Therapies that are proved to delay or prevent this outcome will clearly be of major benefitThe aetiology of DN is unknown. Hyperglycaemia is necessary but not sufficient to develop this complication, as is well demonstrated by observations in subjects with T1DM. Even with the poor glycaemic control seen in patients diagnosed in the first part of the 20th century (when glucose monitoring was not available and the only therapy was short-acting nsulin delivered via hypodermic syringes), the majority of patients (~60%) did not develop nephropathy.³ Furthermore, the incidence of this complication rises until approximately 25-year disease duration, but then falls progressively. This is in keeping with DN emerging in a genetically predisposed cohort while the remainder are at low risk of this complication, rrespective of their level of glycaemia. In addition to genetic susceptibility (which may be modulated via insulin resistance), other factors such as male sex, hypertension, ethnic background and smoking play a roleDN is a good model for progressive chronic renal disease, as its natura history has been extensively studied and parallels that seen in most non-diabetic renal disorders.

In subjects with T1DM who develop DN, there is an initial increase in glomerular filtration rate (GFR), but over time this falls and they begin to leak small amounts of urinary albumin, termed microalbuminuria (MA). The development of MA (albumin excretion rate 20-200µg per minute) is typically seen five to 15 years after diagnosis and is associated with a rise in blood pressure, albeit within the ‘normal range’ Patients subsequently become macroalbuminuric (albumin excretion rate (AER) >200µg/min), at which time blood pressure is elevated and the other microvascular complications of diabetes emerge. From this point, GFR declines in a linear fashion and, with no intervention, a fall of approximately 10ml/min/year leads to ESRD within 10 years. Although extensively studied, the natural history of DN in patients with T2DM is less clear. In a sub-group of patients (especially those with young-onset diabetes), the sequence mirrors that seen in T1DM; however, for the majority of patients, the emergence of MA should be regarded as a cardiovascular risk factor rather than a precursor of ESRD. In keeping with this, many T2DM patients with MA have reduced GFR and are already experiencing premature cardiovascular events, the leading cause of death in subjects with T2DM. The differences in DN between T1 and T2DM probably reflect the different ages of these two disease cohorts and do not nfluence clinical practice. However, they may evoke an element of caution when results seen in one disease are extrapolated to the other.There is an increasing focus on detecting the earliest stages of DN in routine clinical practice. A typical example is the UK General Practice contract that promotes annual checks of MA in all diabetic subjects and the routine estimation of GFR (eGFR) using the Modification of Diet in Renal Disease (MDRD) equation. In patients who screen positive for either or both of these tests, more aggressive control of blood pressure is recommended, with a focus on inhibition of the renin-angiotensin system (RAS). The remainder of this review will focus on the trial evidence in T2DM that supports a reno-protective effect of RAS blockade over and above that achieved by blood pressure reduction alone