Q J Med 2000; 93: 643-646
© 2000 Association of Physicians
Editorial |
Diabetic nephropathy—where next?
Institute of Nephrology, University of Wales College of Medicine, Cardiff
Diabetic nephropathy (DN) is a common complication of diabetes mellitus which has a major impact on patient morbidity and mortality and therefore a profound impact on the delivery of health care in this country. It affects more than one third of patients with insulin-dependent diabetes mellitus (type 1 diabetes),1 and up to a quarter of all patients with non-insulin-dependent diabetes mellitus (type 2 diabetes).2 It is therefore the single most common cause of end-stage renal failure (ESRF) in Western countries. There is a consensus that survival and rehabilitation of diabetic patients on renal replacement programs continues to be inferior to that of non-diabetic patients, although survival has greatly improved since the report of Ghavanmian et al.3 which concluded ‘... there is little prospect of improving the quality of life for patients with diabetic nephropathy and renal failure, and that survival is likely to be short. For some, we only prolong the misery. Dialysis for such patients may be considered as a palliative measure with little likelihood of long term survival.’
Clinically incipient nephropathy first manifests as persistent microalbuminuria, defined as albumin excretion ranging from 20–200 mg/24 h. Subsequently, the onset of overt DN is heralded by the appearance of persistent proteinuria (defined as a total protein excretion of >200 mg/day) associated with the early onset of hypertension. Following the onset of proteinuria, there is a progressive decline in glomerular filtration rate (GFR) which results in end-stage renal disease in 50% of those with overt nephropathy after 5 years.4
There is epidemiological evidence that the development of nephropathy in both type 1 and type 2 diabetes is related to poor glycaemic control. Furthermore, it is now clear that the microvascular complications of diabetes, including DN, may be influenced by strict glycaemic control. The recently completed DCCT trial of 14000 type 1 patients demonstrated conclusively that strict glycaemic control is effective in primary prevention (the development of microalbuminuria), and also secondary prevention (delaying the development of overt nephropathy).5,6 All studies to date however have demonstrated that following development of overt nephropathy, strict glycaemic control does not retard progression of renal disease. The results of the UKPDS trial also demonstrate that strict glycaemic control is associated with both primary and secondary prevention of renal disease in type II diabetes.7 This supports the findings of a smaller Japanese study in type II patients, with a design similar to the DCCT, which also showed a beneficial effect on progression of normoalbuminuria to micro- and macroalbuminuria.8 These studies therefore suggest that in terms of glycaemic control, that there is a ‘window of opportunity’ prior to the onset of overt nephropathy during which strict glycaemic control will benefit the renal outcome.
It is well established that there is a strong correlation between the degree of hypertension and the rate of progression of overt DN in both type 1 and type 2 diabetes. More direct evidence implicating hypertension in the progression of DN comes from the early work of Mogensen et al.9 demonstrating a slower rate of progression of nephropathy following aggressive treatment of hypertension. Much evidence now indicates that lowering blood pressure reduces albuminuria and attenuates the rate of loss of GFR in type 1 diabetes.10 Although substantially less information is available in type 2 diabetes, the recently published UKPDS study clearly demonstrated a reduction in the risk of macrovascular and microvascular complications (including nephropathy) in type 2 diabetes with tight blood pressure control.11 It is now widely accepted therefore, that early and aggressive treatment of arterial hypertension is an important goal in the management of DN in both patient groups, with a blood pressure of <130/85 set as an acceptable goal.12
In identifying and treating patients with hypertension, clinicians have traditionally tended to focus on diastolic blood pressure. In line with the growing recognition of the clinical significance of systolic blood pressure, one of the top priorities of the new British Hypertension Society guidelines is the identification and management of isolated systolic hypertension. The guidelines recommend drug therapy in people with sustained systolic blood pressure 
160 mmHg, with the decision to treat people with sustained systolic blood pressure between 140 and 159 mmHg to be made according to the presence or absence of other risk factors.13 All patients with DN by definition also have the additional risk factors of diabetes and nephropathy. The target to be adopted for isolated sustained systolic hypertension should therefore be a systolic blood pressure of 
140 mmHg.
Although ACE inhibitors are used in the treatment of hypertension, theoretical reasons suggest that this class of agents may have beneficial effects on renal function independent of their anti-hypertensive action. They may alter renal haemodynamics and reduce the intra-glomerular hypertension characteristic of diabetes. In addition, recent studies have demonstrated that ACE inhibitors may also affect mesangial cell function as well as intra-renal cytokine generation.
The beneficial effects of ACE inhibitors in normotensive microalbuminuric type 1 and type 2 patients are now well established, confirming that ACE inhibitors have effects which are divorced from their anti-hypertensive action.14 These studies therefore suggest that introduction of ACE inhibitors is effective in secondary prevention, i.e. delaying progression from microalbuminuria to proteinuria. One recent study also suggests that the use of ACE inhibitors may have a role to play in primary prevention of renal disease in type II diabetes,15 although further studies are required before prescription of these drugs to all type II patients can be recommended. The widely cited studies of Lewis et al. have also demonstrated that ACE inhibitors delay the progression of overt nephropathy in type 1 diabetics, and that this effect is also above and beyond that conferred by their anti-hypertensive effects.16 ACE inhibitors should therefore be considered as the first choice for the treatment of hypertension in patients with either incipient or overt diabetic nephropathy.
This protective effect is not confined to the ACE inhibitor group of drugs. Recent studies suggest that treatment with the angiotensin II receptor antagonist valsartan, slows the progressive rise in albuminuria in both normotensive and hypertensive patients with type 2 diabetes as effectively as an ACE inhibitor.17 Unlike ACE inhibitors, the angiotensin receptor antagonists do not inhibit the breakdown of bradykinin, which may confer an added benefit to renal function. Evidence is now emerging to support this claim as beneficial effects of combining ACE inhibition and angiotensin receptor antagonist have been reported in animal models of renal disease. What is clear is that combination of ACE inhibition and intensified blood pressure control can lead to stabilization and in some cases regression of clinical evidence of DN.18
Despite the mounting evidence demonstrating the efficacy of these specific treatments in the prevention of progression of DN, it is clear that outside the confines of clinical trials the implementation of evidence-based clinical care has been unsuccessful.19–21 This is clearly demonstrated in the recently published follow-up data of the widely cited DCCT trial, where strict glycaemic control achieved over a 10-year period during the study was not matched 2 years after the conclusion of the study, despite the clear benefits of strict glycaemic control shown during the original study.22 It is of note that the benefit of the intensive glycaemic control during the study period was still apparent. Similarly, although there is mounting evidence supporting the use of ACE inhibitors in diabetic nephropathy, recent studies suggest that only a third of diabetic patients with either incipient or overt nephropathy are currently treated with ACE inhibitors.20 There is also ample evidence to demonstrate that implementation of treatment guideline for the management of hypertension is suboptimal in the general population.23,24 This therefore emphasizes the difficulty in implementing evidence-based medicine in the clinical setting.
One factor preventing implementation of treatment guidelines is the late referral of diabetic patients to specialist renal clinics, as highlighted by the recent publication of Burton et al.25 This study demonstrated that the majority of patients were referred at a time when complications or renal failure were already present, and that late referral was associated with sub-optimal clinical management of renal disease. Despite late referral of patients, however, it is also clear that the transfer of care to specialist renal centers may delay the progression of DN and improve patient morbidity.26 Data from the Steno clinic in Denmark have demonstrated that intensified multifactorial intervention when rigorously applied reduces the incidence of microvascular complications and delays the rate of progression of nephropathy.27
A greater understanding of the natural history of DN, and potential therapeutic measures which may delay progression of DN has led to the publication of clear guidelines for screening both for microalbuminuria and proteinuria in diabetic patients. Despite widespread acceptance of the importance of such a policy, one factor implicated in the late referral of patients with DN is the lack of implementation of such a policy. A cross-sectional review in type 2 diabetics in the USA found that annual urine dipstick testing was the least frequently noted prevention practice, being carried out in only 32% of patients,28 while testing for microalbuminuria was performed in only 31% of patients in a study of Arizona Medicare patients.29 In a recently published audit of screening for renal disease in a population of hypertensive or diabetic population in the UK, only 50% of the patients had their renal function checked over a 2-year period, while only 25% had urinalysis performed over the same time period.30
There is now a large published literature which investigates the pathogenesis of diabetic nephropathy. Over the last few years, considerable evidence has accumulated that overproduction of cytokines such as transforming growth factor ß1 (TGF-ß1), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) plays a role in triggering diabetic renal injury.31 Of these, TGF-ß1 has emerged as a key player in the initiation and perpetuation of progressive renal fibrosis in diabetes. It is a relatively ubiquitous cytokine that functions in an autocrine or paracrine fashion to elicit a multiplicity of effects, principally related to cell growth and extracellular matrix accumulation. There is now evidence that TGF-ß1 generation, both within the glomerular and interstitial compartments, is stimulated in diabetes. Both proximal tubular epithelial cells32 and mesangial cells cultured in high glucose express increases in TGF-ß1 mRNA.33 Additionally, treatment of cells with neutralizing anti-TGF-ß1 antibodies results in reversal of the effects of high glucose on cell growth, and inhibits the stimulation of extracellular matrix generation in mesangial cells.33 There is also strong evidence to indicate that TGF-ß1 synthesis is increased in vivo, both in rodent models34,35 and patients suffering from diabetic nephropathy.36,37 This therefore raises the possibility that antagonism of TGF-ß1 may offer a fruitful avenue as a potential future treatment strategy. To date, work in rodent models of diabetic nephropathy has explored this possibility using numerous strategies, including therapy with neutralizing antibodies,38 therapy with antisense TGF-ß1 oligodeoxynucleotides39 and antagonism of TGF-ß1 by the administration of decorin.40 All of these studies have demonstrated some benefit in these animal models. In addition to its role in modulating matrix generation, TGF-ß1 has an important immunomodulatory role; thus any hope of specific antagonism of TGF-ß1 in humans requires very specific targeting, and is therefore some way off at present. Although specific anti-TGF-ß1 treatment strategies may not currently be available, several experimental studies have demonstrated that angiotensin II blockade results in a decrease in TGF-ß1 expression and matrix accumulation. In rodent models of renal disease, maximizing angiotensin II blockade was associated with reduction of glomerular TGF-ß1 expression and reduced renal damage.41 In addition, ACE-inhibitor-induced reduction in serum levels of TGF-ß1 has recently been correlated with long-term renoprotection in diabetic patients.42
In conclusion, in terms of where we should go next, ‘Back to the future’ may be a more appropriate title for this article. Current evidence suggests that rigorous implementation of the screening guidelines and treatment strategies that have been advocated over the past number of years, will clearly benefit individual patients, and reduce the health-care costs associated with renal replacement therapy. However, these intervention strategies, even when implemented successfully, are unlikely to slow the rate of decline in renal function. This highlights the need for a better understanding of the mechanisms which underlie diabetic nephropathy, which may lead to new therapeutic avenues to prevent or reverse established diabetic nephropathy.
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