Long-term complications of diabetes include increased risk of cardiovascular disease and the development of small-vessel (microvascular) complications that can result in blindness from diabetic retinopathy and renal failure from diabetic nephropathy.

Natural History of Diabetic Nephropathy
Hypertension is a leading risk factor for chronic kidney disease (CKD). In people with diabetes, hypertension is highly prevalent, occurring twice as frequently as in those without diabetes. High blood pressure is also often present when diabetes is diagnosed and both conditions cause target organ damage, which includes the development of kidney disease in approximately one-third of patients. The first clinical evidence of renal damage is microalbuminuria (see Table 1), which not only carries a high risk of serious renal disease, but also is associated with significantly increased cardiovascular morbidity and mortality. Without adequate risk factor control at this early (incipient) stage (which must include the rigorous treatment of hypertension), urinary albumin excretion increases by approximately 10–20% each year.

Between 20% and 40% of type 2 diabetic patients with microalbuminuria will progress to overt nephropathy, with the macroalbuminuria contributing to further renal damage. At this stage, the extent of renal impairment is often evaluated in terms of the estimated glomerular filtration rate (GFR), based on serum creatinine concentrations. After 20 years of overt nephropathy, approximately 20% of patients will require a kidney transplant or dialysis because of end-stage renal disease indicated by a GFR of less than 15ml/min/1.73m2.

Inevitably, the management of patients with endstage renal disease places heavy demands on healthcare resources. Even more disconcerting is the fact that the majority of patients with diabetic nephropathy will have experienced a debilitating stroke, heart disease or peripheral artery disease, or will have died of cardiovascular disease, even before end-stage kidney disease develops.

The Relationship Between Systemic and Intraglomerular Blood Pressure
Evidence of renal damage is often found when diabetes is diagnosed, especially if the patient also has high blood pressure. In others, it is detected very soon afterwards. It is postulated that it is not the systemic blood pressure that determines the extent of the renal damage, but the pressure within the glomerular capillaries. A high systemic blood pressure can be associated with increased intraglomerular pressure, but glomerular hypertension can exist even in the presence of seemingly well-controlled hypertension. Elevated intraglomerular pressure leads to structural changes in the glomerulus, at least in part, as a result of oxidative stress and endothelial dysfunction. As the damage progresses, protein leakage increases until microalbuminuria becomes apparent. A vicious cycle ensues.

The advancing loss of glomeruli causes an adaptive elevation of glomerular pressure in an attempt to maintain the GFR. The kidney damage resulting from increased glomerular capillary pressure worsens systemic hypertension, resulting in further glomerular hypertension (see Figure 1).2

The Importance of Systemic Blood Pressure Control
Meta-analysis of clinical trials in diabetic and nondiabetic renal disease has established a direct and continuous relationship between the achieved blood pressure and the decline in GFR with advancing renal impairment.3 In patients with urinary albumin concentrations higher than 1g/24h and a GFR in the range of 13–55ml/min/1.73m2, the optimal blood pressure is <125/75 millimetres of mercury (mmHg).4