Proteinuria and progressive renal disease: towards preventing renal disease Fourth International Symposium, 24-25 September 1997, Montreux, Switzerland

s 1057 Parving H-H, Hommel E, Mathiesen E et al. Prevalence of microPopulation-based studies of microalbuminuria and renal albuminuria, arterial hypertension, retinopathy and neuropathy disease in patients with insulin dependent diabetes. Br Med J 1988; Bo Feldt-Rasmussen; Medical Department P 2132, 296: 156–160 Rigshospitalet, Copenhagen O, Denmark Deckert T, Yokoyama H, Mathiesen E et al. Cohort study of predictive value of urinary albumin excretion for atherosclerotic Microalbuminuria is present when the urinary albumin excrevascular disease in patients with insulin dependent diabetes. Br tion rate (UAER) in a 24-h urine or a short-time collected Med J 1996; 312: 871–874 urine during day time is in the range of 30–300 mg/24-h (20–200 mg/min equivalent to 0.46–4.6 mmol/24 h). A UAER in the microalbuminuric range is a strong predictor of nephropathy in insulin-dependent diabetes (type 1). Because of this close association between microalbuminuria and proProteinuria and glomerular heparan sulphate alterations gressive renal disease in type 1 diabetic patients this associC. J. Ilse Raats, Jacob Van Den Born, Jo H. M. Berden; ation has been intensely studied. Also the epidemiology of Division of Nephrology, University Hospital St Radboud, microalbuminuria and renal disease has been investigated. Nijmegen, The Netherlands From a number of epidemiological studies it appears that the prevalence of microalbuminuria is 12–22%. There are controversies as to the relation between prevalence of microalbumiIntroduction nuria and diabetes duration. A number of studies observe an Heparan sulphate (HS) is the anionic glycosaminoglycan almost unchanged prevalence of microalbuminuria independside-chain of heparan sulphate proteoglycan (HSPG) present ent of diabetes duration. Most of these studies have included in basement membranes, in extracellular matrix and on cell only one urine sample for classification of the albuminuria surfaces. The impact of HS for the permselective properties level. This may constitute a problem because of the high day of the glomerular basement membrane (GBM) was docuto day variation of UAER. Studies including more than one mented by a number of observations. First, enzymatic digesurine sample describe a three fold increase in prevalence of tion of HS by heparitinase caused an enhanced permeability microalbuminuria after 24 years of diabetes compared to 5–9 of the GBM for native ferritin and albumin [1]. Second, an years of diabetes. acute, selective proteinuria could be induced in rats by a single Despite the close relationship between microalbuminuria intravenous injection of a monoclonal antibody directed and diabetic nephropathy it has been shown that the kidney against GBM HS [2]. Third, a reduction in GBM function in terms of glomerular filtration rate declines only in HS-associated anionic sites was demonstrated with cationic the patients with a UAER high in the microalbuminuric probes in several human and experimental proteinuric glomrange. Furthermore, microalbuminuria has also in type 1 diaerulopathies [3]. With recently developed antibodies directed betic patients shown to be an independent risk factor not only against the GBM HSPG core protein and the HS side chain of renal disease but also of cardiovascular disease. The latter [4], we demonstrated a decrease in HS staining in the GBM association seems to be even more prominent in patients with in different human proteinuric glomerulopathies, such as sysnon-insulin dependent diabetes (type 2) as well as in non temic lupus erythematosus (SLE), minimal change disease, diabetic apparently healthy controls. The prevalence of micmembranous glomerulonephritis and diabetic nephropathy, roalbuminuria is as high as 30–40% in type 2 diabetic patients whereas the staining of the HSPG core protein remained and end-stage renal failure only occurs in 3–8% of these unaltered [5]. This suggested changes in the HS side-chains of patients. The strong link between microalbuminuria and diaHSPG. To get more insight into the mechanisms responsible betic nephropathy in type 1, therefore, may also be mediated for this observation, we studied GBM HS expression in varithrough mechanisms similar to those associating microous experimental models of proteinuria. From these investialbuminuria to cardiovascular disease in type 1 and type 2 gations four different mechanisms have emerged until now diabetic patients as well as in apparently healthy subjects. which are discussed below, namely masking of HS by immune complexes, depolymerization of HS by radicals, proteolytic cleavage of HSPG by enzymes released from inflammatory Orchard TJ, Dorman JS, Maser RE et al. Prevalence of complicacells and metabolically induced biochemical changes of HS. tions in IDDM by sex and duration. Diabetes 1990; 39: 1116–1124 Gall M-A, Rossing P, Skott P et al. Prevalence of microand macroalbuminuria, arterial hypertension, retinopathy and large Masking of HS by immune complexes vessel disease in European type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1991; 34: 655–661 SLE is an autoimmune disease characterized by the occurKlein R, Klein BEK, Linton KLP, Moss SE. Microalbuminuria in rence of numerous autoantibodies, primarily directed against a population-based study of diabetes. Arch Intern Med 1992; nuclear antigens. In both human [5] and murine [6 ] SLE 152: 153–158 nephritis, albuminuria is paralleled by a decrease in GBM HS Feldt-Rasmussen B, Borch-Johnsen K, Deckert T, Jensen G, Jensen staining and an increase in immune complex depositions in JS. Microalbuminuria: An important diagnostic tool. Journal of the glomerular capillary wall. This decrease in HS staining Diabetes and Its Complications 1994; 8: 137–145 was inversely correlated with both albuminuria and with The EURODIAB IDDM Complications Study Group. Microvascular and acute complications in IDDM patients. immune complex deposition. Formerly, it was thought that Diabetologia 1994; 37: 278–285 anti-DNA autoantibodies could cross-react with HS in the Joner G, Brinchmann-Hansen O, Torres C G, Hanssen KF. A GBM. Later we could show, however, that antinuclear antinationwide cross-sectional study of retinopathy and microalbumibodies are able to bind to HS and to the GBM via nucleonuria in young Norwegian type 1 (insulin-dependent) diabetic somal antigens [7]. The positively charged histones in these patients. Diabetologia 1992; 35: 1049–1054 nucleosome-containing immune complexes interact with the Damsgaard EM, Mogensen CE. Microalbuminuria in elderly hypernegatively charged HS in the GBM. Despite the decrease in glycaemig patients and controls. Diabetic Med 1986; 3: 430–435 HS staining, the HS content in glomeruli of lupus mice is Mogensen CE, Damsgaard EM, Froland A et al. Microalbuminuria normal, which suggests that HS is masked by immune comin non-insulin-dependent diabetes. Clin Nephrol 1992: 38: [Suppl. 1]: 528–538 plexes. This is supported by the finding that the binding of a