Pathogenesis, prevention, and treatment of diabetic nephropathy

doi:10.1016/S0140-6736(98)01346-4

The Lancet

Volume 352, Issue 9123, 18 July 1998, Pages 213-219

https://doi.org/10.1016/S0140-6736(98)01346-4 Get rights and content

Summary

It is likely that the pathophysiology of diabetic nephropathy involves an interaction of metabolic and haemodynamic factors. Relevant metabolic factors include glucose-dependent pathways such as advanced glycation, increased formation of polyols, and activation of the enzyme, protein kinase C. Specific inhibitors of the various pathways are now available, enabling investigation of the role of these processes in the pathogenesis of diabetic nephropathy and potentially to provide new therapeutic approaches for the prevention and treatment of diabetic nephropathy. Haemodynamic factors to consider include systemic hypertension, intraglomerular hypertension, and the role of vasoactive hormones, such as angiotensin II. The mainstay of therapy remains attaining optimum glycaemic control. Antihypertensive therapy has a major role in slowing the progression of diabetic nephropathy. Agents that interrupt the renin-angiotensin system such as angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists may be particularly useful as renoprotective agents in both the hypertensive and normotensive context.

Section snippets

Natural history

It is possible to assess patients with IDDM even before the onset of overt renal disease, and so clinical investigators have been able to characterise in detail the development of diabetic renal disease.⁴ The classification of nephropathy by Mogensen into several distinct phases can, in general, be used for both forms of diabetes. Initial changes include glomerular hyperfiltration and hyperperfusion—functional changes that are seen more often in IDDM than in NIDDM. The importance of these

Pathophysiology

There may be an interplay of metabolic and haemodynamic pathways in the renal microcirculation in diabetes (figure 1).⁹ Inhibitors of these pathways have increased our understanding of the underlying pathogenic pathways and have led to the development of new approaches to the treatment of diabetic nephropathy (Panel 2).

Because diabetes is a state of chronic hyperglycaemia, it is probable that glucose-dependent processes are involved in diabetic nephropathy. For example, the chronic effects of

Genetic factors

It is likely that genetic factors play a part in the susceptibility to diabetic nephropathy. Indeed, siblings of probands with diabetic nephropathy who have diabetes have a higher incidence of renal disease. A family history of hypertension has also been associated with an increased risk of diabetic nephropathy. Some, but not all, investigators have noted an association between red blood cell sodium-lithium counter-transport activity, which is viewed to be a marker of the risk for essential

Glycaemic control

In both IDDM and NIDDM, it has been shown that hyperglycaemia is a major determinant of progression of diabetic nephropathy. Several studies including the Diabetes Control and Complications Trial²⁴ have indicated that intensified glycaemic control retards the rate of development of both microalbuminuria and overt proteinuria in patients with IDDM with normal albuminuria. In a Japanese study of patients with NIDDM, intensified glycaemic control was also shown to reduce the rate of development of

Conclusions

It is now incumbent on clinicians to carefully monitor patients with IDDM and NIDDM for evidence of early renal disease. This involves regular screening for microalbuminuria, now made more convenient by the advent of reliable urine dipstick methods such as Micral 2⁵⁷ and the ability to concomitantly measure creatinine in an early morning urine specimen, and thus yield an albumin/creatinine ratio. This focus on microalbuminuria, a marker of cardiovascular as well as renal disease, has assisted

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SeminarPathogenesis, prevention, and treatment of diabetic nephropathy

Summary

Section snippets

Natural history

Pathophysiology

Genetic factors

Glycaemic control

Conclusions

Lancet

Lancet

Lancet

Kidney Int

Kidney Int

Diabetes Res Clin Pract

Kidney Int

Lancet

Lancet

Diabetes Res Clin Pract

Cases and observations illustrative of renal disease accompanied with the secretion of albuminous urine

Guy's Hospital Report

Intercapillary lesions in the glomeruli in the kidney

Am JPathol

Diabetic nephropathy

Lancet

How to protect the kidney in diabetic patients: with special reference to IDDM

Diabetes

Patterns of renal injury in NIDDM patients with microalbuminuria

Diabetologia

Diabetic vascular complications

Clin Exp Phamiacol Physiol

Pimagedine Investigator Group. Baseline data from the Pimagedine Action trials

Diabetologia

Effects of polyol- pathway inhibition and dietary myo-inositol on glomerular hemodynamic function in experimental diabetes mellitus in rats

Diabetes

Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor

Science

The role of angiotensin II and bradykinin in experimental diabetic nephropathy: functional and structural studies

Diabetes

Expression of transforming growth factor-pi and type IV collagen in the renal tubulointerstitium in experimental diabetes: effects of angiotensin converting enzyme inhibition

Diabetes

Vascular hypertrophy in experimental diabetes: role of advanced glycation end products

J Clin Invest

Mechanical stretch induces vascular permeability factor in human mesangial cells: mechanisms of signal transduction

Proc Natl Acad Sci USA

Sodium-hydrogen antiport, cell function and susceptibility to diabetic nephropathy

Enhanced G protein activation in IDDM patients with diabetic nephropathy

Diabetologia

Meta-analysis of association of insertion/deletion polymorphism of angiotensin I- converting enzyme gene with diabetic nephropathy and retinopathy

Diabetologia

Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme: observational follow up study

BMJ

Seminar
Pathogenesis, prevention, and treatment of diabetic nephropathy