New and old markers of progression of diabetic nephropathy

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Abstract

The onset of diabetic nephropathy is characterised by a rise in albumin excretion rate (AER) and/or a transient rise in glomerular filtration rate (GFR) (hyperfiltration). Without intervention AER increases exponentially and there is a linear decrease in GFR after onset of overt nephropathy. In overt nephropathy, AER is a predictor of decline in GFR and the early AER response to antihypertensive therapy correlates with long-term decline in GFR. AER can be measured by immunoassay or by other techniques including HPLC. However, HPLC assays result in higher levels of AER in normal subjects compared with immunoassayable AER.

Recent data suggest that there are distinct albuminuric and non-albuminuric pathways to renal impairment in type 1 and type 2 diabetes. In type 2 diabetes, the non-albuminuric pathway may explain a decline in GFR to <60 ml/min/1.73 m2 in approximately one in four subjects after accounting for the use of renin angiotensin system inhibitors.

In established nephropathy (chronic kidney disease (CKD) stages 3 and 4), plasma cystatin C based estimates of GFR are marginally superior to creatinine based estimates. However, cystatin C clearly outperforms creatinine based estimates of GFR decline at GFR levels >60 ml/min/1.73 m2 (CKD stages 1 and 2).

Other potential markers of progression of diabetic nephropathy include transforming growth factor β (TGFβ) and connective tissue growth factor (CTGF). However, long-term studies are needed to define their roles as markers of progression.

Diabetic nephropathy is likely to be more susceptible to intervention at an early stage and accurate estimation of GFR is already possible with cystatin C. However, improved formulas for estimating GFR based on using creatinine or other markers are still required, because this may still provide the most cost effective approach applicable to existing clinical practice.

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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