Before renal replacement therapy was available, the main cause of death in subjects with proteinuria was uremia. About 25% died from myocardial infarction or stroke. Renal replacement therapy reduced deaths from uremia but increased deaths from cardiovascular causes [188].
Pathology
As in diabetic retinopathy, there is no doubt about the influence of hyperglycemia on the development of diabetic nephropathy. However, the causal relationship is less clear. There is no linear relation between the cumulative incidence of any sign of diabetic nephropathy and the duration of diabetes, and more than half of diabetic subjects never develop such nephropathy [176,189]. Normal kidneys transplanted into diabetic recipients may develop typical lesions, but the rate of development varies and is independent of metabolic control [155]. These observations suggest that hyperglycemia is necessary but not sufficient for the development of diabetic nephropathy. Other important pathogenetic factors are hypertension, protein intake, renal hemodynamics, smoking, and genetics.
The hyperglycemia-related pathogenetic effects discussed on pages 11 and 12 are also found in diabetic nephropathy. In addition, synthesis of the glucosaminoglycan heparan sulfate and glycoproteins is impaired [136]. These molecules contribute to the negative charge of the glomerular capillary membranes and are involved in the selectivity of glomerular filtration, which consequently may be reduced. Hemodynamics are another important pathogenetic factor. The impact of hypertension on diabetic nephropathy has been shown in epidemiological and antihypertensive treatment studies [156–159,190,191]. A significant example of direct jeopardizing of the kidney by hypertension is seen in people with unilateral renal artery stenosis, where only the kidney with the patent artery develops glomerulosclerosis [155].
Evidence for a genetic influence comes from family studies. Siblings of probands with nephropathy develop signs of nephropathy several times more often than do siblings of probands without nephropathy [192,193]. Recently epidemiological studies showed an increased incidence of diabetic nephropathy at level of a protein intake exceeding 20% of total energy [194], suggesting a pathogenetic role of nutritional protein.
The clinical picture of diabetic nephropathy is dominated by functional disorders, which may be classified according to Mogensen [195] (Table 1.12). The functional disorders correspond to morphological changes. The early increase in glomerular filtration rate has been explained by the ubiquitously increased blood flow and peripheral vasodilation. It correlates to increased kidney size, glomerular volume, and capillary filtration surface area.
Microalbuminuria develops without apparent morphological changes. It seems to be caused by increased glomerular capillary pressure and a loss of negative charge of the glomerular basement membrane. When the pores of this membrane enlarge, filtration selectivity is lost, and (macro-)proteinuria develops. With mesangial expansion due to continuous deposition of indigestible matrix proteins (formation of AGE on collagen, laminin, fibronectin) and thickening of the endothelial layer, vascular obstruction will occur, which results in a decrease of the filtering area. Histological studies show diffuse or nodular glomerulosclerosis [196–198]. In this situation blood pressure increases, glomerular filtration rate decreases, and progressive renal failure with end stage renal disease will develop.
Management
It is essential to detect diabetic nephropathy at a reversible stage. At Mogensen's stages 1-3 (Table 1.12) the disorders are reversible and renal function may be kept normal if effectively treated. In stages 4 and 5 it may only be possible to delay or possibly halt progression.
The most relevant diagnostic sign is microproteinuria. Microalbuminuria screening should be started not later than five years after diagnosis of type 1 diabetes, and at the time of diagnosis of type 2 diabetes. For correct diagnosis and follow-up monitoring, quantitative determination of albumin in urine collected over precisely measured time periods is essential. An albumin excretion rate (AER) below 30 mg per 24 hours (20 μg/min) is considered normal, whereas an AER above 300 mg per24 hours (200 μg/min) is considered to define macroalbuminuria or proteinuria. In between these two extremes is the range of microalbuminuria. Alternatively, the urinary albumin/creatine ratio may be determined [189].
Prevention and treatment of diabetic nephropathy is based on achieving near-normal metabolic control [127,129–131,199–202], lowering elevated blood pressure to values below 130/80 mmHg [157,158,191], a normal protein intake of 0.8-1.2 g/kg body weight [203,204], cessation of smoking (if applicable), and diagnosis and treatment of nondiabetic renal or urinary tract disease.
In normotensive diabetic subjects ACE inhibitors do not reliably prevent the development of microalbuminuria [205]. In normotensive patients with microalbuminuria, captopril and calcium channel blockers [206–212] retard the progression of nephropathy. In hypertensive subjects both the ACE inhibitor captopril and the β-adrenergic blocker atenolol retard the development of microalbuminuria [158,206]. In hypertensive diabetic subjects with micro- or macroalbuminuria, lowering blood pressure with ACE inhibitors, β-adrenergic blockers, or calcium channel blockers retards the progression of albumin excretion [213–221]. While