This meta-analysis indicates that type 1 diabetic patients with hyperfiltration are 2.7 times more likely to progress to incipient nephropathy than those with normofiltration and that patients who progressed had a higher baseline GFR.
The strength of this analysis is that it is the first study combining estimates from previous smaller observational studies on the risk of progression in the presence of hyperfiltration and thereby allowing more power to detect any differences as significant. However, these findings should be interpreted cautiously, as for both analyses there was apparent heterogeneity. Furthermore, in the hyperfiltration analysis, although not detected in formal tests, a funnel plot supplied evidence of asymmetry, with small published studies observing more marked increases in the risk of progression to nephropathy after hyperfiltration. This pattern is consistent with publication bias (resulting from small studies observing no associations or inverse associations not being published), which, if present, would result in the combined OR overestimating the increased risk of progression to nephropathy after hyperfiltration.
The association between progression and hyperfiltration had an I
2 value of 48%, indicating low to moderate heterogeneity, but this was greater (I
2 = 77%) when the mean GFR between patients who progressed and those who did not was compared. There are various explanations for this marked heterogeneity, including differences in the year of study, glycaemic control, treatments and improvement in screening for complications.
Various techniques were employed throughout the studies to measure the GFR, with some of the studies using a single compartment analysis. This has been shown to overestimate GFR by as much as 25% to 30% in the upper range of clearance values when compared with a two compartment model . The use of this model, if not corrected, would tend to overestimate the numbers of patients with hyperfiltration. When the studies not correcting for this potential weakness were removed from our analysis, heterogeneity did not improve and the combined OR did not markedly change, falling to 2.32 (Fig. 3).
Hyperfiltration has been found to be more prevalent in those with recent onset of diabetes and when glycaemic control is poor [1, 4, 5]. It would therefore be essential to compare duration of diabetes at entry into the study, as patients with shorter disease duration are more likely to have hyperfiltration. The mean duration of diabetes at entry into the studies analysed was 8.1 years, but this ranged from 3.4 to 12.6 years [22, 23]. Patients should therefore have been on established glycaemic therapy even in the studies with the shortest disease duration at baseline. Two studies had calculated odds strongly against hyperfiltration as a risk factor for progression [23, 24]. The first of these had the shortest duration of diabetes, but participants were diagnosed at an older mean age of 18.9 years and followed up for the longest period of time (18.5 years). It is therefore surprising that this group, with a 69% prevalence of hyperfiltration, had the lowest risk of progressing to nephropathy. It is generally recognised that younger age of diabetes onset also leads to a younger age of progression ; however, these older patients were diagnosed years after exposure to pubertal hormonal changes, which are thought to increase hyperfiltration, and perhaps this plays some part in confounding against their overall risk of progression . In other words, the pathophysiology of increased GFR may differ at different ages and these differences may themselves confer variable nephropathy risk.
In one study, the calculated odds of progression at 33.1 was double that of the next nearest (16.4) [22, 29]. There are a number of possible explanations for this disparity of effect, including the fact that this study was the first of its kind, and also the smallest. In addition, progression to microalbuminuria was defined as an increase in urinary albumin excretion (determined by radioimmunoassay) by a factor of more than 3 at follow-up. When compared with all other studies, where microalbuminuria was generally defined as 20 to 200 μg/min, this approach may lead to overestimation of progression to microalbuminuria based upon lower initial urinary albumin excretion. Also, in this study, patients who progressed had a markedly higher baseline GFR (all >150 ml min−1 1.73 m−2) than those not progressing compared with some of the later studies. The role of different levels of hyperfiltration could only be assessed in a larger study or with individual patient level data.
It has been proposed that high glomerular plasma flow increases intracapillary pressure; there is a relative constriction of the efferent glomerular arteriole resulting in a flux of plasma proteins into the mesangium [2, 35, 36]. This, in turn, leads to proliferation of mesangial cells and matrix, a forerunner of glomerulosclerosis. One potential cellular mechanism whereby these haemodynamic changes may lead to this sclerotic process is the effect of stretch induced by increased intraglomerular pressure on increasing fibronectin levels in mesangial cells via p38 mitogen-activated protein kinase, as has been demonstrated in mouse models . This has been shown to increase podocyte hypertrophy in vitro and leads to local activation of the angiotensin system [38, 39].
Hyperglycaemia can cause an increase in GFR, so the role of glycaemic control and diabetes treatment is important. Comparison of baseline glycaemic control across the studies showed that the mean HbA1c in patients with progression was 10.5% vs 9.6% in those not progressing. This may be a confounder in the overall calculated odds of progression. Reported baseline blood pressure was also higher, when available, in the progressing patients (123/77 vs 118/73 mmHg). An adjusted OR would be required to correct for the potential confounding factors of glycaemic control, blood pressure and diabetes duration, but in order to achieve this, individual patient level data would be necessary. However, in view of the age of some of the studies involved, the original data are unlikely to be available.
The progression to overt nephropathy as an endpoint was also assessed. However, three of the studies were not specifically designed or of long enough duration to look for proteinuria [29-31] and a further study did not discriminate between incipient and overt nephropathy , leaving very small numbers for analysis.
Hyperfiltration has been associated with a greater rate of decline in GFR . Additionally, there is a normal physiological decline in GFR associated with ageing. Most of the individual studies assessed here were not adjusted for age-related decline as a factor in GFR prediction or for the effects of hyperfiltration on promoting a more rapid decline in GFR rather than nephropathy as such, so we were unable to analyse these effects in the identified studies [41–43].
In conclusion, in the identified studies, individuals with type 1 diabetes who had glomerular hyperfiltration or elevated GFR subsequently had an increased risk of developing diabetic nephropathy. However, additional studies using patient level data are required to examine whether this increased risk would persist after adjustment for the confounding effects of glycaemic control, diabetes duration and blood pressure. Confirmation of hyperfiltration as a risk marker might enable future studies to assess how early GFR reduction using agents that block the renin–angiotensin–aldosterone system impacts on the development of incipient nephropathy. Ongoing studies are evaluating these drugs, but they are not stratifying treatment based upon baseline GFR [44, 45].