subjected to multiple regression analysis with GFR as a dependent variable. Renal volume was the primary statistical determinant of hyperfiltration, but HbA_1c also significantly correlated with GFR. No correlation was found with glycosylated albumin or blood glucose, but RPF correlated strongly with GFR, and borderline correlation was found between renal volume and HbA_1c. Renal hyperfiltration, defined as a GFR >150 ml/min, was found in approximately 50% of patients with HbA_1c values >9.5%. Other studies suggest that such patients have a much higher risk of developing clinically evident diabetic nephropathy over the ensuing years. Renal volume appears to be the major determinant of GFR, but long-term metabolic control, as evidenced by the level of HbA_1c, also contributes, partly independent of renal volume. Short-term metabolic control, as evaluated by blood glucose and serum-fructosamine, did not correlate with GFR. We suggest that exact determination of GFR and renal volume should be included in long-term prospective controlled intervention trials in patients with insulin-dependent diabetes mellitus (IDDM).     

Patterns of renal injury in NIDDM patients with microalbuminuria

Summary Microalbuminuria predicts overt nephropathy in non-insulin-dependent diabetic (NIDDM) patients; however, the structural basis for this functional abnormality is unknown. In this study we evaluated renal structure and function in a cohort of 34 unselected microalbuminuric NIDDM patients (26 male/8 female, age: 58 ± 7 years, known diabetes duration: 11 ± 6 years, HbA_{1 c}: 8.5 ± 1.6 %). Systemic hypertension was present in all but 3. Glomerular filtration rate (GFR) was 101 ± 27 ml · min^–1· 1.73 m^–2 and albumin excretion rate (AER) 44 (20–199) μg/min. Light microscopic slides were categorized as: C I) normal or near normal renal structure; C II) changes “typical” of diabetic nephropathology in insulin-dependent diabetes (IDDM) (glomerular, tubulo-interstitial and arteriolar changes occurring in parallel); C III) “atypical” patterns of injury, with absent or only mild diabetic glomerular changes associated with disproportionately severe renal structural changes including: important tubulo-interstitial with or without arteriolar hyalinosis with or without global glomerular sclerosis. Ten patients (29.4 %) were classified as C I, 10 as C II (29.4 %) and 14 as C III (41.2 %); none of these patients had any definable non-diabetic renal disease. GFR, AER and blood pressure were similar in the three groups, while HbA_{1 c} was higher in C II and C III than in C I patients. Diabetic retinopathy was present in all C II patients (background in 50 % and proliferative in 50 %). None of the patients in C I and C III had proliferative retinopathy, while background retinopathy was observed in 50 % of C I and 57 % of C III patients. In summary, microalbuminuric NIDDM patients are structurally heterogeneous with less than one third having “typical” diabetic nephropathology. The presence of both “typical” and “atypical” patterns of renal pathology was associated with worse metabolic control, suggesting that hyperglycaemia may cause different patterns of renal injury in older NIDDM compared to younger IDDM patients. [Diabetologia (1996) 39: 1569–1576]     

Constant Glomerular Filtration Rate in Diabetic Nephropathy

ABSTRACT. Twenty-one patients with diabetes of type I and diabetic nephropathy with reduced glomerular filtration rate (GFR) were followed prospectively with regard to GFR, proteinuria, blood pressure and glucosylated haemoglobin (HbA₁). All patients were on antihypertensive treatment. The mean rate of decline in GFR was only 0.38 ml/month = 4.6 ml/year. In one third of the patients, GFR remained constant at a reduced level for at least 24 months. Mean plasma clearance of ⁵¹Cr-EDTA in this group was 48.3±14.6 ml/min/1.73 m² body surface at entry and 48.0±13.6 at the time of evaluation. The patients with constant GFR had significantly less proteinuria and lower systolic as well as mean arterial pressure during the study than patients with falling GFR. They also had significantly lower mean HbA₁ and fewer very high HbA₁ values than patients who deteriorated. The data thus indicate that a combination of good metabolic control and effective blood pressure control may strongly delay the progression of renal insufficiency in diabetic nephropathy. They also show that low degree of proteinuria is a marker of good prognosis.     

Increased kidney size,glomerular filtration rate and renal plasma flow in short-term insulin-dependent diabetics

Summary Glomerular filtration rate (GFR), renal plasma flow (RPF) and kidney volume were measured in thirteen male subjects (mean age 30 years) with short-term insulin-dependent diabetes (mean duration of disease 2.4 years) and fourteen normal male subjects (mean age 29 years). GFR and RPF were measured by constant infusion technique using I¹²⁵-iothalamate and ¹³¹I-hippuran. Kidney size was determined by means of ultrasound. GFR, RPF and kidney volume were increased in the diabetic patients compared to the normal controls, 144 versus 113 ml/ min×1.73m² (p<0.0005), 627 versus 523 ml/ min×1.73 m² (p<0.0025) and 278 versus 224 ml/ 1.73 m² (p<0.0005) respectively. Combining results from diabetic patients and controls revealed a positive correlation between kidney size and GFR (r= 0.70, p<0.001) and between kidney size and RPF (r=0.61, p<0.001). Within the groups kidney size and RPF correlated significantly in the diabetics (p< 0.01) and the same was found for kidney size and GFR (0.025< p<0.05), while no correlations were found in the normal group. GFR and RPF correlated in the diabetics when evaluated separately (r=0.81, p<0.001) and in the controls (r=0.73, p<0.001). The previous and present data suggest that the mechanisms of the elevated GFR in insulin-dependent diabetics are enhanced RPF, increased transglomerular hydrostatic pressure gradient and increased glomerular ultrafiltration coefficient. The increased kidney size is probably the main cause of the above alterations in the GFR determinants.     

Renal hyperfiltration in type 2 diabetes: effect of age-related decline in glomerular filtration rate

Aims/hypothesis We sought to characterise the effect of the age-related decline of GFR on hyperfiltration in type 2 diabetes and to identify clinical characteristics associated with hyperfiltration. Materials and methods GFR was measured in 662 type 2 diabetic patients by plasma disappearance of 99 m-technetium-diethylene-triamine-penta-acetic acid. The prevalence of hyperfiltration was calculated using both an age-unadjusted GFR threshold of >130 ml min⁻¹ 1.73 m⁻² and an age-adjusted threshold incorporating a decline of 1 ml min⁻¹ year⁻¹ after the age of 40. The hyperfiltering patients were compared with type 2 diabetic subjects who had a GFR between 90 and 130 ml min⁻¹ 1.73 m⁻² and were matched for age, sex and disease duration to allow for identification of modifiable factors associated with hyperfiltration. Results The prevalence of hyperfiltration was 7.4% when age-unadjusted and 16.6% when age-adjusted definitions were used. The age-unadjusted vs -adjusted prevalence rates for hyperfiltration were 50 vs 50%, 12.9 vs 23.4% and 0.3 vs 9.0% for patients aged <40 years, 40 to 65 years and >65 years, respectively. Both the age-unadjusted and -adjusted hyperfiltration groups had lower mean diastolic blood pressure and lower serum creatinine levels than the control groups. Although the age-unadjusted hyperfiltration group had larger kidneys compared to the control group, this difference was no longer significant when the age-adjusted definition was used. There were no differences in HbA₁c, mean arterial pressure, antihypertensive use, insulin therapy, dyslipidaemia, frequency of macro- or microvascular complications, BMI, urinary sodium, urea and albumin excretion between the groups. Conclusions/interpretation Hyperfiltration was still more common among younger patients with type 2 diabetes even after adjusting for the expected age-related decline in GFR. Hyperfiltration was associated with a lower mean diastolic blood pressure independent of age.     

Role of insulin-like growth factor (IGF)-1 in the modulation of renal haemodynamics in Type I diabetic patients

Aims/hypothesis. We investigated in normotensive Type I (insulin-dependent) diabetic patients with normoalbuminuria the role of growth hormone-induced IGF-1 in the modulation of renal haemodynamics.¶Methods. We measured glomerular filtration (GFR) and renal plasma flow (RPF) at baseline and at 24 h after injection of different doses of growth hormone (0.1, 0.2, 0.4 U · kg^–1· body weight^–1) in six patients with normal GFR under a euglycaemic clamp. We also examined a 24-h profile of plasma growth hormone and IGF-1 during usual insulin therapy in two other groups each with seven patients with a lower (from 93 to 114 ml · min^–1· (1.73 m²)^–1) and higher (from 121 to 146 ml · min^–1· (1.73 m²)^–1) GFR.¶Results. Plasma growth hormone concentrations peaked 2 h after its injection and plasma concentrations of IGF-1 peaked about 24 h after the growth hormone injection. There was a significant increase in GFR and RPF 24 h after the highest dose of the growth hormone injection (corresponding to the highest IGF-1 concentration), from baseline values of 115 ± 24 and 536 ± 141 ml · min^–1· (1.73 m²)^–1 to 160 ± 33 and 657 ± 137 ml · min^–1· (1.73 m²)^–1, respectively (p < 0.01 for GFR and p < 0.05 for RPF). No differences were observed in the 24-h profile of growth hormone and IGF-1 plasma concentrations between the two groups; growth hormone and IGF-1 concentrations were lower than those obtained after the injection of 0.4 U · kg^–1· body weight^–1 of growth hormone.¶Conclusion/interpretation. These results show that pharmacological growth hormone-induced IGF-1 concentrations are required to modify renal haemodynamics in Type I diabetic patients and suggest that, under the “physiological” conditions of diabetes, IGF-1 has no role as a mediator of glomerular hyperfiltration. [Diabetologia (2000) 43: 922–926]     

Long-term glycaemic control directly correlates with glomerular filtration rate in early Type 1 diabetes mellitus before the onset of microalbuminuria

Hyperfiltration occurs early in diabetes mellitus and has been implicated in the development of microalbuminuria. Our aim was to re-examine the controversial relationship between glycaemic control and glomerular filtration (GFR) in normoalbuminuric, normotensive, non-obese patients with short duration Type 1 diabetes mellitus (DM). We studied 75 Type 1 DM patients, 35 male, aged 18–42 years, with a duration of diabetes of 4–8 years. GFR was determined by inulin clearance; hyperfiltration was defined as above 145 ml min⁻¹ 1.73 m⁻² (equivalent to 2 SD above mean for a control population). Analysis was by paired Student’s t-testing and linear regression. GFR correlated significantly with HbA_1c (r = 0.47, p < 0.0001) and fructosamine (r = 0.24, p = 0.035). Mean HbA_1c and fructosamine in the 13 patients with hyperfiltration was significantly higher than in the rest of the group (HbA_1c: 9.2 % (95 % C.I. 7.9–10.4 %) vs 7.6 % (7.2–7.9), p = 0.002; fructosamine: 479 μmol l⁻¹ (450–507) vs 410 μmol l⁻¹ (388–432), p = 0.009. This significant difference persisted even when the two highest values of HbA_1c or fructosamine were removed from analysis. Effective renal plasma flow, assessed by PAH clearance, also correlated in all patients with HbA_1c (r = 0.31, p = 0.039). We conclude that poor glycaemic control directly correlates with hyperfiltration and renal hyperperfusion in early Type 1 DM. Copyright © 1998 John Wiley & Sons, Ltd.     

Lipoprotein lipase gene variants and progression of nephropathy in hypercholesterolaemic patients with type 2 diabetes

Objective. Recent prospective studies have identified hyperlipidaemia as an independent determinant of diabetic nephropathy. Lipoprotein lipase (LPL) is a key enzyme in the postprandial processing of triglycerides and VLDL. Among a number of common sequence variants of the LPL, HindIII has been associated with coronary heart disease and, more recently, with microalbuminuria in type 2 diabetes. We evaluated the progression of renal disease in hypercholesterolaemic type 2 diabetic patients in relation to this polymorphism. Design and subjects. We followed up for 4 years 65 consecutively enrolled microalbuminuric patients with type 2 diabetes; of whom 28 had hypercholesterolaemia (6.62 ± 0.9 mmol L^?1, group A) and 37 were normocholesterolaemic (4.68 ± 0.5 mmol L^?1, group B). Main outcome measures. After performing the genetic analyses, albumin excretion rate (AER) and estimated glomerular filtration rate (GFR), calculated by the simplified equation of the MDRD Study Group, were repeated every year. Results. In group A, AER increased more (?AER: 11 [38] vs. 4 [18] μg min^?1 per year in group B, P < 0.0001) while GFR declined faster (?3.5 ± 2.1 vs. ?2.0 ± 1.4 mL min^?1 per year, P < 0.02). Patients homozygous for the allele + of HindIII showed a significantly faster decline of GFR and a higher increase of AER (both P = 0.0001) even after adjustment for cholesterol levels and anthropometric variables. Conclusions. In hypercholesterolaemic type 2 diabetic patients with microalbuminuria, the renal disease has an accelerated course, particularly in those carrying the H₊/H₊ genotype of the HindIII polymorphism at the LPL locus.     

Renal autoregulation is normal in newly diagnosed, normotensive, NIDDM patients

Summary Abnormalities of renal autoregulation with glomerular hyperfiltration and raised intraglomerular pressure have been suggested as important factors in the initiation and development of diabetic nephropathy. Angiotensin converting enzyme (ACE) inhibition appears to have a specific reno-protective role in diabetic nephropathy, possibly by reducing intraglomerular pressure. The acute effects of ACE inhibition on renal haemodynamics in normotensive, non-insulin-dependent diabetes mellitus (NIDDM) have not been previously reported. We measured simultaneous glomerular filtration rate (GFR) and renal plasma flow (RPF) in 29 (4 female) subjects, mean age 52 years (range 27–70), using ⁵¹Cr EDTA and ¹²⁵I Hippuran. Clearances were corrected to 1.73 m^–2. All patients were normotensive (blood pressure < 75^th centile for age and sex), newly diagnosed ( < 30 days), taking no antihypertensive or hypoglycaemic medication. Subjects were randomly allocated (double blind) to receive the ACE inhibitor trandolapril 4 mg day^–1 (H) (hypotensive dose), trandolapril 0.5 mg day^–1 (L) (non-hypotensive dose) or placebo (P) for 10 days after which renal haemodynamics were remeasured. For all subjects baseline GFR, RPF and filtration fraction (FF) were 97 ± 21 ml min^–1 mean ± SD, 439 ± 120 ml min^–1 and 22.3 ± 2.9 % respectively. Glomerular hyperfiltration (GFR > 120 ml min^–1) was only demonstrated in 3 subjects (10.3 %). In group H mean arterial pressure (103 ± 8 vs 93 ± 9 mmHg, p < 0.001) and FF (23.8 ± 2.3 vs 20.0 ± 4.0 %, p = 0.03) fell while RPF increased (376 ± 111 vs 426 ± 60 ml min^–1, p = 0.02), there was no significant change in GFR. No significant change in mean arterial pressure, GFR, RPF or FF occurred in groups P and L. These studies suggest that in newly diagnosed normotensive NIDDM subjects normal renal autoregulation occurs and glomerular hyperfiltration is uncommon. [Diabetologia (1998) 41: 206–211] Received: 2 July 1997 and in revised form: 16 September 1997     

Reduction of Leucocyte Proteolytic Enzyme Activity in Diabetic Patients with Microalbuminuria and Proteinuria: Its Possible Role in Diabetic Nephropathy

Mesangium enlargement and glomerular basement membrane thickening are cardinal features of diabetic nephropathy. The reasons for these changes are uncertain but decreased degradation of extracellular matrix may play a role. Mesangium degradation can be modulated by factors intrinsic to the kidney or by factors in the circulation. In this study the capacity of leucocyte proteolytic enzymes to degrade mesangium matrix materials was investigated. Leucocytes were obtained from 57 patients with NIDDM (age 58.3 ± 8.8 years, duration 9.4 ± 7.3 years, body mass index (BMI) 30 ± 6 kg m⁻², HbA_1c 7.7 ± 2.0 %) and 21 control subjects (age 55.1 ± 14.6 years, BMI 25 ± 4 kg m⁻²). Leucocyte lysates from control and NIDDM subjects with normal AER degraded matrix to the same extent (40.6 ± 8.2 % vs 42.9 ± 13.5 %) while lysates from patients with microalbuminuria and proteinuria were less able to degrade matrix (33.0 ± 14.2 % and 26.1 ± 12.7 %, respectively). There was a significant inverse correlation between matrix degradation and AER (r = − 0.49) and multiple regression analysis showed that AER was the most important factor determining degradation rate (R² = 0.24). Degree of metabolic control, age, and blood pressure were not significant factors. The major enzyme(s) responsible for the matrix degradation was identified as metalloproteinase(s). We conclude that leucocytes from diabetic patients with abnormal albumin excretion have a decreased proteolytic capacity to degrade extracellular matrix. This may play a role in the glomerular basement membrane thickening and mesangium expansion which occurs in diabetic nephropathy.     

Long-term treatment with nifedipine reduces urinary albumin excretion and glomerular filtration rate in normotensive type 1 diabetic patients with microalbuminuria

The aim of the present study was to investigate the renal effects of long-term treatment with the calcium channel blocker nifedipine in normotensive type 1 diabetic patients with microalbuminuria. In a randomized, double-blind trial, 15 type 1 diabetic patients were treated with either nifedipine (n=8; dosage 30 mg/day) or placebo (n=7) for 12 months. At baseline and after 6 and 12 months of therapy, the albumin excretion rate (UAER, radioimmunoassay), glomerular filtration rate (GFR, chromium 51 ethylenediamine tetra-acetic acid clearance) and renal plasma flow (RPF, iodine 125 hippuran clearance) were determined. Nifedipine treatment caused a significant reduction of UAER after 6 and 12 months (median, Q₁/Q₃ in mg/24 h): baseline 84 (65/163); 6 months 35 (23/90),P<0.02; 12 months 39 (15/79),P<0.05. GFR was significantly decreased by nifedipine treatment (baseline 157±15, 6 months 122±8, 12 months 111±47 ml/min;P<0.05, mean ± SEM), whereas RPF remained constant. Nifedipine treatment did not influence systolic (baseline 121±7, 12 months 124±2 mmHg, mean ± SEM) or diastolic (baseline 72±2, 12 months 74±3 mmHg) arterial blood pressure. With placebo treatment no significant alterations of UAER, GFR, RPF and arterial blood pressure were observed. Metabolic control was constant throughout the whole study period. Thus, 1 year's treatment with nifedipine reduces the UAER and GFR in normotensive type 1 diabetic patients without influencing the systemic arterial blood pressure. The data, however, do not present a recommendation for the general use of nifedipine in these patients as the exact intrarenal mechanism of calcium channel blockers in humans remains to be established.     

Fibrinogen and AER are major independent predictors of 11-year cardiovascular mortality in type 2 diabetes: the Casale Monferrato Study

Aims/hypothesis Fibrinogen and elevated AER increase cardiovascular mortality, but few data are available in the type 2 diabetic population. We have conducted an 11-year follow-up study of the Casale Monferrato cohort to assess: (1) the long-term predictive role of AER independently of conventional risk factors; (2) the shape of its relationship with cardiovascular mortality; and (3) whether fibrinogen has a predictive effect independent of the increased cardiovascular risk associated with nephropathy.Methods During the follow-up period (1991–2001) a population-based cohort of 1,565 patients was regularly examined, and measurements of HbA₁c were centralised. Multivariate Cox proportional hazards modelling was employed to assess the role of fibrinogen and AER as predictors of all-cause and cardiovascular mortality, independently of baseline variables and individual cumulative average values of HbA₁c during follow-up.Results In 10,890.2 person-years of observations, 685 deaths were identified, giving an all-cause mortality rate of 63.4 per 1,000 person-years (95% CI 58.8–68.3). In Cox regression analyses, the strongest predictor of cardiovascular mortality was macroalbuminuria (relative risk 2.18, 95% CI 1.62–2.94), which was mainly associated with a high risk of short-term mortality. No increased risk was evident until the upper microalbuminuric range of AER values. Plasma fibrinogen was also a major independent predictor, and its role was not modified by AER, or by the exclusion of subjects developing chronic renal failure or diabetic nephropathy during follow-up.Conclusions/interpretation The results indicate that: (1) AER is the main independent predictor of 11-year cardiovascular mortality; (2) this effect is mainly evident in the upper range of microalbuminuria and in macroalbuminuria; and (3) fibrinogen has an independent effect on cardiovascular mortality, but no synergistic effect with AER, suggesting that both endothelial dysfunction and chronic inflammation are involved in the excess cardiovascular mortality of type 2 diabetic patients.     

Continuous subcutaneous insulin infusion is more effective than multiple daily insulin injections in preventing albumin excretion rate increase in Type 1 diabetic patients

Aims To compare the effect of continuous subcutaneous insulin infusion (CSII) and multiple daily insulin injections (MDI) on albumin excretion rate (AER) in Type 1 diabetic patients. Methods In a 3‐year multicentre retrospective observational study, 110 Type 1 diabetic patients treated with CSII were compared with 110 patients treated with MDI matched at baseline for age, sex, diabetes duration and HbA_1c. At entry, 90 patients in each group had normal AER and 20 persistent microalbuminuria. AER, estimated glomerular filtration rate (eGFR), HbA_1c, lipids and blood pressure were assessed. Results HbA_1c was lower in the CSII than in the MDI group (8.1 ± 0.9 vs. 8.4 ± 1.3%; P < 0.005 after 3 years). Blood pressure and eGFR were similar during the study. AER [median (95% confidence interval)], similar at baseline [6.0 μg/min (9, 21) in the CSII group vs. 4.4 (8, 16) in the MDI group, NS] was significantly lower in the patients treated with CSII both at year 2 and at year 3 of follow‐up [4.7 μg/min (6, 12) vs. 6.4 (13, 29), P < 0.002]. This difference was observed even when normo‐ and microalbuminuric patients were analysed separately. Nine patients progressed to microalbuminuria in the MDI group and only one in the CSII group. Nine patients regressed to normoalbuminuria in the CSII group, whereas only two regressed to normoalbuminuria in the MDI group. Conclusions Despite a small benefit in terms of improved glycaemic control, CSII therapy may be useful in decreasing the progressive increase in AER in Type 1 diabetic patients.     

Serum uric acid and progression of diabetic nephropathy in type 1 diabetes

Aims

Uric acid (UA) is a risk factor for CKD. We evaluated UA in relation to change in GFR in patients with type 1 diabetes.

Factors associated with progression to macroalbuminuria in microalbuminuric Type 1 diabetic patients: the EURODIAB Prospective Complications Study

Aims/hypothesis Type 1 diabetic patients who develop microalbuminuria are clearly disadvantaged in terms of their risk of morbidity and mortality from renal and cardiovascular diseases. It is therefore important to identify potential factors that can predict progression to macroalbuminuria.Methods This is a 7-year follow-up study of 352 microalbuminuric Type 1 diabetic patients from 31 European centres. Risk factors at baseline were compared in patients who progressed to macroalbuminuria and in patients who remained microalbuminuric or reverted to normoalbuminuria. Risk factors and albumin excretion rate (AER) were measured centrally.Results Over 7.3 years, 13.9% of the microalbuminuric patients progressed to macroalbuminuria, 35.5% remained microalbuminuric and 50.6% reverted to normoalbuminuria. Independent baseline risk factors for progression to macroalbuminuria were HbA₁c (7.9% vs 6.8%, p=0.004), AER (64.4 vs 44.9 µg/min, p=0.0001) and—after adjusting for diabetes duration, HbA₁c and AER—body weight (72 vs 67 kg, p=0.05). Independent factors associated with regression to normoalbuminuria were diabetes duration (15 vs 18 years, p=0.004), AER (37.2 vs 44.9 µg/min, p=0.0001) and—after adjusting for diabetes duration, HbA₁c and AER—waist-to-hip ratio (0.83 vs 0.86, p=0.05) and incidence of peripheral neuropathy at baseline (24% vs 38%, p=0.001). Blood pressure and smoking did not emerge as risk factors at baseline for the outcome of microalbuminuria.Conclusions/interpretation A significant fraction of microalbuminuric Type 1 diabetic patients will progress to overt proteinuria. Patients with higher AER values, sub-optimal metabolic control, excess body fat and peripheral neuropathy may carry a particularly high risk of clinical nephropathy requiring aggressive therapeutic intervention.Abbreviations AER albumin excretion rate - CVD cardiovascular disease - Gamma GT gamma-glutamyltransferase - OR odds ratio - PCS Prospective Complications Study - RR relative risk - SERR standardised estimates of relative risk - SREs standardised regression effects - vWF von Willebrand Factor     

Influence of glycemic control and hypertension on urinary microprotein excretion in non-insulin-dependent diabetes mellitus

In order to evaluate the influence of glycemic control and hypertension on the development of diabetic nephropathy, we measured urinary excretion of albumin (AER) and other microproteins in non-insulin-dependent diabetes mellitus (NIDDM), and reexamined the 103 patients who had had AER < 300 μg/min at the initial study 12–18 months later. AER in the patients with HbA₁c ≧ 7.5% increased significantly in both the normoalbuminuric (AER < 30 μg/min) and microalbuminuric (30–300 μg/min) groups, whereas no significant change in AER was observed in the patients with HbA₁c < 7.5%. In the microalbuminuric group, AER in both hypertensive and normotensive patients increased significantly. In this group, the change in AER correlated positively with the change in α₁-microglobulin (α 1M). These results indicate that glycemic control has a greater influence on the development of nephropathy in its early stage than hypertension and that α 1M is as a good predictor of nephropathy as albumin.     

Indications of Low Sex Hormone Binding Globulin (SHBG) in Young Females with Type 1 Diabetes,and an Independent Association to Microalbuminuria

Sex hormone binding globulin (SHBG) is normally decreased during puberty and inversely related to insulin resistance. Microalbuminuria is rare before puberty in Type 1 diabetes implicating that sex hormones may contribute to its development. We investigated SHBG levels in young females with >5 years of Type 1 diabetes, and the association to microalbuminuria. Ten diabetic females with, and 15 without microalbuminuria, and 17 healthy controls in pubertal stage 4–5 were compared regarding anthropometric data, fasting serum levels of SHBG, testosterone, insulin, insulin-like growth factor-1 (IGF-1), lipids and lipoproteins. Multiple regression analyses were performed to study variables with independent influences on SHBG and albumin excretion rate (AER), respectively, in Type 1 diabetes. SHBG was lower and testosterone/SHBG ratio higher in normoalbuminuric females with diabetes than in controls. This was further emphasized in diabetic patients with microalbuminuria. IGF-1 was lower in Type 1 diabetes than in controls, and significantly decreased in microalbuminuric as compared to normoalbuminuric diabetic patients. IGF-1 was only correlated to SHBG in healthy controls. In Type 1 diabetes, applying stepwise multiple regression analysis, insulin dose, BMI, and HbA_1c had a significant and independent inverse influence on SHBG (r² = 0.77, p < 0.001). With log AER as the dependent variable, low SHBG, low IGF-1, HbA_1c, and age added to the regression (r² = 0.65, p = 0.004), whereas BMI, insulin dose and blood pressure did not. In conclusion, SHBG is decreased in young females with Type 1 diabetes, influenced by increased insulin requirements, BMI and HbA_1c. In turn, low SHBG seems to be independently associated to elevated AER in these patients. Prospective studies are necessary to confirm our results.     

Renal hemodynamics in experimentally galactosemic dogs and diabetic dogs

To examine the association between renal hemodynamic abnormalities and the development of diabetic kidney disease, glomerular filtration rate (GFR) and renal plasma flow (RPF) have been determined in dogs with alloxan-induced diabetes or experimental galactosemia of 1 to 5 years duration. GFR and RPF were significantly greater than normal in insulin-deficient diabetic dogs. GFR was also significantly greater than normal in the galactosemic animals, and RPF tended to be elevated even though GFR and RPF were measured at time of day when plasma galactose is no longer elevated. GFR and effective RPF (eRPF) were found to increase in normal animals upon acute elevation of blood galactose or glucose concentration. Thus, GFR is supranormal in experimental galactosemia, as well as in diabetes, although galactosemia has been shown not to cause nephromegaly, mesangial expansion, or glomerular obliteration, which are typical of diabetes. Administration of an aldose reductase inhibitor (Sorbinil) at dosages sufficient to significantly reduce erythrocyte polyol concentration did not significantly influence GFR or RPF in diabetic or galactosemic dogs.     

Acute and long-term renal effects of angiotensin converting enzyme inhibition in normotensive, normoalbuminuric insulin-dependent diabetic patients

Glomerular filtration rate (GFR) (thalamate clearance), renal plasma flow (RPF) (hippuran clearance), and urinary albumin excretion rate (AER) were measured in 10 normoalbuminuric, normotensive insulin-dependent diabetic patients and 8 normal subjects before and during acute angiotensin converting enzyme (ACE) inhibition by means of enalapril (10 mg IV). The effect of placebo versus enalapril (30 mg day-1) was also studied for 3-month treatment periods in the insulin-dependent diabetic patients. Acute ACE-inhibition caused a decline in filtration fraction (FF) from 0.259 +/- 0.011 (+/- SE) to 0.237 +/- 0.013 (2p less than 0.01) in the diabetic patients, and from 0.210 +/- 0.010 to 0.188 +/- 0.006 (2p less than 0.02) in the normal subjects. Mean arterial blood pressure was lowered from 90 +/- 1 to 84 +/- 2 mmHg (2p less than 0.01) and from 91 +/- 1 to 86 +/- 2 mmHg (2p less than 0.05). No significant change in blood glucose, AER or fractional albumin excretion (theta Alb) was seen in either group. After 3 months of enalapril treatment FF was decreased from 0.253 +/- 0.011 to 0.235 +/- 0.011 (2p less than 0.05), AER from 5.6 x/ divided by 1.7 to 4.3 x/divided by 1.6 micrograms min-1 (2p less than 0.01) and theta Alb from 1.22 +/- 0.22 x 10(-6) to 0.92 +/- 0.12 x 10(-6) (2p less than 0.02). The decline in total renal resistance was not significant (0.175 +/- 0.013 to 0.165 +/- 0.012 mmHg ml-1 min-1) and significant changes in GFR, RPF, mean arterial pressure or HbA1c were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)