Diabetic nephropathy is the primary cause of renal failure in the US and most developed countries, accounting for over 40% of prevalent patients initiating dialysis in the US Endstage Renal Disease (ESRD) program. Pathologically, diabetic nephropathy is thought to have a similar histological presentation in both type 1 and type 2 diabetic patients, although less is known about the early presentation of type 2 diabetic nephropathy due to less precision regarding the date of onset of diabetes.
Diabetic nephropathy is the primary cause of renal failure in the US and most developed countries, accounting for over 40% of prevalent patients initiating dialysis in the US Endstage Renal Disease (ESRD) program. Pathologically, diabetic nephropathy is thought to have a similar histological presentation in both type 1 and type 2 diabetic patients, although less is known about the early presentation of type 2 diabetic nephropathy due to less precision regarding the date of onset of diabetes. The natural history of diabetic nephropathy has been shown to have five stages of progression:
- hyperfiltration with normal renal function;
- histological changes without clinically evident disease;
- incipient diabetic nephropathy or microalbuminuria;
- overt diabetic nephropathy (macroalbuminuria, reduced renal function); and
- renal failure requiring dialysis.
Over the last two decades, randomized controlled interventional trials have shown that early treatment of diabetic nephropathy at the microalbuminuria or third stage of disease with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) improves glycemic and blood pressure control, and decreases progression of early diabetic nephropathy to renal failure and the need for dialysis. This article reviews evidence for the treatment of diabetic nephropathy, describes current treatment recommendations, and discusses new medication classes that have treatment potential of diabetic nephropathy.
What is Diabetic Nephropathy ?
Diabetic nephropathy appears in patients with both type 1 and type 2 diabetes after five to 10 years of active diabetes, and is heralded by the onset of abnormal amounts of albumin in the urine, termed microalbuminuria, defined as a urinary albumin excretion rate of 20–200μg/min in a timed specimen, 30–300mg/24 hours, or an albumin to creatinine ratio of 30–300g albumin/mg creatinine on a morning spot urine test. The spot urine/creatinine ratio has been shown to have high sensitivity and specificity for urinary albumin excretion compared with a timed measurement of urinary albumin. Factors associated with false positive tests include:
- poorly controlled diabetes;
- morbid obesity;
- febrile acute illness;
- pregnancy;
- urinary tract infection;
- excessive protein ingestion;
- congestive heart failure; or
- hematuria.
It is recommended that annual microalbuminuria assessment be conducted until the onset of frank proteinuria. Once microalbuminuria has been documented, evidence-based treatment for diabetic nephropathy includes lifestyle changes (proper diet, weight control, exercise), glycemic control, blood pressure control, and initiation of ACE inhibitors or ARBs.
Glycemic Control Trials in Diabetic Nephropathy
Several randomized trials have shown that improved glycemic control in both type 1 and 2 diabetic patients decreases the risk of diabetic nephropathy and other complications. Reichard et al. reported in type 1 patients that intensified insulin therapy (hemoglobin (Hb) A1C level of 7.1%) compared with standard therapy (Hb A1C=8.5%) decreased retinopathy by 60% and diabetic nephropathy by 90% compared with standard treatment. The US-conducted Diabetes Control and Complications Trial (DCCT) found that intensive insulin treatment compared with regular insulin treatment reduced the risk of microalbuminuria by 39% and macroalbuminuria (greater than 300mg albumin/gram of creatinine) by 54%. Severe hypoglycemia was the most significant adverse event in the intensely treated group. Observational follow-up of the original DCCT cohort, renamed the Epidemiology of Diabetes Interventions and Complications (EDIC) study, showed that those patients originally randomized to strict glycemic control maintained their risk reduction advantage and had a 56% reduction in the risk of microalbuminuria and an 85% reduction in risk of macroalbuminuria at four years of follow-up even without a specific intervention.
Similarly, several randomized controlled trials in type 2 patients have evaluated intensive glycemic control and have found that improved glycemic control decreases the risk of diabetic nephropathy and other complications. Conducted in Japanese type 2 diabetic patients, the Kumamoto study was one of the first studies to report that intensive (Hb A1C=7.1%) compared with conventional glycemic control (Hb A1C=9.4%) in type 2 diabetic patients was associated with a primary risk reduction (21%) and secondary prevention (20.5%) of diabetic nephropathy. Likewise, the UK Prospective Diabetes Study (UKPDS-33) showed that intensive treatment with insulin compared with sulfonylurea drugs reduced a combined microvascular end-point (micro-albuminuria, retinopathy by 25%, and micro-albuminuria at six years by 29%), although macroalbuminuria and renal failure were not significantly reduced. As with the DCCT, subjects treated as part of the insulin therapy group sustained more hypoglycemic episodes than the standard care group. Comparison of metformin with conventional insulin use and sulfonylureas in the UKPDS-34 showed that metformin was associated with a reduction in the combined end-point of complications (32%), diabetes-related death (42%), and all cause mortality (36%), although diabetes-related deaths were increased in the combined metformin and sulfonylurea use group.
Hypertension Trials
Several randomized controlled trials have shown that reduction of hypertension reduces the risk of progression of diabetic nephropathy and other complications in both type 1 and type 2 diabetic patients. Data from the Collaborative Study Group showed that blood pressure control to average levels of 137/85 was associated with a 43% reduction in the doubling of creatinine and a 46% reduction of the number of patients who required dialysis or transplantation, or who died. Likewise, results from UKPDS-38 showed that blood pressure control to an average of 144/82mmHg decreased the risk of microalbuminuria by 71% at six years, and of microvascular disease by 63%. Comparison of captopril with atenolol in the UKPDS-39 resulted in a similar reduction in microvascular and macrovascular end-points and albuminuria, specifically when blood pressure was controlled to an average of 144/81. Finally, the Heart Outcomes Prevention Evaluation (HOPE) study and the sub-study Microalbuminuria, Cardiovascular, and Renal Outcomes in HOPE (MICRO-HOPE), conducted primarily in the diabetic population, found the angiotensin-converting enzyme inhibitor ramipril was associated with a reduction in diabetic nephropathy (24%) that was not due to differences in blood pressure attainment between intervention and placebo. ACE Inhibitor / ARB Trials in Diabetic Nephropathy
Data from randomized controlled trials of treatment of early diabetic nephropathy with ACE-inhibitors have shown that ACE-inhibitors and ARBs should be considered as standard therapy for both type 1 and type 2 diabetic nephropathy. In a small randomized controlled trial of type 1 diabetic patients, Mathiesen et al. showed that treatment with captopril (25–100mg/d) versus placebo decreased the progression of diabetic nephropathy by 30%. In addition, researchers from the Collaborative Study Group showed that use of captopril reduced the risk of doubling of serum creatinine by 43% (p=0.014) and decreased the risk of progression of diabetic nephropathy to dialysis, transplantation, or death in 46% (p=0.021) of type 1 patients.To evaluate whether ACE inhibitors could decrease the rate of development of diabetic nephropathy in normotensive type 1 patients, researchers from the Eurodiab Controlled Trial of Lisinopril in Insulin Dependent Diabetes (EUCLID) study showed that lisinopril (10–20mg) resulted in significant risk reduction of urine albumin excretion (18.8%), and significantly reduced the albumin excretion in those with microalbuminuria at baseline, but not those with normal albuminuria.
Similarly, data reported from large randomized controlled trials conducted in type 2 patients confirmed that treatment of early diabetic nephropathy with ACE inhibitors decreased progression of diabetic nephropathy. Ravid randomized 156 type 2 patients to enalapril (10mg) versus placebo and found a 12.5% risk reduction in progression of microalbuminuria. In the MICROHOPE trial, conducted in both type 1 and 2 elderly diabetic patients with at least one risk factor for cardiovascular disease, there was a 25% (95% confidence interval, 12 to 36) risk reduction in the combined endpoint of myocardial infarction, stroke, and cardiovascular death, and a 16% risk reduction in the progression of microvascular disease defined as diabetic nephropathy, dialysis, and diabetic retinopathy. There was a nonsignificant decrease in the progression of proteinuria in that trial.
Compared with placebo and calcium channel blockers, several angiotensin receptor blockers have been proven to be beneficial in diabetic nephropathy. Losartan improved proteinuria at 12 weeks compared with felodipine in a small randomized controlled trial. More recently, investigators for the Irbesartan Diabetic Nephropathy Trial (IDNT) reported that irbesartan was associated with a 40% to 60% decreased risk of development of diabetic nephropathy in type 2 patients compared with placebo, while Lewis et al. reported that irbesartan treatment was associated with 33% decreased risk of progression of diabetic nephropathy to renal failure compared with placebo and the calcium channel blocker amlodipine. In addition, the Losartan Renal Protection Study (RENAAL) showed that losartan reduced the progression of doubling of serum creatinine by 25% and renal failure by 28% in type 2 diabetic patients compared with placebo. Finally, in a small randomized controlled crossover trial, Jacobsen et al. showed the benefits of ACE inhibitor/ARB combination therapy in reducing the progression of diabetic nephropathy in type 1 patients. On-going long-term trials of ACE inhibitors versus ARBs versus combination therapy will determine which treatment combinations are beneficial for primary and secondary prevention of diabetic nephropathy.
Lipid Reduction Treatment and Diabetic Nephropathy
Although hyperlipidemia has been shown to be a risk factor for diabetic nephropathy, limited data exist as to the benefits of lipid reduction therapy on the primary and secondary prevention of diabetic nephropathy. In a small crossover trial,Tonolo et al. found that after 52 weeks of treatment with simvastatin (20mg/day), cholesterol and low density lipoprotein (LDL) were decreased as expected; however, urinary microalbuminuria excretion was also decreased by 25%, without similar decrease in creatinine clearance. Researchers from the Greek Atorvastatin and Coronary heart disease Evaluation (GREACE) study found that atorvastatin use was associated with a 10.9% increase in glomerular filtration rate (GFR) compared with a mean reduction of 4.9% in the placebo-treated group. Similarly, in an underpowered trial in type 1 diabetic subjects, Fried et al. found that simvastatin was associated with a slower rise in microalbumin when compared with placebo.
In addition, Smulders reported that gemfibrozil was associated with decreased progression of microalbuminuria compared with placebo in a small trial of diabetic patients. Although there is experimental evidence for beneficial effects of certain classes of lipid-lowering agents on diabetes, no large-scale randomized double blind controlled trial has been conducted in the diabetes population that proves these drugs are beneficial in preventing diabetic nephropathy and its progression.
Peroxisome Proliferators-activated Receptor Trials
Peroxisome proliferators-activated receptors (PPARs) are ligand-activated transcription factors with diverse cell functions such as control of adipocyte differentiation, control of mechanisms of inflammation, induction of fatty acid metabolism, and cell cycle regulation. As a class of drug, the thiazolidinediones, such as rosiglitazone and troglitazone, activate the gamma PPAR receptor (PPARγ), and are now being used as monotherapy for type 2 diabetes mellitus. Although rosiglitazone has been shown to reduce non-traditional markers of proinflammatory cytokines, few data exist as to the benefits of PPARγ medications on the primary or secondary prevention of diabetic nephropathy. Likewise, very limited data indicate that rosiglitizone is safe in patients with early diabetic nephropathy.33 Imano found that troglitazone compared with metformin significantly reduced urinary albumin excretion at one year. In addition, Nakamura found that troglitazone reduced microalbuminuria and type IV collagen deposition in 32 type 2 patients with diabetic nephropathy. Troglitazone has been removed from the market due to its associations with fulminant hepatic failure, but more recent studies with rosiglitizone appear promising.
In a small underpowered open label randomized controlled trial of rosiglitazone versus glyburide in type 2 diabetic patients, Bakis reported rosiglitazone was associated with significant reduction of urinary albumin excretion compared with glyburide that was primarily due to reduction in blood pressure. Large randomized trials are needed to ascertain the benefit of the PPARs in the treatment of diabetic nephropathy.
Conclusion
Although significant improvement in the treatment of diabetic nephropathy has occurred over the past 25 years, diabetic nephropathy remains the primary cause of kidney failure and is projected to increase exponentially over the next few years. Patients with overt diabetic nephropathy manifested by macroalbuminuria and renal insufficiency remain difficult to treat, and few randomized controlled trials have been conducted in this population that specifically evaluate preventive therapy. Much can be undertaken to improve translation of current evidence into clinical practice, which has been shown to improve outcomes in this population.
Further research should be targeted at illumination of basic mechanisms of disease, translation of basic research findings into clinical practice, and the development of process measures to transform clinical evidence into standard clinical practice, which will result in improvement of diagnosis and treatment of diabetic nephropathy.■
