Treatment of diabetic nephropathy

Abstract

INTRODUCTION Approximately one-third of patients with type 1 diabetes mellitus (DM)1,2 and one-sixth of patients with type 2 DM develop overt diabetic nephropathy (DN).3 Once DN is present, the interval to the onset of end-stage renal disease (ESRD) varies from 4 years in earlier studies4 to over 10 years in recent studies5 and is similar in type 1 and type 2 diabetes. Although type 2 diabetes is now the most common cause of ESRD in Western countries, many people with renal disease and type 2 diabetes do not reach ESRD because cardiovascular mortality is increased twofold and four-to eightfold in the presence of microalbuminuria or overt nephropathy, respectively.6 The modifiable risk factors for DN include glycaemic control, blood pressure, dyslipidaemia and smoking. Unmodifiable risk factors include male sex; duration of diabetes; and familial, genetic and ethnic factors. In type 1 diabetes, the incidence of DN rises to 2-3% per year 10-13 years after the onset of diabetes, but then falls to 0.5-1% per year after 20 years of diabetes.7,8DEFINITION OF DIABETIC NEPHROPATHY (DN) The structural features of DN were described originally by Kimmelstiel and Wilson in 1936 as a glomerulopathy with diffuse and/or nodular intercapillary glomerulosclerosis.9 The nodular changes are still considered specific for diabetes, although the diffuse lesions are also seen in other renal diseases. It was recognized that these ultrastructural changes were accompanied by increases in proteinuria. However, progress in the field was slow until the development of sensitive immunoassays for urinary albumin10 and the demonstration that increases in albuminuria are detectable several years before changes occur in total proteinuria.11-13Although DN may be defined by both functional and structural criteria, functional criteria alone are generally used in clinical practice. The major functional parameter of DN is albumin excretion rate (AER), which may increase more than 100-fold during the evolution of DN (for example from 10 to 1000 μg/min). Biphasic changes in glomerular filtration rate (GFR), consisting of an initial increase followed by progressive decline, also occur in DN, but are not routinely used to define early stages of DN. Initial increases in AER and GFR, although very sensitive, are not always sufficiently specific to diagnose DN, and should be regarded as surrogate markers for the ‘hard’ clinical end point of a progressive decline in GFR, which occurs 10-15 years later. In unusual clinical circumstances or for research purposes, changes in AER and GFR need to be correlated with renal ultrastructural changes. Renal biopsy is particularly useful in distinguishing three entities occurring in older people with type 2 diabetes: non-diabetic renal disease,typical DN defined according to the original Kimmelstiel-Wilson criteria and atypical DN with a focus on renal interstitial and vascular changes (Figure 3.1).14,15The five studies summarized in Figure 3.1 emphasize the heterogeneity of renal ultrastructural morphology in type 2 diabetes and demonstrate differences in classification of renal disease among different investigators. Two studies have related renal ultrastructural changes to the course of diabetic nephropathy in patients with type 2 diabetes. Ruggenenti et al16 showed that the rate of decline of GFR is more closely related to the level of albuminuria than to renal ultrastructural category. Christensen et al17 also showed that the level of albuminuria is related to the level of GFR loss but, in addition, demonstrated a faster rate of decline in GFR in patients with diabetic glomerulopathy than in patients with glomerulonephritis or normal glomerular structure.