Albuminuria reflects widespread vascular damage

Diabetologia, Apr 1989

Summary Albuminuria in Type 1 (insulin-dependent) diabetes is not only an indication of renal disease, but a new, independent risk-marker of proliferative retinopathy and macroangiopathy. The coincidence of generalised vascular dysfunction and albuminuria, advanced mesangial expansion, proliferative retinopathy, and severe macroangiopathy suggests a common cause of albuminuria and the severe renal and extrarenal complications associated with it. Enzymes involved in the metabolism of anionic components of the extracellular matrix (e.g. heparan sulphate proteoglycan) vulnerable to hyperglycaemia, seem to constitute the primary cause of albuminuria and the associated complications. Genetic polymorphism of such enzymes is possibly the main reason for variation in susceptibility.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://link.springer.com/content/pdf/10.1007%2FBF00285287.pdf

Albuminuria reflects widespread vascular damage

Diabetologia Albuminuria reflects widespread vascular damage* The Steno hypothesis T. Deckert B. Feldt-Rasmussen K. Borch-Johnsen T. Jensen A. Kofoed-Enevoldsen Steno Memorial Hospital Gentofte Denmark Summary. Albuminuria in Type 1 (insulin-dependent) diabetes is not only an indication of renal disease, but a new, independent risk-marker of proliferative retinopathy and macroangiopathy. The coincidence of generalised vascular dysfunction and albuminuria, advanced mesangial expansion, proliferative retinopathy, and severe macroangiopathy suggests a common cause of albuminuria and the severe renal and extrarenal complications associated with it. Enzymes involved in the metabolism of anionic components of the extracellular Diabetes; albuminuria; extracellular matrix; heparan sulphate; vascular dysfunction - 9 Springer-Verlag 1989 Albuminuria indicates a poor prognosis in Type I (insulin-dependent) diabetic patients [ 1 ]. However, only about 35% of patients with Type 1 diabetes will ever develop Albustix, (Ames, Bucks, England) positive albuminuria [ 2 ], Why is albuminuria associated with such a poor prognosis, and why do only 35% of Type 1 diabetic patients develop A[bustix positive albuminuria? Onset of albuminuria Albuminuria is not present at the onset of Type 1 diabetes. Shortly after the onset of Type I diabetes, the urinary albumin excretion rate (UalbV) is normal or sub-normal [ 3 ]. However, in the 35% o f patients who later develop persistent proteinuria, UalbV increases in an exponential way at about 20% per year [ 4 ]. The rate of increase varies between patients and the intra individual variations of UalbV are quite large [ 5 ]. When UalbV is persistently more than 30 mg/24 h, it is clearly abnormal and we speak of incipient nephropathy. After a further 5-10 years, UalbV has increased to more than 300 mg/24 h, which is the macroalbuminuric range at which Albustix becomes positive. Thus, Albustix positive proteinuria is a late event in a long-lasting process which starts shortly after the onset of diabetes (BorchJohnsen K, Skovgaard LT, Keiding N, DeckertT. To matrix (e.g. heparan sulphate proteoglycan) vulnerable to hyperglycaemia, seem to constitute the primary cause of albuminutia and the associated complications. Genetic polymorphism of such enzymes is possibly the main reason for variation in susceptibility. be published). But why only in 35% of patients, and why is prognosis so poor? Albuminuria, more than an indicator of renal disease Albuminuria is generally believed to reflect renal disease. This is also true in Type I diabetes as seen in Table 1 and Figure 1 which demonstrate changes in the glomerular filtration rate (GFR) in a trans-sectional study (Table 1) and during a 2-year prospective study in long-term Type 1 diabetic patients with different levels of UalbV (Fig. 1). A persistent decrease in G F R means loss of glomerular filtration surface due to advanced mesangial expansion [ 6,7 ]. Research during recent years has, however, demonstrated that albuminuria in Type I diabetes is not only associated with renal alterations but also with proliferative retinopathy [ 8-11 ] and cardiovascular mortality [ 12 ]. An association with cardiovascular mortality is not only present in Type 1 diabetic patients but also in non-diabetic subjects [ 13-15 ] and Type2 (non-insulin-dependent) diabetic patients [ 16-18 ]. The increased cardiovascular mortality in patients with albuminuria is only partly due to a higher prevalence of cardiowascular risk factors [ 19 ], such as smoking [ 20, 21 ], lipids [ 22, 23 ] high blood-pressure [ 8, 14, 16 ] and plasma fibrinogen [ 22, 24 ]. Thus, albuminuria is not only an indication of renal disease but also a new, strong and independent risk-marker of proliferative retinopathy and cardiovascular death. " 0 13o This is an interesting observation. How does albuminutia indicate cardiovascular damage? Our hypothesis is that albuminuria reflects a more generalised vascular process which affects the glomeruli, the retina and intima of large vessels simultaneously. We therefore looked for indicators ofgeneralised vascular dysfunction [ 25, 26 ] and studied the coincidence o f some of the complications associated with albuminuria [ 8, 12, 27 ]. To assess alterations of the vascular system in general, measurement of the transcapillary escape rate (TER) of albumin and fibrinogen was undertaken and some markers of endothelial cell function were measured. As can be seen in Figure 2, long-term diabetic patients with normal UalbV had a normal albumin T E R of about 5%. This means that 5% of the intravascular albumin mass will leave the vascular space per hour. But diabetic patients with elevated UalbV have a 50% increase in the albumin TER. Similar results were obtained with fibrinogen and a statistically significant (p< 0.01) correlation was found between the albumin TER and that of fibrinogen ( r = 0.72) (Bent-Hansen L and Deckert T, to be published). Two observations were of interest. Firstly, an increase in albumin TER was observed in patients with the slightest increase of UalbV (Fig.2). Secondly, the increase in TER was not due to increased vascular surface [28], longer diabetes duration, higher blood-pressure or poorer diabetic control [ 25 ] but only related to increased UalbV. If the increased albumin and fibrinogen TER refleets increased vascular permeability, these observations might indicate increased extravascular coagulation [ 29 ] which leads to an increased release of von Willebrand factor [ 30 ]. In fact, von Willebrand factor, a marker of endothelial dysfunction, was increased in albuminuric patients, but normal in long-term diabetic patients with normal UalbV [ 31, 32 ]. Similar results were seen with other markers of endothelial lesions such as angiotensin converting enzyme [ 33-35 ] and plasminogen activator [113]. Thus, albuminuria seems to indicate widespread vascular dysfunction 9 The coincidence of albuminuria along with progressiw~ mesangial expansion, proliferative retinopathy a n d / o r macroangiopathy was striking. As can be seen in Figure 3 some mesangial expansion can be seen in nearly all long-term diabetic patients. But only in patients with increasing UalbV does mesangial expansion progress so seriously that the G F R begins to decline [ 6, 7 ]. Some cases of proliferative retinopathy can also be seen in patie,nts with normal UalbV, but, as soon as UalbV increases the incidence of proliferative retinopathy increases enormously (Fig. 4) [8]. Also, some diabetic patients with normal UalbV will die from coronary heart disease (CHD), but the cumulative incidence of C H D increases remarkably in patients after the onset o f albuminutia [ 27 ]. In the absence of album177 mesangial expansion remains unimportant and never leads to renal insufficiency. Without albuminuria the incidence of proliferative retinopathy and cardiovascular events remains low. Thus, the process which leads to albuminuria would also seem to be a serious promotor of mesangial expansion, retinopathy and macroangiopathy. Mechanism of the generalised process leading to albuminuria What is the mechanism of this widespread process ? It can hardly be exclusivelyrelated to hyperglycaemiaor the associates of hyperglycaemia like the sorbitol pathway or non-enzymatic glycation. No doubt poor blood sugar Significant difference ( p < 0.05) compared with a control subjects, b group 1, e group 2, d group 3 and e group 4; Results are given as m e a n _ SD regulation plays an important role in the development o f albuminuria [ 36-39 ]. However, the correlation between metabolic control and the development o f persistent albuminuria is p o o r [ 38, 39 ]. Poor glycaemic control is a necessary, but not a sufficient condition to cause the development o f albuminuria. This is also indicated in Figure 5 which demonstrates HbAoc in Type 1 diabetic patients with albuminuria a n d long-term diabetic patients with Type i diabetes for more t h a n 40 years but with normal UalbV. Thus, it w o u l d seem that some patients are susceptible to the deleterious effects o f p o o r diabetes control, whereas others are resistant. Elevation o f blood-pressure can hardly in itself be the c o m m o n cause o f the generalised vascular dysfunction and organ-damage. It is true that elevated blood-pressure is seen early in diabetic patients with albuminuria as seen in Table 2, but the blood-pressure is not significantly elevated before UalbV is > 100 rag/24 h. Similar results were seen in a prospective study o f 200 normoalbuminuric Type 1 diabetic patients. A m o n g these patients 15 developed persistent microalbuminuria during a 5year follow-up. These patients h a d similar blood-pressure readings to those who remained in the normoalbuminuric range for several years [ 40 ]. Thus, blood-pressure elevation does not appear simultaneously with, or before, but after the increase o f UalbV, probably due to a disequilibrium between s o d i u m reabsorpfion a n d glomerular filtration capacity, a hypothesis which is presently being tested. This does not m e a n that bloodpressure is without significance for the prognosis o f diabetic patients with albuminuria. Increased bloodpressure might well be an i n d e p e n d e n t p r o m o t o r of mesangial expansion [ 41 ], retinopathy [ 8 ] and macroangiopathy [ 16 ] but it is not the cause o f albuminuria, and the blood-pressure elevation per se can neither explain the high cardiovascular mortality [ 16 ] nor the deleterious mesangial expansion [ 42 ] a n d the high incidence of proliferative retinopathy [ 8 ]. N o r does increased intraglomerular pressure seem to be the cause o f albuminuria [ 43-45 ]. Years before and after onset of persistent proteinurla Fig.4. The annual incidence(newcasesper year)of proliferativeretinopathy in 110 patientswithTypeI (insulin-dependent)diabeteswho developed clinical nephropathy (UalbV>300 rag/24 h) at 0. 110 age-, diabetes duration- and sex-matchedpatients who did not develop clinicalnephropathy are shownas control subjects[ 9 ] Alteration of the composition of the extracellular matrix We believe that the cause of this generalised process is a genetically determined alteration in the composition of the extracellular matrix. The evidence for the importance of genetic factors comes from several studies. 1) The incidence of albuminuria is significantly higher in males compared to females [ 1 ]. 2) Long-term Type I diabetic patients who have had diabetes for more than 40 years with normal UalbVhave a distribution of tissue type antigens which is significantly different from Type I diabetic patients with nephropathy [ 46 ]. 3) Furthermore, albuminutia is more frequently observed in diabetic siblings of diabetic patients with albuminuria than in diabetic siblings of diabetic patients without albuminuria [ 47 ]. It has also been postulated that the N a + / L i + counter transport activity in erythrocytes can be used as a genetic marker for patients who later develop albuminuria [ 48, 49 ]. However, this is not the case in Copenhagen. In ongoing studies we did not find that parents of diabetic patients with nephropathy have higher blood-pressure [501 than parents of patients without albuminuria. The evidence for the involvement of the extracellular matrix comes from studies of the composition and charge of the glomerular basement membrane (GBM) and other filtration barriers in diabetic animals and human subjects [ 51-57 ]. The GBM is condensed extracellular matrix. It is negatively charged, partly due to its content of heparan sulphate [ 58-60 ]. It is, however, difficult to measure minor alterations in the complex composition of GBM. We therefore studied alterations in the glomerular charge selectivity which might reflect qualitative changes of the GBM. By measuring the renal clearance of pairs of plasma proteins which differ in charge but not in molecular size, alterations o f the charge selectivity of the GBM can be identified. We have used nonglycated and glycated albumin [61,621, glycated albumin being more negatively charged in comparison to nonglycated [ 62 ]. We have also used neutral IgG and the anionic charged IgG4 fraction [64, 651. The ratio between the clearance of the less anionic and the more anionic plasma proteins is the selectivity index (SI). A decrease of SI indicates loss of the charge selectivity. With both pairs o f plasma proteins we found a highly significant loss of charge selectivity in albuminuric patients with Type 1 diabetes (Fig. 6). These findings have been confirmed by others [ 55, 66, 67 ]. Interestingly, loss of charge selectivity could be seen already in patients with UalbV of 30-50 mg/24 h [ 65 ] i.e. at the very beginning of incipient nephropathy where size selectivity of the GBM seems to be normal [ 66, 68 ]. The combination o f normal size selectivity and reduced charge selectivity strongly indicates that loss of charge selectivity is due to a reduction of negative charges of the GBM and not to increased pore size. These conclusions are strengthened by histochemical analyses of anionic sites within the GBM, which demonstrated a negative correlation between the density of negative charges and albuminuria in Type 1 diabetic patients [ 69, 70 ]. A reduction of fixed negative charge density induced by diabetes has been demonstrated in the GBM [ 71 ] as well as in Bruch's membrane [721, (the extracellular matrix between the chorioid and the pigment epithelium o f the retina), on erythrocytes [731and in the arterial intima [741.These observations indicate that diabetes leads to a generalised reduction of negative charges of extracellular matrix and plasma membranes, reflecting qualitative changes in the composition o f the membranes. In diabetic patients with albuminutia these alterations seem to be severe enough to induce changes in permeability. Loss of heparan sulphate proteoglycan in diabetes What does the loss of anionic charge mean in biochemical terms? There are several reasons to believe that the loss of anionic charge is due to a loss of normal heparan sulphate proteoglycan, the main glycosaminoglycan component o f basement membranes o f glomeruli [ 54, 75 ], aortic myomedial cells [761, mesangium [54, 771 and endothelial plasma membranes [78]. T. Deckert et al.: Albuminuria reflects widespread vascular damage 1) The loss of heparan sulphate in the GBM leads to loss of anionic sites and albuminuria [ 79-81 ]. 2) Within the GBM a loss of heparan sulphate has been demonstrated in diabetic patients with nephropathy [531. 3) The multiplicity of the effects of heparan sulphate proteoglycan might well explain the strong association between vascular dysfunction and renal and extrarenal complications [ 82 ]. Heparan sulphate proteoglycan not only inhibits the glomerular filtration of albumin but also contributes to the integrity of the pore size of the GBM [ 83, 84 ]. Thus, loss of heparan sulphate proteoglycan has been demonstrated to lead to disruption of the microstructure of the GBM [84]. These alterations would explain the increase of fractional IgG clearance seen in albuminuric diabetic patients [ 55, 64 ] and the changes in dextran clearance in these patients [ 66, 68 ]. Heparan sulphate proteoglycan also strongly inhibits mesangial cell growth [ 85 ],and loss of heparan sulphate has been shown to be a strong promotor of mesangial expansion [ 85, 86 ]. It has also been shown that heparan sulphate proteoglycan in plasma membranes of endothelial cells have important antithrombogenic properties [ 87-89 ]. Thus, heparin-like components which accelerate thrombin-antithrombin complex formation have been identified in retinal microvascular endothelial cell preparations [90]. Loss of normal sulphated heparan sulphate in retinal capillaries might, therefore, contribute to the formation of microthrombi and/or platelet plugs followed by areas of non-perfusion, the forerunners of proliferative retinopathy in diabetes [ 91, 92 ]. In fact, increased platelet adhesion in vivo has been demonstrated in albuminuric diabetic patients [19]. The formation of platelet plugs will lead to increased local concentrations of platelet derived growth factor, potent mitogens of a number of cells including mesangial cells [ 93-95 ]. Besides antithrombogenic properties, heparan sulphate proteoglycan binds lipoprotein lipase [ 96 ], stimulates its activity [ 97 ] and inhibits smooth muscle cell proliferation in arteries [ 98 ]. Loss of heparan sulphate might, therefore, very well represent a serious promotor of atherosclerosis [ 82, 87, 99, 100 ]. 4) Finally, diabetes affects heparan sulphate metabolism and leads to loss of normally sulphated heparan sulphate in extracellular matrix and plasma membranes [ 51, 54, 102 ]. Usually heparan sulphate is sulphated within the Golgi apparatus of many cells [ 103-105 ]. The key enzyme of sulphation is N-deacetylase [106]. After sulphation has taken place, heparan sulphate is incorporated into plasma and basement-membranes where it contributes to the anionic charge of the extracellular matrix [ 58-60 ] and the integrity of the collagen network [ 83, 84 ]. Loss of anionic charge in GBM and increased glomerular permeability due to decreased sulphation of glomerular heparan sulphate has been described in experimental membraneous nephropathy [80]. In diabetic Slalb lO. 5. 2. 02 lo. 5' 2. o.,~ animals inappropriate sulphation of heparan sulphate has been demonstrated [ 57, 107-110 ] probably due to impaired activity of the deacetylase enzyme [ 107 ]. Therefore, we hypothesize that albuminuria and the associated complications are due to genetic polymorphism of enzymes involved in the metabolism of heparan sulphate proteoglycan e.g. N-deacetylase. Genetic polymorphism of diabetes-sensitive enzymes involved in the metabolism of glycosaminoglycans has been demonstrated in the Uppsala strain of Sprauge Dawley rats [ 111 ]. According to our hypothesis, patients who develop albuminuria are characterised by iso-enzymes which are extremely vulnerable to poor dJiabetes control (Fig. 7). In these patients a critical reduction of normal heparan sulphate would be expected, leading to albuminuria and progression of mesangial expansion, retinopathy and macroangiopathy, whereas persons equipped with isoenzymes less vulnerable to hyperglycaemia would be protected. Thus, the polymorphism of enzymes involved in the metabolism of heparan sulphate proteoglycan might be the reason for the heterogeneous prognosis of poorly regulated diabetic patients and for the fact that only 35% of Type 1 diabetic patients develop albuminuria. Vulnerable to poor metabolic control, the presence ENVIRONMENT BIOCHEMICAL ALTERATION CLINICAL SIGNS 1 1 POORGLYCAEMICCONTROL (HbAlc > 8,0%) 1 I NON-CRITICAL l DECREASE OF HS 1 NO LEAKAGE (BENIGN ANGIOPATHY) 1 CRITICAL DECREASE OF HS I 1 LEAKAGE (MALIGNANT ANGIOPATHY) of this enzyme not only in epithelial and endothelial cells of the glomeruli but also in the mesangium, the retina and intima of large vessels, might explain why albuminuria in Type 1 diabetes reflects widespread vascular damage. Acknowledgements.Besides the authors, A. Kverneland, L. Bent-Hansen, Elisabeth R. Mathiesen, Kirsten Norgaard, Pablo Vidal, Benny S. Welinder, Marja Deckert and Hanne Foght have contributed to this work. Their enthusiasm and skilful assistance is highly appreciated. 1. Borch-Johnsen K , Kragh Andersen P , Deckert T ( 1985 ) The effect of proteinuria on relative mortality in Type 1 (insulin-dependent) diabetes mellitus . Diabetologia 28 : 590 - 596 2. Andersen AR , Sandahl Chrisfiansen J , Andersen JK , Kreiner S , Deckert T ( 1983 ) Diabetic nephropathy in Type 1 (insulin-dependent) diabetes: An epidemiological study . Diabetologia 25 : 496 - 501 3. Mogensen CE ( 1971 ) Urinary albumin excretion in early and long-term juvenile diabetes . Scand J Clin Lab Invest 28 : 183 - 193 4. Christensen CK , Mogensen CE ( 1985 ) The course of incipient diabetic nephropathy: studies of albumin excretion and blood pressure . Diabetic Med 2 : 97 - 102 5. Feldt-Rasmussen B , Dinesen B , Deckert M ( 1985 ) Enzyme immunoassay: an improved determination of urinary albumin in diabetics with incipient nephropathy . Scand J Clin Lab Invest 45 : 539 - 544 6. Ellis EN , Steffes MW , Goetz FC , Sutherland DER , Mauer SM ( 1986 ) Glomerular filtration surface in Type I diabetes mellitus . Kidney Int 29 : 889 - 894 7. Deckert T , Feldt-Rasmussen B , Borch-Johnsen g" Kverneland A , Frokjaer Thomsen O ( 1986 ) Clinical assessment and prognosis of complication of diabetes . Transplant Proc 18 : 1636 - 1638 8. Kofoed-Enevoldsen A , Jensen T , Borch-Johnsen K , Deckert T ( 1987 ) Incidence of retinopathy in Type I (insulin-dependent) diabetes: Association with clinical nephropathy . J Diabetic Complications 3 : 96 - 99 9. Vigstrup J , Mogensen CE ( 1985 ) Proliferative diabetic retinopathy: at risk patients identified by early detection of microalbuminutia . Acta Ophthalmol 63 : 530 - 534 10. Barnett AH , Dallinger K , Jennings R , Fletcher J , Odugbesan O ( 1985 ) Microalbuminuria and diabetic retinopathy . Lancet 1 : 53 - 54 11. Klein R , Klein BEg. Moss SE , Davis MD , DeMets DL ( 1986 ) The Wisconsin Epidemiologic Study of Diabetic Retinopathy: Proteinuria and retinopathy in a population of diabetic persons diagnosed prior to 30 years of age . Diabetic Renal-Retinal Syndrome 3 : 245 - 264 12. Borch-Johnsen K , Kreiner S ( 1987 ) Proteinuria - A predictor of cardiovascular mortality in insulin-dependentdiabetes mellitus . Br Med J 294 : 1651 - 1654 13. Kannel WB , Stampfer MJ , Castelli WP ( 1984 ) The prognostic significance of proteinuria: the Frammingham Study . Am Heart J 108 : 1347 - 1352 14. Yudkin JS , Forrest RD , Jackson CA ( 1988 ) Microalbuminuriaas predictor of vascular disease in non-diabetic subjects . Lancet 2 : 530 - 533 15. Damsgaard EM , Froland A , Mogensen CE ( 1988 ) Microalbuminuriais a strong predictor of 6-year mortality of elderly Type 2 (non-insulin-dependent)diabetic patients and non-diabeticsubjects. A prospective study . Diabetologia 31 : 483 - 484A 16. Nelson RG , Pettitt DJ , Carraher MJ , Baird HR , Knowler WC ( 1988 ) The effect of proteinuria on mortality in non-insulin-dependent diabetes mellitus . Diabetes 37 : 1499 - 1504 17. Schmitz A , Vaeth M ( 1988 ) Microalbuminufia:A major risk factor in non-insulin-dependentdiabetes. A 10-year follow-up study of 503 patients . Diabetic Med 5 : 126 - 134 18. Jarrett RJ , Viberti GC , Argyropoulos A , Hill RD , Mahmud U , MmTellsTJ ( 1984 ) Microalbuminuriapredicts mortality in noninsulin-dependentdiabetes . Diabetic Med 1 : 17 - 19 19. Valdorf-Hansen F , Jensen T , Borch-Johnsen K , Deckert T ( 1987 ) Cardiovascular risk factors in Type1 (insulin-dependent) diabetic patients with and without proteinuria . Acta Med Scand 222 : 439 - 444 20. Telmer S , Sandahl Christiansen J , Andersen AR , Nerup J , Deckert T ( 1984 ) Smoking habits and prevalence of clinical diabetic microangiopathy in insulin-dependent diabetics . Acta Med Scand 215 : 63 - 68 21. Stegmayr B , Lithner F ( 1987 ) Tobacco and end stage diabetic nephropathy . Br Med J 295 : 581 - 582 22. Jensen T , Stender S , Deckert T ( 1988 ) Abnormalities in plasma concentration of lipoproteins and fibrinogens in Type i (insulindependent) diabetic patients with increased urinary albumin excretion . Diabetologia 31 : 142 - 145 23. Mattock MB , Keen H , Viberti GC , E1-Gohari MR , Murrels TJ , Scott GS , Wing JR , Jackson PG ( 1988 ) Coronary heart disease and urinary albumin excretion rate in Type 2 (non-insulin-dependent) diabetic patients . Diabetologia 31 : 82 - 87 24. Bent-HansenL , Deckert T ( 1988 ) Metabolism of albumin and fibrinogen in Type 1 (insulin-dependent) diabetes mellitus . Diabetes Res 7 : 159 - 164 25. Feldt-Rasmussen B ( 1986 ) Increased transcapillary escape rate of albumin in Type 1 (insulin-dependent)diabetic patients with microalbuminuria . Diabetologia 29 : 282 - 286 26. Bent-HansenL , Feldt-Rasmussen B , Kverneland A , Deckert T ( t987 ) Transcapillary escape rate and relative metabolic clearance of glycated and non-glycated albumin in Type I (insulindependent) diabetes mellitus . Diabetologia 30 : 2 - 4 27. Jensen T , Borch-Johnsen K , Kofoed-EnevoldsenA , Deckert T ( 1987 ) Coronary heart disease in young Type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy: Incidence and risk factors . Diabetologia 30 : 144 - 148 28. Leinonen H , Mafikainen E , JuntunenJ ( 1982 ) Permeability and morphology of skeletal muscle capillaries in Type I (insulin-dependent) diabetes mellitus . Diabetologia 22 : 158 - 162 29. Dvorak HF , Senger DR , Dvorak AM , Harvey VS , McDonagh J ( 1985 ) Regulation of extravascular coagulation by microvascular permeability . Science 227 : 1059 - 1060 30. Ribes JA ; Francis CW , Wagner DD ( 1987 ) Fibrin induced release of yon Willebrand factor from endothelial cells . J Clin Invest 79 : 117 - 123 31. Jensen T ( 1989 ) Increased plasma level of von Willebrand factor in Type I (insulin-dependent) diabetic patients with incipient nephropathy . Br Med J 298 : 27 - 28 32. Porta M , Townsend C , Clover GM , Nanson M , Alderson AR , McCraw A , Kohner EM ( 1981 ) Evidence for functional endothelial cell damage in early diabetic retinopathy . Diabetologia 20 : 597 - 601 33. Feldt-Rasmussen B , Mathiesen ER , Deckert T , Giese J , Christensen NJ , Bent-HansenL , Nielsen MD ( 1987 ) Central role for sodium in the pathogenesis of blood pressure changes independent of angiotensin, aldosterone and catecholamines in Type 1 (insulin-dependent) diabetes mellitus . Diabetologia 30 : 610 - 617 34. Toop MJ , Dallinger KJC , Jennings PE , Barnett AH ( 1986 ) Angiotensin-converting enzyme (ACE): relationship to insulin dependent diabetes and microangiopathy . Diabetic Med 3 : 455 - 457 35. LiebermanJ, SastreA ( 1980 ) Serum angiotensin-converting enzyme: Elevations in diabetes mellitus . Ann Intern Med 93 : 825 - 826 36. Deckert T ( 1988 ) Glycemic control and complications . In: AlbertiKGMM, KrallLP (eds) The diabetes annual 4 .Elsevier Science Publishers, B.V. , pp 496 - 518 37. KrolewskiAS, WarramJH, ChristliebAR et al. ( 1985 ) The changing natural history of nephropathy in Type 1 diabetes . Am J Med 78 : 785 38. Feldt-Rasmussen B , Mathiesen ER , Deckert T ( 1986 ) Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin-dependent diabetes . Lancet 2 : 1300 - 1304 39. Norgaard K , Storm B , Graae M , Feldt-Rasmussen B ( 1988 ) Microalbuminuria and retinal changes in children with Type 1 (insulin-dependent) diabetes mellitus are related to long-term poor metabolic control . Diabetologia 31 : 527A 40. Mathiesen ER , Ronn B , Jensen T , Storm B , Deckert T ( 1988 ) Microalbuminuria precedes elevation in blood pressure in diabetic nephropathy . Diabetologia 31 : 519A 41. Parving HH , Andersen AR , Smidt UM , Hommel E , Mathiesen ER , Svendsen PA ( 1987 ) Effect of antihypertensive treatment on kidney function in diabetic nephropathy . Br Med J 294 : 1443 - 1447 42. Deckert T , Parving HH , Andersen AR , Sandahl Christiansen J , Oxenboll B , Svendson PAa , Telmer S , Christy M , Lauritzen T , Frookj0er Thomsen O , Kreiner S , AndersenJR, Binder C , NerupJ ( 1982 ) Diabetic nephropathy. A clinical and morphometric study . In: Eschwege E (ed) Diabetes epidemiology . Elsevier Biomedical Press B.V., pp 235 - 243 43. Bank N , Klose R , AynedjianHS, Nguyen D , Sablay LB ( 1987 ) Evidence against increased glomerular pressure initiating diabetic nephropathy . Kidney Int 31 : 898 - 905 44. Mauer SM , Steffes MW , Azar S , Brown DM ( 1988 ) Thoughts on the pathogenesis of diabetic nephropathy . Diabete Metab 14 : 206 45. Anderson S , Brenner BM ( 1988 ) Pathogenesis of diabetic glomerulopathy: Hemodynamic considerations . Diabetes Metab Rev 2 : 163 - 177 46. Svejgaard A , Jakobsen BK , Platz P , Ryder LP , Nerup J , Christy M , Borch-Johnsen K , Parving HH , Deckert T , MolstedPedersen L , KOhlC, Buschard K , Green A ( 1986 ) HLA associations in insulin-dependentdiabetes: search for heterogeneity in different groups of patients from a homogeneous population . Tissue Antigens 28 : 237 - 244 47. Seaquist ER , Goetz FC , Rich S , Barbosa J ( 1987 ) Concordance for nephropathy in diabetic siblings: Evidence of genetic susceptibility to diabetic kidney disease . Diabetes 36 : [Suppl]: 105A 48. Krolewski AS , Canessa M , Warram JH , Laffel LMB , Christlieb R , Knowler WC , Rand LI ( 1988 ) Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus . N Eng J 3 : 140 - 145 49. Mangili R , Bending JJ , Scott G , Li LK , Gupta A , Viberti GC ( 1988 ) Increased sodium-lithiumcountertransport activity in red cells of patients with insulin-dependentdiabetes and nephropathy . N Engl J 3 : 146 - 150 50. Viberti GC , Keen E [, Wiseman MJ ( 1987 ) Raised arterial pressure in parents of proteinuric insulin dependent diabetics . Br Med J 295 : 515 - 517 51. RohrbachDH, Wagner CW , StarVL, Martin GR , Brown KS , YoonJW ( 1983 ) Reduced synthesis of basement membrane heparan sulfate proteoglycan in streptozotocin-induced diabetic mice . J Biol Chem 19 : 11672 - 11677 52. Schleicher E , Wieland OH ( 1984 ) Changes of human glomerular basement membrane in diabetes mellitus . J Clin Chem Clin Biochem 22 : 223 - 227 53. ShimomuraH, Spiro RG ( 1987 ) Studies on macromolecular components of human glomerular basement membrane and alterations in diabetes . Diabetes 36 : 374 - 381 54. Wu V-Y , Wilson B, Cohen MP ( 1987 ) Disturbances in glomerular basement membrane glycosaminogylcans in experimental diabetes . Diabetes 36 : 679 - 683 55. VibertiGC, Keen H ( 1984 ) Relevance to pathogenesis and prevention of diabetic nephropathy . Diabetes 33 : 686 - 692 56. Hawthorne GC , MacLellan JR , Mythen M , Alberti KGMM , Turner GA ( 1986 ) Studies on glomerular basement membrane in experimental diabetes using lectin histochemistry in Wistar rats . Diabetologia 29 : 495 - 499 57. Cohen MP , Klepser H , Wu V-Y ( 1988 ) Undersulfation of glomerular basement membrane heparan sulfate in experimental diabetes and lack of correction with aldose reductase inhibition . Diabetes 37 : 1324 - 1327 58. Bray J , RobinsonG ( 1984 ) Influence of charge on filtration across renal basement membrane films in vitro . Kidney Int 25 : 527 - 533 59. Kanwar YS , VeisA, Kimura JH , Jakubowski ML ( 1984 ) Characterization of heparan sulfate-proteoglycan of glomerular basement membranes . Proc Natl Acad Sci 81 : 762 - 766 60. Stow JL , Sawada H , Farquhar MG ( 1985 ) Basement membrane heparan sulfate proteoglycans are concentrated in the laminae rarae and in podocytes of the rat renal glomerulus . Proc Natl Acad Sci 82 : 3296 - 3300 61. KvernelandA, Feldt-Rasmussen B , Vidal P , Welinder B , BentHansen L , Soegaard U , Deckert q"(1986) Evidence of changes in renal charge selectivity in patients with Type I (insulin-dependent) diabetes mellitus . Diabetologia 29 : 634 - 639 62. KvernelandA, Welinder B , Feldt-Rasmussen B , Deckert T ( 1988 ) Improved metabolic control does not alter the charge-dependent glomerular filtration of albumin in uncomplicated Type 1 (insulin-dependent) diabetes . Diabetologia 31 : 708 - 710 63. Vidal P , Welinder BS , Deckert T , Hansen B ( 1988 ) Charge heterogeneity of glycated human serum albumin . In: Schafer-Nielsen C (ed) Proceedings. VCH Verlagsgesellschaft, Weinheim, pp 468 - 473 64. Deckert T , Feldt-Rasmussen B , Djurup R , Deckert M ( 1988 ) Glomerular size and charge selectivity in insulin-dependent diabetes mellitus . Kidney Int 33 : 100 - 106 65. Deckert T , Feldt-Rasmussen B , Djurnp R , Deckert M ( 1987 ) Glomerular size and charge selectivity in Type 1 (insulin-dependent) diabetes meUitus . Diabetologia 30 : 513A 66. Nakamura Y , Myers BD ( 1988 ) Charge selectivity of proteinuria in diabetic glomerulopathy . Diabetes 37 : 1202 - 1211 67. Houhala IA , Pasternack A ( 1987 ) Fractional dextran and protein clearances in glomerulonepbritis and in diabetic nephropathy . Clin Sci 72 : 289 - 296 68. Tomlanovich SJ , Jones HW , Meyers BD ( 1986 ) Glomerular capillary wall dysfunction in progressive diabetic nephropathy . Diab Neph 5 : 23 - 2 , 6 69. Vernier RL , Sisson-Ross S , Mauer SM ( 1986 ) Cytochemical studies of the anionic changes in the kidney in Type 1 diabetes mellitus . Diab Neph 5 : 15 - 18 70. Rohrbach R ( 1986 ) Reduced content and abnormal distribution of anionic sites (acid proteoglyeans) in the diabetic glomerular basement membrane . Virchows Arch (Cell Pathol) 51 : 127 - 135 71. Morikawa A , Watanabe K , Ishii K ( 1987 ) A study of anionicsites in glomernlar basement membrane (GBM) in the spontaneously diabetic chinese hamsters of Asahikawa Colony (CHA) . Diabetes 36 [Suppl] 1: 106A 72. CaldwellRB, SlapnickSM; McLaughlinBJ ( 1986 ) Decreased anionic sites in Bruch's membrane of spontaneous and drug-induced diabetes . Invest Ophthalmol Vis Sci 27 : 1691 - 1697 73. Gambaro G , BaggioB, Cicerello E , Mastrosimone S , Marzaro G , Borsati A , Crepaldi G ( 1988 ) Abnormal erythrocyte charge in diabetes mellitus . Diabetes 37 : 745 - 748 74. RazI, HaviviY, YaromR ( 1988 ) Reduced negative surface charge on arterial endothelium of diabetic rats . Diabetologia 31 : 618 - 620 75. Kanwar YS , Faraquhar MG ( 1979 ) Presence of heparan sulfate in glomerular basement membrane . Proc Natl Acad Sci 76 : 1303 - 1307 76. HeickendorffL, Ledet T ( 1984 ) Glycosaminoglycans of arterial basement membrane-like material from cultured rabbit aortic myomedial cells . Bichim Biophys Acta 798 : 276 - 282 77. Kanwar YS , Jakubowski MI , Rosenzweig IJ ( 1983 ) Distribution of sulfated glycosamingoglycans in the glomerular basement membrane and mesangial matrix . Eur J Cell Biol 31 : 290 - 295 78. RobinsonJ, Gospodarowicz D ( 1984 ) Effect of p-Nitrophenyl-[ID-xyloside on proteoglycan synthesis and extracellular matrix formation by bovine corneal endothelial cell cultures . J Biol Chem 259 : 3818 - 3824 79. Rosenzweig LJ , Kanwar YS ( 1982 ) Removal of sulfated (heparan sulfate) or nonsulfated (hyaluronicacid) glycosaminoglycans results in increased permeability of the glomerular basement membrane to 125I-bovineserum albumin . Lab Invest 47 : 177 - 183 80. Groggel GC , Stevenson J , Hovingh P , Linker A , Border WA ( 1988 ) Changes in heparan sulfate correlate with increased glomerular permeability . Kidney Int 33 : 517 - 523 81. Cotran RS , Rennke HG ( 1983 ) Anionicsites and the mechanisms of proteinuria . N Engl J 309 : 1050 - 1052 82. Gallagher JT , Lyon M , Steward WP ( 1986 ) Structure and function of heparan sulphate proteoglycans . Biochem J 236 : 313 - 325 83. Tarsio JF , Reger LA , Furcht LT ( 1988 ) Molecular mechanisms in basement membrane complications of diabetes . Diabetes 37 : 532 - 539 84. Hunsicker LG , Shearer TP , Shaffer SJ ( 1981 ) Acute reversible proteinuria induced by infusion of the polycation hexadimethfine . Kidney Int 20 : 7 - 17 85. Castellot JJ , Hoover RL , Harper PA , Karnovsky MJ ( 1985 ) Heparin and glomerular epithelial cell-secreted heparin-like species inhibit mesangial-cell proliferation . Am J Pathol 120 : 427 - 435 86. Purkerson ML , Toll& sen DM , Klahr S ( 1988 ) N-desulfated/acetulated heparin ameliorates the progression of renal disease in rats with subtotal renal ablation . J Clin Invest 81 : 69 - 74 87. Marcum JA , McKenneyJB , Rosenberg RD ( 1984 ) Acceleration of thrombin-antithrombincomplex formation rat hindquarters via heparin-like molecules bound to the endothelium . J Clin Invest 74 : 341 - 350 88. Marcum JA , Atha DH , Fritze LMS , Nawroth P , Stern D , Rosenberg RD ( 1986 ) Cloned bovine aortic endothelial cells synthesize anticoagulantly active heparan sulfate progeoglycan . J Biol Chem 261 : 750 % 7517 89. Pejler G , B~ickstr6mG, Lindahl U ( 1987 ) Structure and affinity for antithrombin of heparan sulfate chains derived from basement membrane proteoglycans . J Biol Chem 262 : 5036 - 5043 90. Marcum JA , Fritze L , Galli SJ , Karp G , Rosenberg RD ( 1984 ) Microvascular heparin-like species with anticoagulant activity . Am J Physiol 245 : H725 - H733 91. Ishibashi T , Tanaka K , Taniguchi Y ( 1981 ) Platelet aggregation and coagulation in the pathogenesis of diabetic retinopathy in rats . Diabetes 30 : 601 - 606 92. Dallinger KJC , Jennings PE , Toop MJ , Gyde OHB , Barnett AH ( 1987 ) Platelet aggregation and coagulation factors in insulindependent diabetics with and without microangiopathy . Diabetic Med 4 : 44 - 48 93. Deuel TF , Huang JS ( 1984 ) Platelet-derived growth factor: structure, function and roles in normal and transformed cells . J Clin Invest 74 : 669 - 676 94. AbboudHE, PopticE, DiCorletoP ( 1987 ) Production of platelet-derived growth factor-like protein by Rat Mesangial cells in culture . J Clin Invest 80 : 675 - 683 95. Donadio JV , Ilstrup DM , Holley KE , Romero JC ( 1988 ) Platelet-inhibitor treatment of diabetic nephropathy: A 10-year prospective study . Mayo Clin Proc 63 : 3 - 15 96. Williams MP , Streeter HB , Wusteman FS , Cryer A ( 1983 ) Heparan sulphate and the bindingoflipoproteinlipase to porcine thoracic aorta endothelium . Biochim Biophys Acta 756 : 83 - 91 97. Staprans I , Felts JM , CouserWG ( 1987 ) Glycosaminoglycans and chylomicron metabolism in control and nephrotic rats . Metabolism 36 : 496 - 501 98. Castellot JJ , Beeler DL , Rosenberg RD , Karnowsky MJ ( 1984 ) Structural determinants of the capacity of heparin to inhibit the proliferation of vascular smooth muscle cells . J Cell Physiol 120 : 315 -- 320 99. Dybdahl H , Ledet T ( 1987 ) Diabetic macroangiopathy . Diabetologia 30 : 882 - 886 100. Stender S , Hjelms E ( 1987 ) In vivo transfer of cholesterol from plasma into human aortic tissue . Scand J Clin Lab Invest 47 : 21 - 29 101. Berenson GS , Radhakrishnamurthy B , Srinivasan SR , Vijayagopal P , Dalferes ER , Sharma C ( 1984 ) Recent advances in molecular pathology . Exp Mol Pathol 41 : 267 - 287 102. Kanwar YS , Rosenzweig LJ , Linker A , Jakubowski ML ( 1983 ) Decreased de novo synthesis of glomerular proteoglycans in diabetes: Biochemical and autoradiographic evidence . Proc Natl Acad Sci 80 : 2272 - 2275 103. Hassel JM , Noonan DM , Ledbetter SR , Laurie GW ( 1986 ) Biosynthesis and structure of the basement membrane proteoglycan containing heparan sulphate side-chains . In: Evered D , Whelan J Functions of the proteoglycans . John Wiley & Sons, Chichester New York Brisbane Toronto, pp 204 - 222 104. Lindahl U , H~56kM ( 1978 ) Glycosaminogylcans and their binding to biological macromolecules . Annu Rev Biochem 47 : 385 - 417 105. Graham JM , WinterbourneDJ ( 1988 ) Subcellular localization of the sulphation reaction of heparan sulphate synthesis and transport of the proteoglycan to the cell surface in rat liver . Biochem J 252 : 437 - 445 106. LindahlU, FeingoldDS, Rod6nL ( 1986 ) Biosynthesis of heparin . TIBS 11 : 221 - 225 107. Kjell6n L , Bielefeld D , Hook M ( 1983 ) Reduced sulfation of liver heparan sulfate in experimentally diabetic rats . Diabetes 32 : 337 - 342 108. Spiro MJ ( 1987 ) Sulfate metabolism in the alloxan-diabetic rat: relationship of altered sulfate pools to proteoglycan sulfation in heart and other tissues . Diabetologia 30 : 259 - 267 109. Klein JD , Brown DM , Oegema TR ( 1986 ) Glomerular proteoglycans in diabetes . Diabetes 35 : 1130 - 1142 110. Levy P , Picard J , Bruel A ( 1984 ) Evidence for diabetes-induced alterations in the sulfation of heparan sulfate in intestinalepithelial cells . Life Sci 35 : 2613 - 20 111. Eriksson UJ , Kjell6n L , Unger E ( 1986 ) Decreased levels of high molecularweight proteoglycan in diabetic rats of a malformation prone strain . Diabetologia 29 : 545A 112. Mauer SM , SteffesMW, Ellis EN , Sutherland DER , Brown DM , Goetz FC ( 1984 ) Structural-functional relationships in diabetic nephropathy . J Clin Invest 74 : 1143 - 1155 113. Jensen T , Bjerre-Knudsen J , Feldt-Rasmussen B , Deckert T ( 1989 ) Features of endothelial dysfunction in early diabetic nephropathy . Lancet I: 461 - 463


This is a preview of a remote PDF: https://link.springer.com/content/pdf/10.1007%2FBF00285287.pdf

T. Deckert, B. Feldt-Rasmussen, K. Borch-Johnsen, T. Jensen, A. Kofoed-Enevoldsen. Albuminuria reflects widespread vascular damage, Diabetologia, 1989, 219-226, DOI: 10.1007/BF00285287