Torsten Deckert

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.

Effect of low-dose heparin on urinary albumin excretion in insulin-dependent diabetes mellitus

We investigated the effect of heparin on urinary albumin excretion in patients with insulin-dependent diabetes mellitus. 39 patients with persistent urinary albumin excretion of 30-300 mg/24 h were randomly treated for 3 months with subcutaneous injections twice daily of isotonic saline, 5000 IU unfractionated heparin, or 2000 anti-Xa IU low-molecular-weight heparin. Unfractionated and low-molecular-weight heparin induced a significant reduction in urinary albumin excretion (p = 0.04 and p = 0.004). The mechanism and clinical relevance is unknown but deserve further attention.

Central Role of TGF-β in the Pathogenesis of Diabetic Nephropathy and Macrovascular Complications: A Hypothesis

Patients with insulin‐dependent diabetes mellitus (IDDM) and albuminuria are at high risk for severe micro‐ and macrovascular complications. Diabetic vascular complications are characterized by structural alterations of extracellular matrix (ECM) components in glomeruli and large vessel walls, namely, accumulation of collagen IV, collagen VI and fibronectin and relative decrease of heparan sulphate proteoglycan (HSPG). We hypothesize that the defect remodelling of ECM contributing to nephropathy and macrovascular disease is induced by overproduction of transforming growth factor‐beta (TGF‐β). Recent reports indicate that hyperglycaemia, increased intraglomerular pressure, and glycated proteins potentially induce overproduction of TGF‐β in diabetes. TGF‐β stimulates production of ECM components such as collagen IV, fibronectin, proteoglycans (decorin and biglycan) without increasing HSPG. TGF‐β overproduction leads to glomerulosclerosis and TGF‐β is a causal factor in myointimal hyperplasia after balloon injury of carotid artery. It mediates angiotensin II modulator effect on smooth muscle cell growth. These findings may indicate TGF‐β overproduction to be a common pathogenetic step explaining the well‐known association between micro‐ and macrovascular complications in diabetic patients. TGF‐β antagonists, such as decorin, betaglycan, and possibly also heparin, might be potential candidates for future therapy to prevent diabetic vascular disease.

Reduced glomerular size- and charge-selectivity in clinically healthy individuals with microalbuminuria

Abstract. The pathophysiologic mechanism behind microalbuminuria, a potential atherosclerotic risk factor, was explored by measuring fractional clearances of four endogenous plasma proteins of different size and electric charge (albumin, β2‐microglobulin, immunoglobulin G, and immunoglobulin G4). Twenty‐eight clinically healthy individuals with microalbuminuria, defined as a urinary albumin excretion of 6.6–150μg min‐1, and 60 matched control subjects were studied. Fractional immunoglobulin G clearance was higher (geometric means (95% confidence intervals)) 3.0 (2.3–3.9) × 10‐6, n= 28, vs. 2.1 (1.8–2.4) × 10‐6, n= 60; P= 0.02), whereas the ratio immunoglobulin G clearance/immunoglobulin G4 clearance was lower (geometric means (95% confidence intervals)) 1.8 (1.4–2.2), n= 28, vs. 2.3 (2.0–2.5), n= 60; P= 0.03) in microalbuminuric than in normoalbuminuric individuals. Fractional β2‐micro‐globulin clearance was similar in the two groups. Since total IgG and the IgG4 subclass are of similar size and configuration but electrically neutral and negative, respectively; these findings indicate that microalbuminuria is associated with decreased size‐ and charge‐selectivity of the glomerular vessel wall. Hypotheti‐cally, such alterations may reflect generalized vascular abnormalities linking microalbuminuria to athero‐genesis.

Effects of heparin and aminoguanidine on glomerular basement membrane thickening in diabetic rats

The effects of heparin and aminoguanidine on glomerular basement membrane thickening were studied in streptozotocin diabetic Sprague‐Dawley rats. A placebo‐treated group and a non‐diabetic group served as controls. All diabetic rats remained severely hyperglycaemic (23 mmol/l) throughout the 8‐month study period. At the end of this time relative kidney weight was significantly increased in diabetic control rats (4.9±0.5 g/kg b.w.) compared with non‐diabetic rats (3.3±0.3 g/kg). This increase was not affected by the intervention treatments. Glomerular basement membrane thickness increased 32% in diabetic control rats (240±24 nm) compared with non‐diabetic rats (182±20 nm). This increase was prevented by s.c. treatment with both unfractionated and low molecular weight heparins, while basement membrane thickness was the same in animals treated with oral heparins and aminoguanidine and untreated diabetic rats. Macroscopic malignant kidney tumours were seen in three aminoguanidine‐treated rats. In conclusion, subcutaneously administered heparin prevents diabetes‐induced glomerular basement membrane thickening.

Microalbuminuria: An important diagnostic tool

The concept of microalbuminuria is reviewed. Measuring the urinary albumin excretion rate and testing for microalbuminuria is well established in the control and treatment of patients with insulin-dependent diabetes mellitus. Microalbuminuria predicts nephropathy and early cardiovascular death. In the presence of microalbuminuria frequent examinations are warranted for early detection of retinopathy, blood-pressure rise, and for optimizing the glycemic control. In patients with non-insulin-dependent diabetes, the independent value of microalbuminuria as a cardiovascular risk factor is not yet clarified. The urinary albumin excretion rate should be measured at diagnosis, because the indications are that presence of microalbuminuria reinforces the urge to intervene against other well-documented cardiovascular risk factors (hypertension, dyslipidemia, tobacco, and obesity). In the nondiabetic population, there is accumulating evidence that an elevated urinary albumin excretion rate is associated with early cardiovascular morbidity and mortality. Large scale cross-sectional and prospective studies are needed in order to clarify further the role of microalbuminuria as an independent risk factor in the background population.

Possible effect of angiotensin-converting enzyme inhibition on glomerular charge selectivity

Angiotensin-converting enzyme (ACE) inhibitors are known to reduce urinary albumin excretion (UAE) in diabetic patients. Animal studies have shown that, besides diminishing the glomerular capillary pressure, ACE inhibitors might reduce albuminuria by influencing glomerular charge selectivity through glomerular preservation of heparan sulphate proteoglycan. In humans, an indirect measurement of glomerular charge selectivity can be obtained by calculating the glomerular charge selectivity index (SI), a clearance ratio of IgG/IgG4, two identically sized but differently charged molecules. The aim of the present study was to evaluate the effect of ACE inhibition on charge selectivity by comparing SI in type I (insulin-dependent) diabetic patients with microalbuminuria after 6 years of treatment either with or without captopril. Thirty-five of 45 patients participating in a prospective randomized study evaluating the effect of captopril in preventing the development of diabetic nephropathy were included in the present study, 17 being treated with captopril, 18 left as untreated controls. The selectivity index was calculated after measuring s-IgG, u-IgG, s-IgG4, and u-IgG4. The results demonstrated a higher selectivity index in the captopril-treated group [1.21 (0.51-1.94) median (range)] compared to the control group [0.94 (0.31-1.87)], however, the difference was not statistically significant (p = 0.16). A negative correlation between the selectivity index and UAE was demonstrated in the captopril-treated group (r = -0.77; p = 0.0004), whereas the correlation in the control group did not reach statistical significance (r = -0.3; p = 0.2).(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic variation of a collagen IV α1-chain gene polymorphism in Danish insulin-dependent diabetes mellitus (IDDM) patients: Lack of association to nephropathy and proliferative retinopathy

In insulin‐dependent (Type 1) diabetes mellitus (IDDM) the development of nephropathy is partly due to genetic susceptibility. Previously one study has demonstrated a relationship between a HindIII restriction polymorphism of the collagen IV α1‐chain gene and diabetic nephropathy. The aim of the present study was to evaluate such as association in a case–control study including 207 Danish IDDM patients: 116 with nephropathy (urinary albumin excretion rate (AER) > 300 mg 24 h−1) and 91 without nephropathy (AER < 30 mg 24 h−1). Using genomic DNA, HindIII restriction fragment length analysis revealed a bi allele polymorphism visualized by Southern hybridization with a cDNA probe recognizing the collagen IV α1‐chain gene. No differences in genotype frequencies or allele frequencies were demonstrated comparing patients with and without nephropathy: p = 0.39 and p = 0.96, respectively. Neither were there any difference in genotype frequencies or allele frequencies when the patients were stratified according to the presence of proliferative retinopathy: p = 0.44 and p = 0.84, respectively. Pooling the diabetic groups revealed genotype frequencies and allele frequencies comparable to those found in 57 healthy unrelated Danish individuals. We conclude that in a Danish IDDM population a HindIII restriction polymorphism of the collagen IV α1‐chain gene is not associated with diabetic nephropathy, diabetic retinopathy or with diabetes per se.

Skeletal muscle lipoprotein-lipase activity in insulin-dependent diabetic patients with and without albuminuria

In patients with insulin-dependent diabetes mellitus (IDDM), albuminuria reflects widespread vascular dysfunction. Albuminuria has been associated to defects of heparan sulfate proteoglycan (HSPG) within the extracellular matrix. Our hypothesis is that loss of HSPG in vascular walls reduces the HSPG-bound lipoprotein-lipase activity (LPLA), thereby causing elevated levels of plasma triglyceride (TG) seen in IDDM patients with albuminuria. The aim of the present study was to evaluate whether LPLA in muscle capillaries could be related to TG in IDDM patients with and without albuminuria. This is a cross-sectional study including ten healthy control subjects (group C), nine patients with IDDM and urinary albumin excretion rate (AER) of 30 mg/24 h or less (group D0) and 20 patients with IDDM and AER greater than 30 mg/24 h (group DA). Muscle LPLA, plasma TG, total cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and very-low-density lipoprotein cholesterol (VLDL) were measured. Between groups no difference in total cholesterol, TG, VLDL, and LDL was found. In patients with albuminuria, LPLA was reduced compared to controls, however, the difference between the groups was not statistically significant [median (range)] 35.9 mU/g (20.4-103) versus 44.6 mU/g (28.2-57.2) and 40.9 mU/g (21.7-53.5) in group DA, C, and D0, respectively, p = 0.76. AER was not correlated to LPLA. An overall negative correlation between TG and LPLA was found; r = -0.33, p = 0.04, supported by an overall significant positive correlation between LPLA and HDL; r = 0.32, p = 0.045. We conclude that, in insulin-dependent diabetes mellitus, skeletal muscle lipoprotein-lipase activity is associated with plasma triglyceride, while an association between lipoprotein-lipase activity and urinary albumin excretion is questionable.

Heparin, a possible therapy for diabetic complications: The effect on mesangial and myomedial cells in vivo and in vitro, especially in relation to extracellular matrix

M esangial and arterial myomedial cells are mesanchymal cells with contractile and phagocytotic properties. Proliferation as extracellular matrix (ECM) expression and secretion of these cells is known as important events in the pathogenesis of glomerular diseases and atherosclerosis, and cell/ECM interactions appear to play an important role in the regulation of the cell growth? Albuminuria is believed to reflect glomerular disease in type I (insulin-dependent) diabetes. Recent epidemiological studies demonstrated that albuminuria in type I diabetes is not only associated with renal alterations as glomerular basement membrane thickening and mesangial expansion but also with proliferative retinopathy and coronary heart disease.%’ This indicates a possible link of diabetic microangiopathies and premature arteriosclerosis.6,7 According to the Steno hypothesis the link between microand macroangiopathy is due to structural defects of the ECM, most importantly decreased concentration of heparansulfate (HS).8 This defect might be present not only within the glomeruli, but also within the capillary