Treating Diabetic Nephropathy in Primary Care: Intensive Multifactorial Strategies in the Prevention of End-Stage Renal Disease

More than half of all patients with diabetes suffer from diabetic microvascular complications, and diabetic nephropathy afflicts between 20% and 40% of patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM).^1-7 Diabetic nephropathy has been categorized into two stages based on the degree of urinary albumin excretion (UAE): microalbuminuria (spot collection: 30-299 μg/mg creatinine) and macroalbuminuria (spot collection: ≥300 μg/mg creatinine).⁴ Microalbuminuria is both a predictor of progression of nephropathy and an independent risk factor for cardiovascular disease (CVD).^4, Evidence to date suggests that the risk for developing diabetic nephropathy and CVD begins when UAE values are still within the normoalbuminuric range (<30 μg/mg creatinine).^4,9

Patients that do not receive effective treatment for diabetic nephropathy can experience renal failure, leading to end-stage renal disease (ESRD).⁴ The incidence of ESRD continues to rise in diabetic populations in the United States,¹⁸ and diabetes represents the most common single cause of ESRD in the United States, Europe, and Japan.¹⁹  Approximately 50% of patients with T1DM that have overt nephropathy progress to ESRD within 10 years, and more than 75% do over 20 years.¹⁰ Although only 20% of patients with T2DM progress to ESRD within 20 years, because patients with type 2 diabetes account for approximately 90% of patients with diabetes, they constitute over half of those requiring dialysis.¹⁰ However, early intervention can modify, or perhaps even reverse, diabetic nephropathy.^11-17 Reducing the risk of ESRD from diabetic nephropathy can be achieved with current treatments for glycemia, blood pressure (BP), and dyslipidemia. Recent clinical trials have conclusively demonstrated that intensive control of risk factors can result in regression of diabetic nephropathy; even remission of microalbuminuria is possible. Thus, the critical challenge for primary care providers is to translate successful clinical trial results into daily practice to improve clinical outcomes.

Nephropathy in Type 1 Diabetes

To identify prognostic factors for progression of early-stage nephropathy in T1DM, the Joslin Study of the Natural History of Microalbuminuria followed 386 patients with persistent microalbuminuria over 6 years and found that a minority (19%) progressed to overt proteinuria, whereas the majority (approximately 60%) regressed to normal albumin excretion levels over 6 years of follow-up.¹⁴  Regression was independently associated with microalbuminuria of short duration, A1C <8%, low systolic BP (<115 mmHg), and low levels of both cholesterol and triglycerides (<198 mg/dL and <145 mg/dL, respectively). The strongest modifiable risk factors associated with regression were lipid levels and glycemic control. The odds of regression of microalbuminuria approximately doubled when levels of either cholesterol or triglycerides were low. The results from this study support the need for not only strict glycemic control, but also intensive pharmacologic targeting of BP and atherogenic lipids for the management of microalbuminuria in T1DM. A longitudinal analysis of the natural history of microalbuminuria in adolescents with T1DM also identified glycemic control and hypercholesterolemia as modifiable risk factors for persistent microalbuminuria.²⁰ Therefore, the association of shorter duration of microalbuminuria with regression and the evidence that controlling risk factors for nephropathy can result in regression are compelling reasons for yearly screening of all normoalbuminuric patients with T1DM.

Nephropathy in Type 2 Diabetes

The United Kingdom Prospective Diabetes Study (UKPDS) analyzed the development and annual progression of nephropathy in subjects with T2DM and found that from the time of diagnosis of diabetes, the annual progression rate in terms of the percentage of patients transitioning from one stage of nephropathy to the next was 2.0% per year from normoalbuminuria to microalbuminuria, 2.8% per year from microalbuminuria to macroalbuminuria, and 2.3% per year from macroalbuminuria to elevated plasma creatinine or renal replacement therapy * (RRT).²¹ Patients with elevated plasma creatinine or RRT had an annual death rate of 19.2%, and there was an increased risk of cardiovascular death with nephropathy (P <0.0001). Thus, the early identification and treatment of patients with microalbuminuria is crucial in reducing the risk for the excess renal complications and CVD associated with T2DM.

Intensive targeting of all modifiable risk factors is currently the best approach to risk reduction for diabetic nephropathy in T2DM. The Steno‑2 clinical trial compared the effects of standard versus intensive multifactorial intervention in subjects with T2DM and microalbuminuria.^15,22,23 Intensive therapy included the pharmacologic targeting of hyperglycemia, hypertension, dyslipidemia, and microalbuminuria. All patients were prescribed an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II‑receptor blocker (ARB), irrespective of BP levels. Treatment resulted in significant declines of A1C levels, systolic and diastolic BP, fasting cholesterol and triglyceride levels, and UAE rate among the intensive therapy group compared to the conventional group. The relative risk reduction in nephropathy for subjects receiving intensive therapy was 61%. Intensive therapy also provided an absolute risk reduction of 20% in CVD events.

The value of tight BP and glycemic control in the management of nephropathy has also been demonstrated by an intervention study in Japanese patients with T2DM.²⁴ In the Kashiwa Study, the incidence of early-phase diabetic nephropathy was followed over an 8‑year period that included 273 patients with normo- or microalbuminuria who were not taking any medication at the initial visit. If A1C <6.5% was not achieved with diet and exercise, oral hypoglycemic agents were administered alone or in combination. At year 8, 97% of patients were receiving oral hypoglycemic agents and 20% were taking antihypertensive agents. Their mean A1C was 6.5%, mean systolic BP was 127 mm Hg, and mean diastolic BP was 72 mm Hg. Fifteen percent of the normoalbuminuric patients progressed to albuminuria, and 17% progressed to macroalbuminuria; however, 21% regressed to normoalbuminuria. Significant independent relationships existed between development of albuminuria and higher mean systolic BP, and between regression and lower achieved mean systolic BP. Among patients who achieved mean systolic BP <120 mmHg, development of albuminuria was 3%, progression was 11%, and regression was 44% over 8 years. Albumin excretion at year 8 was positively correlated with systolic BP and baseline albuminuria. Thus, when A1C levels were maintained at £6.5% and systolic BP at £120 mmHg, development and progression of albuminuria decreased and the likelihood of regression increased. The Kashiwa Study extends the evidence base for improved outcomes in type 2 diabetes attainable through meticulous control of systemic risk factors.

Renin-angiotensin system blockade to prevent progression of diabetic nephropathy

Elevated BP and increased UAE predict the initiation and/or progression of diabetic nephropathy. Research has focused on antihypertensive agents that modify the renin-angiotensin system (RAS) because of their salutary effect on the glomerulus.⁹ Large-scale randomized controlled trials have shown that ACE inhibitors and ARBs slow the deterioration of renal function and reduce proteinuria, and for this reason are the most widely used antihypertensive agents in diabetic patients.²⁵ The Joint National Committee on Prevention, Diagnosis and Management of Hypertension and the American Diabetes Association (ADA) recommend that both normotensive and hypertensive patients with diabetes should preferentially receive ACE inhibitors or ARBs as first-line treatment for diabetic nephropathy.^26,27 The available evidence suggests that the effects of ACE inhibitors and ARBs on renal outcomes (ESRD, doubling of creatinine, prevention of progression of micro- to macroalbuminuria, regression of micro- to normoalbuminuria) are similarly beneficial. Reliable estimates of the effect of ACE inhibitors versus ARBs on renoprotection are not yet available because of small sample sizes in head-to-head trials.²⁸

ACE inhibitors and ARBs act on different sites in the RAS, and therefore combinations of the two agents have been studied for potentially superior renoprotective effect among patients with diabetic nephropathy. Although dual blockade trials to date have shown statistically significant reductions in albuminuria and BP in T1DM and T2DM, they are limited by small numbers of subjects and relatively short durations of treatment.^19,29 At this time, there are no established guidelines on the use of dual blockade therapy in diabetic nephropathy.

Guidelines for screening and management

ESRD need not be an inevitable consequence of diabetic nephropathy. Early detection is considered a high priority and requires only a spot urine sample.^4,8,9 The necessity for screening at the time of diagnosis is supported by approximately 7% of patients presenting with microalbuminuria at the time of diagnosis of T2DM,⁹ Screening for microalbuminuria should be performed 1 year after diagnosis in patients with T1DM, especially in patients with poor metabolic control and after the onset of puberty. If microalbuminuria is absent, the screening must be repeated annually for patients with either T1DM or T2DM.⁹

Early and aggressive use of currently available pharmacologic interventions that address known risk factors, such as hyperglycemia, hypertension, and dyslipidemia, is recommended. The ADA and the European Association for the Study of Diabetes (EASD) have developed a comprehensive algorithm for managing hyperglycemia in T2DM that recommends the first intervention should be metformin therapy with lifestyle modification.³⁰ A1C levels should then be measured at least every 3 months and dual therapy with antihyperglycemic agents should be initiated as soon as A1C is >7.0%. If metabolic goals are not achieved or maintained, thiazolidinediones, sulfonylureas, and/or insulin are recommended additions to metformin and lifestyle management.³⁰  Treatments that have become available since the algorithm was published, such as incretin mimetics and incretin enhancers that utilize glucagon-like peptide 1 (GLP-1) pathway to lower A1C, could also be considered as part of an effective treatment regimen.^31-33 For patients with either T1DM or T2DM, the ADA-EASD algorithm recommends that treatments should be rigorously targeted to an A1C <7.0%, and carefully monitored thereafter.

Aggressive use of agents with renoprotective effects, such as ACE inhibitors and ARBs, can reduce the progression of renal disease, making the treatment of hypertension a critical element in avoiding ESRD. Smoking may be a risk factor for the development of diabetic nephropathy since it has been related to progression from normo- to microalbuminuria.¹⁹ Anemia has also been identified as a risk factor for diabetic nephropathy; clinical practice guidelines for anemia in chronic kidney disease are available from the National Kidney Foundation,³⁴ and hemoglobin and hematocrit targets for the anemia of chronic kidney disease have recently undergone systematic review.³⁵ Specific recommendations for the screening and management of diabetic nephropathy have recently been published by the ADA.^4,10

*Renal replacement therapy encompasses peritoneal dialysis, hemodialysis, and renal transplantation.³⁶

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