New and old markers of progression of diabetic nephropathy
Introduction
Diabetic nephropathy is initiated by hyperglycaemia, but several pathways, both sequential and parallel, modulate its progression. Glucose transporter-1 (GLUT-1) regulates glucose entry into renal cells. Glucose and its metabolites subsequently activate protein kinase C, the polyol pathway and non-enzymatic glycation, and these pathways contribute to renal functional and structural changes. Superimposed on this are transient and/or long-term changes in blood pressure, and haemodynamics, which accentuate changes in growth factors and other modulators of AER and GFR. Recent data favour a two-dimensional view of nephropathy which includes initial separation and subsequent close coupling of changes in AER and GFR as nephropathy develops (Fig. 1). Initial changes in albuminuria, in response to antihypertensive therapy, are strongly predictive of subsequent progression of GFR in late nephropathy but not in early nephropathy. There are many candidate markers that are associated with progression of experimental nephropathy, but there is little evidence in humans to suggest that they are more sensitive than changes in AER or more specific than changes in GFR.
Section snippets
Albuminuria as a marker of progression
In subjects predisposed to diabetic nephropathy who do not receive adequate treatment, there is an exponential increase in AER over several years. This perception has traditionally been categorised as an increase from normo to micro to macroalbuminuria [1] (Table 1). However, albuminuria, while being a sensitive index of altered renal handling of proteins, lacks specificity for diabetic nephropathy.
The question of whether albuminuria should be measured by immunoassay or by high performance
Categorical versus continuous assessment of progression
Stages of nephropathy, whether assessed by AER or GFR impose a categorical assessment of progression to these two variables, which are essentially continuous. This may cause problems in interpreting progression in clinical trials or in clinical practice. Furthermore, cardiovascular deaths may lead to survival bias especially in studies of progression of late nephropathy and this may complicate assessment of progression and the effects of treatment on progression of nephropathy. The dilemma of
Albuminuric and non-albuminuric pathways to renal insufficiency
In order to place into perspective the role of changes in AER in progression of nephropathy, it is important to integrate the categorical concept of microalbuminuria originating in the 1980s [5], [6], [7] and the more recently described Kidney Disease Outcomes Quality Initiative (K/DOQI) classification of stages of CKD by the National Kidney Foundation in 2002 [8]. This two-dimensional view recognises that there are stages of progression of GFR and AER which may occur concurrently and which can
Glomerular filtration rate as a marker of progression of diabetic nephropathy
Traditionally, GFR has been considered to be a less sensitive index of progression of nephropathy (Table 3). For instance, a progressive decrease in GFR is more easily demonstrated after the onset of overt nephropathy in type 1 diabetes. However, recent studies suggest a direct link between hyperfiltration and subsequent progressive decline in GFR [16]. This link remains tenuous as the study by Rudberg et al. [17] suggests continuity from hyper to normo to hypofiltration whereas other studies
Estimating and measuring rates of change of GFR
The spectrum of rates of change of GFR as a marker of progression of diabetic nephropathy at CKD stage 3 (GFR 60–30 ml/min/1.73 m2) has been studied in a number of ways. In a community study of non-diabetic subjects in Norway the annual rate of decline of GFR has recently been shown to be 1 ml/min [29]. By contrast, untreated diabetic nephropathy in type 1 diabetic patients has been shown by early studies to be associated with a rate of decline of GFR of around 12 ml/min per year [30], [31]. In the
The role of AER/GFR relationships in assessment of progression of diabetic nephropathy
Two recent studies have provided interesting insights into the relationship between progressive renal function decline and the course of albumin excretion rate in initially microalbuminuric patients. In a multifactorial intervention study in hypertensive patients with type 2 diabetes and microalbuminuria, an eight year intention to treat analysis showed that intensive intervention resulted in halving of albuminuria whereas the control group showed an increase [37]. By contrast, both groups
Role of cytokines as markers of progression of diabetic nephropathy
A potential role for cytokines, such as connective tissue growth factor (CTGF) and transforming growth factor β (TGFβ), as markers of progression of nephropathy has emerged from studies of experimental diabetes. The first human renal biopsy study, to suggest a link between CTGF and ultrasound changes, was performed in 65 subjects, with only three having diabetes [44]. In that study, the number of CTGF messenger RNA (mRNA) positive cells was closely related to the renal biopsy fibrosis score and
Future markers of progression
The above considerations focus on current markers of progression. It may be possible in the future to use genetic markers not only to detect the manifestations of progression but also to predict progression of renal disease [49]. In this respect, it is possible that studies of the urinary proteome may ultimately lead to methods for earlier detection of progression of diabetic nephropathy [50]. However, present proteomics methods are focussed on attempting to differentiate the phenotype of
Summary
In summary, two pathways to renal insufficiency (nonalbuminuric and albuminuric) have been defined in diabetic nephropathy. In later stages, albuminuria can predict progression on an intention to treat basis. In early nephropathy, albuminuria is a very sensitive, but not necessarily specific, marker of progression. The fact that three recent studies indicate that either regression or progression of microalbuminuria is linked to changes in GFR on a post hoc basis, but not on an intention to
Conflict of interest statement
There are no conflicts of interest to declare.
Acknowledgements
The study was supported by NHMRC grant no. 266505: Albuminuric and non-albuminuric pathways to renal impairment in diabetic nephropathy.
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