Diabetic nephropathy: new approaches for improving

0 downloads 0 Views 583KB Size Report
patients with diabetes starting renal replacement therapy. (RRT) increased sevenfold ..... transcription factor Nrf2 (79), which up-regulates production of over 250 ...
review

JNEPHROL 2013; 26 ( 6) : 975- 985 DOI: 10.5301/jn.5000281

Diabetic nephropathy: new approaches for improving glycemic control and reducing risk Guntram Schernthaner 1, Gerit Holger Schernthaner 2

Abstract

Department of Medicine I, Rudolfstiftung Hospital, Vienna - Austria 2 Department of Medicine II, Medical University of Vienna, Vienna - Austria 1

Introduction

Nephropathy is a common consequence of diabetes, with a high prevalence in patients with type 1 (15%25%) and type 2 diabetes mellitus (T2DM; 30%-40%). Nephropathy is associated with a poor prognosis and high economic burden. The risk of developing nephropathy increases with the duration of diabetes, and early diagnosis and treatment of risk factors for nephropathy (e.g., tight control of glycemia and hypertension) can reduce the development and progression of diabetic nephropathy. Advances in our understanding of the mechanisms of renal complications associated with diabetes and the etiology of nephropathy have identified additional risk factors for nephropathy, and novel therapeutic options are being explored. This review discusses the pathophysiology of diabetic nephropathy and common risk factors. Furthermore, we discuss emerging treatments for T2DM that could potentially slow or prevent the progression of diabetic nephropathy. The use of incretin-based therapies, such as the dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagonlike peptide-1 (GLP-1) analogs, is growing in patients with T2DM, due to their efficacy and tolerability profiles. As renal safety is a key factor when choosing treatment options to manage patients with T2DM, drugs that are suitable for use in patients with varying degrees of renal impairment without a requirement for dose adjustment, such as the DPP-4 inhibitor linagliptin, are of particular use. The ongoing advances in T2DM therapy may allow optimization of glycemic control in a wide range of patients, thereby helping to reduce the increasing morbidity and mortality associated with diabetic nephropathy. Key words: Diabetes, Diabetic nephropathy, Dipeptidyl peptidase-4 inhibitors, Glucagon-like peptide-1 analogs, Renal safety

The global prevalence of diabetes is currently estimated at 366 million and is predicted to rise to 552 million by 2030 (1). Nephropathy is a common consequence of both type 1 diabetes mellitus and type 2 diabetes mellitus (T2DM); occurring in 15% to 25% (2, 3), and 30% to 40% of patients, respectively (4). Although extremely common in the United States – where 39.7% of adult patients with T2DM show some degree of chronic kidney disease (CKD) (4), ranging from asymptomatic changes to renal failure requiring dialysis or transplantation (Tab. I) (5, 6) – diabetes-associated renal complications are also increasingly a global problem. In Australia, the number of T2DM patients initiating dialysis increased fivefold between 1993 and 2007 (7), while in Japan, the number of patients with diabetes starting renal replacement therapy (RRT) increased sevenfold between 1983 and 2005 (8). However, recent data from the United States show that the crude and age-adjusted incidence of end-stage renal disease (ESRD) per 100,000 of the diabetic population declined from 1995 to 2006 (9). Improved patient outcomes require the adoption of treatment strategies that minimize the risk of the development and progression of diabetic nephropathy. Additionally, impaired renal function arising from diabetic nephropathy, concurrent disease or senescence is relatively common among patients with T2DM, and increases the chance of adverse events when using renally excreted agents. Therefore, it is vital to consider renal safety when discussing optimal antihyperglycemic treatments with individual patients. This review discusses the pathophysiology of diabetic nephropathy, the associated risk factors and the widening choice of treatments that could potentially slow or prevent the progression of nephropathy.

© 2013 Società Italiana di Nefrologia - ISSN 1121-8428

975

Schernthaner and Schernthaner: Diabetic nephropathy and glycemic control

TABLE I CLASSIFICATION OF DIABETIC NEPHROPATHY (5, 6) Classification

Characteristics

Glomerular filtration rate

Excretion of albumin

Blood pressure

Onset

1. Hyperfiltrationhypertrophy

Reversible mild microalbuminuria

Elevated compared with normal

Slightly increased

Normal in type 2

Present at time of diagnosis

2.  Silent stage

Thickened glomerular basement membrane and expanded mesangium

Normal

Type 2: may be 380 mg/day

Hypertension

15-25 years after diagnosis

5. Uremic

ESRD

0-10

Decreasing

Hypertension

25-30 years after diagnosis

ESRD = end-stage renal disease.

The clinical and economic burden of diabetic nephropathy Patients with long-standing T2DM are at a high risk of developing diabetic nephropathy. In an Italian cohort, 11.8% of T2DM patients with normal or near-normal kidney function at baseline developed CKD over a median follow-up of 5 years (10). In an analysis of 5,097 subjects enrolled in the United Kingdom Prospective Diabetes Study (UKPDS), 24.9% of patients with T2DM developed microalbuminuria, 5.3% developed macroalbuminuria and 0.8% showed elevated plasma creatinine or required RRT within the first 10 years after diagnosis. Each year of the study, 2.0% of patients with T2DM developed microalbuminuria, 2.8% progressed from microalbuminuria to macroalbuminuria and 2.3% developed elevated plasma creatinine (≥175 μmol/L) or RRT requirement from macroalbuminuria (11). After a median follow-up of 15 years, 38% of patients with T2DM developed albuminuria, and 28% developed renal impairment (estimated creatinine clearance