expected to double within the next pressure susceptibility to vascular damage: generalized 10 years, onset of diabetes occurs earlier, and the individ- vasodilation [21], impaired autoregulation of flow and ual diabetic patient lives longer and therefore is at pressure [22], nocturnal hypertension due to impaired greater risk for developing late complications, including blood pressure lowering during the night [23], a greater diabetic nephropathy. In this presentation I will review rise in systemic blood pressure during exercise in longrisk factors and markers for the development and pro- term diabetic patients compared with non-diabetics, and gression of diabetic nephropathy and will summarize the increased blood pressure variation over 24 hours (autocurrent approaches to the prevention and treatment of nomic neuropathy). Finally, an elevated blood pressure diabetic nephropathy. I will not, however, discuss the promotes progression in a variety of non-diabetic netreatment of ESRD with transplantation and dialysis. phropathies, as demonstrated in the MDRD study [24]. A relentless but highly variable rate of decline in GFR Studies in various experimental animal models and (1 to 24 mL/min/year, median 12 mL/min/year) charac- human disease suggest that proteinuria itself contributes terizes patients with both type 1 and type 2 diabetes with to renal damage [25]. The worst prognosis has been shown nephropathy [2–4]. Simultaneously, arterial blood pres- in type 1 diabetic patients with diabetic nephropathy and sure and albuminuria progressively rise and the nephrotic nephrotic-range proteinuria. We have confirmed and exsyndrome ensues in 40% to 50% of patients. The patient tended this finding to the early stages of diabetic nephropwith type 1 diabetes predominantly develops diastolic athy [13]. Since then, other observational studies and hypertension, whereas the type 2 diabetic patient typi- treatment trials have confirmed these findings [7, 15]. In cally manifests systolic hypertension. A close correlation our recent prospective study, we documented a threshold exists between the degree of diabetic glomerulopathy effect of albuminuria equal to 600 mg/24 h [16]. Furtherand the level of GFR [5] and, even more important, in more, intervention that has ameliorated the progression the rate of decline in GFR [6]. Before advanced renal of diabetic and nondiabetic renal disease always has been replacement strategies became available and the advo- associated with a reduction in proteinuria, a so-called surcacy of early and aggressive antihypertensive therapy, rogate end point. The MDRD study [24] and the Ramipril death occurred on average 5 to 10 years after the onset Efficacy in Nephropathy (REIN) study [26] have demonof persistent proteinuria [4, 8-11]. End-stage renal disease strated that proteinuria has a major role in the progreswas the major cause of death in type 1 diabetic patients sive loss of GFR in non-diabetic glomerulopathies. with nephropathy; cardiovascular disease dominated in Originally, Nyberg et al demonstrated a correlation proteinuric type 2 diabetic patients. between HbA1C and the rate of GFR decline in 18 patients Increased arterial blood pressure is an early and fre- with type 1 diabetes who received aggressive antihyperquent phenomenon in diabetic nephropathy [12]. A close tensive treatment for 18 months [27]. This finding was correlation between blood pressure and the rate of de- confirmed and extended in several studies dealing with cline in GFR has been documented in patients with type 1 larger numbers of patients and longer observation interand type 2 diabetes [13-15]. Recently, we have confirmed vals [14, 15, 28, 29]. In our long-term prospective study, and extended this finding by measuring GFR, blood pres- we generated a two-hit model with mean blood pressure sure, albuminuria, HbA1C, and serum cholesterol every and glycosylated HbA1C below and above the median year for 7 years (range, 3 to 14 years) in 301 consecutive values (102 mm Hg and 9.2%, respectively). The study type 1 diabetic patients with diabetic nephropathy re- revealed a rate of decline in GFR of only 1.5 mL/min/ cruited during 1983 to 1997 [16]. The statistical analysis year in the lowest stratum compared to 6.1 mL/min/year revealed no threshold for the adverse impact of systemic in the highest stratum (P 0.001) [16]. In contrast, most blood pressure (BP) on the rate of decline in GFR. The of the studies in patients with type 2 diabetes and proteindamaging effect of systemic BP is probably due to trans- uria have failed to demonstrate any significant impact mission of pressure downstream to the kidney. Intraglo- of glycemic control [3, 4]; the literature contains one merular hypertension has been documented in rats with exception [30]. streptozotocin-induced diabetes [17] and possibly occurs In 1982, Moorhead et al hypothesized that hyperlipidin human diabetes [18]. emia promotes progression in chronic renal disease after In 1982, Hostetter et al introduced the concept that the initiating event has damaged the glomerular capillary increased glomerular hydraulic pressure plays an impor- wall, thereby allowing increased passage of lipids and tant role in the initiation and progression of experimental lipoproteins into the mesangium [31]. Several studies in diabetic glomerulopathy [17]. At the same time, long- patients