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Diabetic Nephropathy

Figure 1: Albumin Excretion Rate and Glomerular Filtration Rate Concordance and Discordance


This emphasises that higher levels of albuminuria, even within the normoalbuminuric range, predict a faster decline in eGFR.


In summary, the traditional concept of the natural history of DN that links the transition from micro- to macroalbuminuria as the key to heralding a significant decline in GFR has been challenged. More recent data suggest that AER and GFR are complementary rather than obligatory manifestations of DN (see Figure 1). Therefore, according to this new model, both AER and GFR should be measured as markers of DN (see Figure 2).

Traditional concept New model according to more recent data AER = albumin excretion rate; GFR = glomerular filtration rate.

Figure 2: Albumin Excretion Rate and Glomerular Filtration Rate as Indices of Diabetic Nephropathy

120 15 V M μ N 30 III 60

N = normoalbinuria; µ = microalbinuria; M = macroalbinuria. The evolution of diabetic neuropathy is shown in the form of two dials: on the left representing stages of albumin excretion rate and on the right representing stages of glomerular filtration rate (GFR) (chronic kidney disease stages I to V, with numbers indicating GFR in ml/min/1.73 m2).

In the Diabetes control and complications trial/epidemiology of diabetes interventions and complications cohort (DCCT/EDIC) study, the long-term analysis, performed over 15 years, of subjects with type 1 diabetes showed a persistent decline in estimated GFR (eGFR) to <60 ml/min/1.73 m2 in 89 of 1,439 subjects, of whom 21 had normoalbuminuria.8

When expressed per 1,000 person-years, this

translated into 36.1 macro-, 1.3 micro- and 1.0 normoalbuminuric subjects progressing to CKD stage 3.

The relationship between early renal function loss and AER has also been studied in type 2 diabetes. In a long-term study of 195 Pima Indians with type 2 diabetes, early renal function decline was defined as a rate of GFR loss of ≥3.3 % per year over four years.9

In this study,

GFR was measured directly by the urinary clearance of iothalamate. The prevalence of early renal function decline during this initial period was 32 % in participants with normal urinary albumin:creatinine ratio at baseline, 42 % in those with microalbuminuria and 74 % in those with macroalbuminuria (p<0.001). Subsequent follow-up showed that the cumulative incidence of end-stage renal disease (ESRD) 10 years after the initial period was 41 % in those with early renal function decline and 15 % in those without.9

It was concluded that an

early decline in GFR often occurs before the onset of macroalbuminuria, but that a decline predictive of ESRD is strongly dependent on the progression to macroalbuminuria.

Studies of eGFR gradients in patients with type 2 diabetes have also shown that the rate of decline in renal function increases progressively from 2 to 8 ml/min/1.73 m2 per year, adjusted for age and baseline eGFR, as albuminuria increases from <10 to >1,000 mg/g

28 II IV I 90

Effects of Treatment on Assessment of Renal Function in Diabetes

This approach has resulted in markedly improved long-term renal outcomes. However, there are short- and long-term treatment effects that complicate the interpretation of renal function tests. For instance, ACE inhibitors and ARBs usually, but not always, decrease AER in micro- or macroalbuminuric patients. In macroalbuminuric patients, a larger initial decrease in AER predicts greater attenuation of the long-term rate of decline of GFR.12


contrast, in microalbuminuric patients, the initial decrease in AER during antihypertensive therapy has not been shown to predict attenuation of the subsequent rate of decline of GFR.13


analyses of several trials have shown that, in microalbuminuric patients, increases in AER are linked to a faster decline in GFR.1,14


follows that decreases in AER induced by RAS inhibitors may create problems in interpreting renal function tests. For instance, ‘normoalbuminuria’ induced by RAS inhibitors may revert to microalbuminuria after cessation of therapy. Antihypertensive therapy, including RAS inhibitors, may also cause an early decline in GFR, which is reversed on cessation of therapy, indicating a haemodynamic mechanism.15

In line with early changes in AER, the

extent of the early decline in GFR induced by antihypertensive therapy predicts the long-term attenuation of GFR.16

Lipid lowering therapy may also influence rates of decline of GFR. In the Collaborative atorvastatin diabetes study (CARDS), atorvastatin reduced the eGFR gradient by 0.38 ml/min/1.73 m2 per year in subjects with elevated AER.17

In the Fenofibrate intervention and

event lowering in diabetes (FIELD) study, fenofibrate decreased eGFR acutely (but this was reversed on cessation of therapy);18

it is not yet

clear whether this was due to an effect of fenofibrate on renal creatinine handling or to a direct effect of fenofibrate on GFR.

Several studies have evaluated the effects of intensive glucose control on early GFR loss in diabetes. In type 2 diabetes, both the Action in diabetes and vascular disease: PreterAx and Diamicron MR controlled evaluation (ADVANCE) and the Action to control cardiovascular risk in diabetes (ACCORD) studies showed that intensive glucose control reduced the risk of incident microalbuminuria but with no benefit on eGFR.19–21

A follow-up of the United Kingdom prospective diabetes study (UKPDS) showed no benefit on albuminuria or serum creatinine in the intensive glucose control arm.22

In type 1 diabetes, the DCCT/EDIC study

showed that the intensive glucose control arm had a decreased risk of micro- and macroalbuminuria.23

On long-term follow-up, the intensive EUROPEAN ENDOCRINOLOGY

In the 30 years since the description of microalbuminuria as an indicator of early DN, there have been major changes in diabetes management. Instead of being confined to glycaemic control, diabetes care has become multifactorial and now includes aggressive control of blood pressure and dyslipidaemia, as highlighted in the Steno 2 study.11

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