Diabetic Nephropathy: Diagnosis, Prevention, and Treatment

Jorge L. Gross, MD; Mirela J. de Azevedo, MD; Sandra P. Silveiro, MD; Luís Henrique Canani, MD; Maria Luiza Caramori, MD; Themis Zelmanovitz, MD

Disclosures

Diabetes Care. 2005;28(1):164-176. 

In This Article

Prevention and Treatment

Prevention: Normoalbuminuric Patients

The basis for the prevention of diabetic nephropathy is the treatment of its known risk factors: hypertension, hyperglycemia, smoking, and dyslipidemia. These are also risk factors for cardiovascular disease and should be vigorously treated.

Intensive Blood Glucose Control

Clinical trials have consistently demonstrated that A1c levels <7% are associated with decreased risk for clinical and structural manifestations of diabetic nephropathy in type 1 and type 2 diabetic patients. In the Diabetes Control and Complications Trial (DCCT), intensive treatment of diabetes reduced the incidence of microalbuminuria by 39%.[95] It is interesting to note that patients randomized to strict glycemic control had a long-lasting reduction of ~40% in the risk for development of microalbuminuria and hypertension 7-8 years after the end of the DCCT.[96] In the UKPDS, a 30% risk reduction for the development of microalbuminuria was observed in the group intensively treated for hyperglycemia.[97] Moreover, in the Kumamoto Study, intensive glycemic control also reduced the rate of development of micro- and macroalbuminuria.[98] Therefore, intensive treatment of glycemia aiming at A1c <7% should be pursued as early as possible to prevent the development of microalbuminuria.

Intensive Blood Pressure Control

Treatment of hypertension dramatically reduces the risk of cardiovascular and microvascular events in patients with diabetes. Hypertension is common in diabetic patients, even when renal involvement is not present. About 40% of type 1 and 70% of type 2 diabetic patients with normoalbuminuria have blood pressure levels >140/90 mmHg.[99] In the UKPDS, a reduction from 154 to 144 mmHg on systolic blood pressure reduced the risk for the development of microalbuminuria by 29%.[100]

Blood pressure targets for patients with diabetes are lower (130/80 mmHg) than those for patients without diabetes.[101] In the HOT (Hypertension Optimal Treatment) study, a reduction of diastolic blood pressure from 85 to 81 mmHg resulted in a 50% reduction in the risk of cardiovascular events in diabetic but not nondiabetic patients.[102]

Renin-Angiotensin System Blockade

The role of ACE inhibitors in the prevention of diabetic nephropathy in patients with type 1 diabetes has not been defined. The use of perindopril during 3 years in normotensive normoalbuminuric type 1 diabetic patients delayed the increase in albuminuria.[103] In patients with type 2 diabetes, ACE inhibitors and ARBs both diminish the risk for diabetic nephropathy[104,105] and reduce the occurrence of cardiovascular events.[106] In the MICRO-HOPE (Heart Outcomes Prevention Evaluation) study,[106] ramipril (10 mg/day) decreased the risk of overt nephropathy by 24% and the risk of cardiovascular death in patients with type 2 diabetes who were >55 years of age with one additional cardiovascular risk factor by 37%. Moreover, ramipril reduced UAE at 1 year and at the end of the study.[106] Therefore, ACE inhibitors have been shown to be beneficial for reno- and cardioprotection in patients with type 2 diabetes.

The goal of treatment is to prevent the progression from micro- to macroalbuminuria, the decline of renal function in patients with macroalbuminuria, and the occurrence of cardiovascular events. The treatment principles are the same as those adopted for the prevention of diabetic nephropathy, although in this case multiple and more intensive strategies must be used. The strategies and goals are described in Table 2 .

The effect of strict glycemic control on the progression from micro- to macroalbuminuria and on the rate of renal function decline in macroalbuminuric patients is still controversial. In the DCCT study, intensified glycemic control did not decrease the rate of progression to macroalbuminuria in patients with type 1 diabetes who were microalbuminuric at the beginning of the study.[95,107] The Microalbuminuria Collaborative Study Group reported similar findings.[108] However, these studies[107,108] were underpowered to detect an effect of intensified glycemic control on the progression from micro- to macroalbuminuria. Moreover, improvement of glycemic control, especially if associated with lower blood pressure levels, reduced the renal function decline in proteinuric type 1 diabetic patients.[109]

In patients with type 2 diabetes, very few studies analyzed the role of blood glucose control on the progression of diabetic nephropathy. In the Kumamoto Study, a reduction in the conversion from micro- to macroalbuminuria was observed with intensive treatment.[98] Although the effects of strict glycemic control on the progression of diabetic nephropathy are not firmly established, it should be pursued in all these patients.

Some oral antihyperglycemic agents seem to be especially useful. Rosiglitazone, as compared with glyburide, has been shown to decrease UAE in patients with type 2 diabetes. This suggests a beneficial effect in the prevention of renal complications of type 2 diabetes.[110] Also, the use of antihyperglycemic agents in proteinuric type 2 diabetic patients should take renal function into account. Metformin should not be used when serum creatinine is >1.5 mg/dl in men and >1.4 mg/dl in women due to the increased risk of lactic acidosis.[111] Sulfonylureas and their metabolites, except glimepiride, are eliminated via renal excretion and should not be used in patients with decreased renal function.[112] Repaglinide[113] and nateglinide[114] have a short duration of action, are excreted independently of renal function, and have a safety profile in patients with renal impairment. However, at this point, sulfonylureas and insulin secretagogues are usually not very effective due to the low endogenous production of insulin resulting from the long duration of diabetes. Thus, most type 2 diabetic patients with diabetic nephropathy should be treated with insulin.

In microalbuminuric type 1 and type 2 diabetic patients, numerous studies have demonstrated that treatment of hypertension, irrespective of the agent used, produced a beneficial effect on albuminuria.[115] Renin-angiotensin system (RAS) blockade with ACE inhibitors or ARBs confers an additional benefit on renal function. This renoprotective effect is independent of blood pressure reduction[115,116] and may be related to decreased intraglomerular pressure and passage of proteins into the proximal tubule.[117] These drugs decrease UAE and the rate of progression from microalbuminuria to more advanced stages of diabetic nephropathy. A meta-analysis of 12 trials evaluating 698 nonhypertensive microalbuminuric type 1 diabetic patients showed that treatment with ACE inhibitors decreased the risk of progression to macroalbuminuria by 60% and increased the chances of regression to normoalbuminuria.[118] ARBs were also effective in reducing the development of macroalbuminuria in microalbuminuric type 2 diabetic patients. Irbesartan (300 mg/day) reduced the risk of progression to overt diabetic nephropathy by 70% in a 2-year follow-up study of 590 hypertensive microalbuminuric type 2 diabetic patients.[119] Additionally, a 38% reduction in UAE was observed, with 34% of patients reversing to normoalbuminuria. It is also interesting to note that UAE was still reduced 1 month after the withdrawal of irbesartan.[120] In another trial, valsartan 80 mg/day produced a greater reduction in UAE than amlodipine (44 vs. 8%) with the same degree of blood pressure reduction.[116] These data reinforce the idea that the antiproteinuric effect of ARBs is blood pressure independent. Although there is no long-term study comparing the effects of ACE inhibitors and ARBs on the progression from microalbuminuria to overt diabetic nephropathy, both agents led to a similar reduction in albuminuria in a 12-week study[121] and a 1-year study.[122] Therefore, the use of either ACE inhibitors or ARBs is recommended as a first-line therapy for type 1 and type 2 diabetic patients with microalbuminuria, even if they are normotensive.[14]

In proteinuric patients, Mogensen[123] was the first to demonstrate, almost 30 years ago, that treatment of hypertension reduced albuminuria and the rate of GFR decline in type 1 diabetic patients. Subsequently, other studies have clearly demonstrated that aggressive treatment of hypertension has a strong beneficial effect in reducing GFR decline in proteinuric type 1 diabetic patients.[124] This reduction in GFR decline was predicted by reduction in albuminuria.[125] According to the MDRD (Modification of Diet in Renal Disease) trial, the lower the blood pressure, the greater the preservation of renal function in nondiabetic patients.[126] Patients with proteinuria >1 g/day and renal insufficiency had slower decline in renal function when blood pressure was <125/75 mmHg.[126] Although this study included mainly nondiabetic patients, this goal also has been recommended for proteinuric diabetic patients.[127] Addition of ACE inhibitors in proteinuric type 1 diabetic patients[128] or ARBs in macroalbuminuric type 2 diabetic patients[129,130] decreased proteinuria and renal function decline. Although there was no difference in the cardiovascular event rate, a significantly lower incidence of congestive heart failure was observed among patients receiving ARBs.[129] The antiproteinuric effect of ARBs has certain characteristics. It occurs early (within 7 days) after treatment is started and persists stable thereafter,[131] and it is independent of blood pressure reduction[116] and has a dose-response effect beyond the doses needed to control blood pressure.[132] An acute increase in serum creatinine of up to 30-35%, stabilizing after 2 months, might occur in proteinuric patients with creatinine values >1.4 mg/dl starting ACE inhibitors. This raise in creatinine is associated with long-term preservation of renal function, and therefore ACE inhibitors should not be stopped.[133] Greater increases should raise the suspicion of renal-artery stenosis. Inhibition of the RAS, especially with ACE inhibitors, might raise serum potassium levels, particularly in patients with renal insufficiency.[134] For these reasons, albuminuria, serum creatinine, and potassium should be checked monthly during the first 2-3 months after starting treatment with ACE inhibitors or ARBs. Recently, Mogensen et al.[121] developed the new concept of dual blockade of the RAS. ACE inhibitors and ARBs interrupt the RAS at different levels, and the combination of these classes of drugs may have an additive effect on renoprotection. The combination of candesartan (16 mg/day) and lisinopril (20 mg/day) was more effective in reducing blood pressure and UAE ratio in hypertensive patients with type 2 diabetes than either drug alone.[121] Other studies have also demonstrated that the combination of ACE inhibitors and ARBs had a synergistic effect in blood pressure and UAE reduction in patients with type 1 and type 2 diabetes with diabetic nephropathy. RAS dual blockade is more effective in reducing UAE than maximal recommended doses of ACE inhibitors alone.[135] Even though no long-term trials analyzing the benefit of RAS dual blockade in diabetic nephropathy are available, in nondiabetic proteinuric patients the COOPERATE (Combination Treatment of Angiotensin-II Receptor Blocker and Angiotensin-Converting-Enzyme Inhibitor in Nondiabetic Renal Disease) trial has shown that dual therapy was superior to monotherapy at its maximal doses in retarding the progression of renal disease in a 3-year follow-up.[136] The combination of spironolactone, an aldosterone antagonist, with an ACE inhibitor was also more effective in reducing UAE and blood pressure in micro- and macroalbuminuric type 2 diabetic patients than the ACE inhibitor alone.[137]

A detailed discussion of the agents used to treat hypertension in patients with diabetic nephropathy is beyond the scope of this article, and recent guidelines[101,138] and reviews on this subject are available.[127,139,140] Therefore, only general guidelines will be discussed here, taking into account the special characteristics of these patients. To reach the blood pressure goal of 130/80 mmHg in diabetic patients in general,[101] or 125/75 mmHg in patients with proteinuria >1.0 g/24 h and increased serum creatinine, three to four antihypertensive agents are usually necessary.[141] It is more important to reach the blood pressure goals than to use a particular agent, since most patients will require several agents. However, due to the known renoprotective effect of ACE inhibitors and ARBs, treatment should start with either of these agents. Patients with systolic blood pressure 20 mmHg or diastolic blood pressure 10 mmHg above the goal should start treatment with two agents. An ACE inhibitor or ARB and a low-dose thiazide diuretic (12.5-25 mg/day) can be initially used, but loop diuretics (furosemide) should be used instead of thiazides in patients with GFR <30 ml/min, corresponding to a serum creatinine of 2.5-3.0 mg/dl.[101] ARBs are an excellent alternative if ACE inhibitors are not tolerated (cough) and are the preferred agents for type 2 diabetic patients with left ventricular hypertrophy[104] and/or micro- or macroalbuminuria.[106,119,129] ARBs and ACE inhibitors can be combined if there is no reduction in albuminuria or if blood pressure target levels are not reached, even before maximizing the dose of each agent. Additional agents should be added as needed. Calcium channel blockers have an additional effect on reducing blood pressure levels. These agents should only be used in combination with an ACE inhibitor and should not be used in patients with a recent coronary event. β-Blockers are especially useful in patients with myocardial ischemia, since these drugs reduce cardiovascular events and mortality in patients with baseline pulse rate >84 bpm.[141] Possibly, a metabolic neutral compound, carvedilol, should be used. The combination of β-blockers and nondihydropyridine calcium channel blockers should be used with caution, since both agents have negative chronotropic effects. Blood pressure treatment could be assessed by 24-h ambulatory monitoring in the following situations: in patients with treatment-resistant hypertension, when there is a suspicion of white coat hypertension, or to detect drug-induced or autonomic neuropathy-related hypotensive episodes.[138]

Diet Intervention

Replacing red meat with chicken in the usual diet reduced UAE by 46% and reduced total cholesterol, LDL cholesterol, and apolipoprotein B in microalbuminuric patients with type 2 diabetes in a 4-week study.[142] This was probably related to the lower amount of saturated fat and the higher proportion of polyunsaturated fatty acids found in chicken meat than in red meat. The beneficial effect of polyunsaturated fatty acids on endothelial function[143] could also reduce UAE. A normal protein diet with chicken as the only source of meat may represent an additive strategy for the treatment of microalbuminuric type 2 diabetic patients. However, long-term studies are necessary. According to a meta-analysis[144] of five studies including a total of 108 patients, dietary protein restriction slowed the progression of diabetic nephropathy in patients with type 1 diabetes. More recently, a 4-year randomized controlled trial in 82 patients with type 1 diabetes with progressive diabetic nephropathy showed that a moderately low-protein diet (0.9 g · kg-1 · day-1) reduced the risk of end-stage renal disease or death by 76%, although no effect on GFR decline was observed.[145] The mechanisms by which a low-protein diet may reduce progression of diabetic nephropathy are still unknown, but might be related to improved lipid profile and/or glomerular hemodynamics.

Dyslipidemia

The goal for LDL cholesterol is <100 mg/dl for diabetic patients in general and <70 mg/dl for diabetic patients with cardiovascular disease.[146] The effect of lipid reduction by antilipemic agents on progression of diabetic nephropathy is still unknown. So far, there have been no large trials analyzing whether the treatment of dyslipidemia could prevent the development of diabetic nephropathy or the decline of renal function. However, there is some evidence that lipid reduction by antilipemic agents might preserve GFR and decrease proteinuria in diabetic patients.[147] In the Heart Protection Study, 40 mg simvastatin reduced the rate of major vascular events and GFR decline in patients with diabetes, independent of cholesterol levels at baseline, by 25%.[148] Moreover, the results of the recently presented CARDS (Collaborative Atorvastatin Diabetes Study), which showed a marked reduction of cardiovascular events in patients with diabetes and at least one additional risk factor for coronary artery disease, suggest that all diabetic patients should be taking statins (www.cardstrial.org).

Anemia may occur in patients with diabetic nephropathy even before the onset of advanced renal failure (serum creatinine <1.8 mg/dl), and it has been related to erythropoietin deficiency.[149] Furthermore, anemia has been considered a risk factor for progression of renal disease and retinopathy.[150] Until the results of the ongoing ACORD (Anemia Correction in Diabetes) study[151] become available, it is recommended to start erythropoietin treatment when Hb levels are <11 g/dl. The target Hb levels should be 12-13 g/dl, and the potential risk of elevation of blood pressure levels with erythropoietin treatment should be taken into account.[150]

Low-dose aspirin has been recommended for primary and secondary prevention of cardiovascular events in adults with diabetes. This therapy did not have a negative impact on renal function (UAE or GFR) in type 1 and type 2 diabetic patients with micro- or macroalbuminuria.[152,153] However, the subgroup analysis of the Primary Prevention Project trial did not show a significant reduction in the occurrence of cardiovascular events in 1,031 diabetic patients using low-dose aspirin (100 mg/day).[154] Although this study was underpowered to analyze the effect on the development of cardiovascular events, these data raise the issue that diabetic patients could be less responsive to aspirin therapy (aspirin resistance). In fact, a recent study demonstrated a reduced response of platelets from diabetic subjects to treatment with aspirin (150 mg/day). This phenomenon was associated with higher levels of A1c, lower concentration of HDL cholesterol, and higher concentration of total cholesterol.[155] Therefore, diabetic patients might benefit from aspirin doses >100-150 mg/day or use of other antiplatelet agents such as clopidogrel.

Patients with microalbuminuria frequently have other cardiovascular risk factors, such as hypertension and dyslipidemia. In the Steno-2 study, multifactorial intervention was compared with conventional treatment in 160 microalbuminuric type 2 diabetic patients.[156] The targets were to achieve blood pressure levels <130/80 mmHg, fasting serum cholesterol <175 mg/dl, fasting serum triglycerides <150 mg/dl, and A1c <6.5%. The multifactorial intervention consisted of a stepwise implementation of lifestyle changes and pharmacological therapy, including a low-fat diet, a three to five times a week light-to-moderate exercise program, a smoking cessation program, and prescription of ACE inhibitors or ARBs and aspirin. The intensively treated group had a 61% reduction in the risk of developing macroalbuminuria and a 58 and 63% reduction in the risk of retinopathy and autonomic neuropathy, respectively. Most importantly, a 55% reduction in the risk for the development of a composite end point consisting of death from cardiovascular causes, nonfatal myocardial infarction, revascularization procedures, nonfatal stroke, and amputation was also observed in the multifactorial intervention group.

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