The principles of prevention and treatment of DN are the same. However, the role of each factor could be different in each stage of disease. It is important to define the DN stage that is the target of intervention (microalbuminuria, proteinuria or GFR) and the outcome of interest. Two recent meta-analyses have demonstrated different results when evaluating different outcomes, such as proteinuria, GFR decline or progression to ESRD [
105,
106]. Both, ACE inhibitors and angiotensin receptor blockers (ARBs) seem to be effective reducing proteinuria and decreasing the creatinine doubling rate, but not decreasing mortality [
106]. Probably the best treatment is a multiple risk factor interventional approach, but due to a practical point of view each aspect will be addressed individually. The goal to be pursued is retarding the development or progression of DN and to decrease the subject's cardiovascular risk and mortality.
Clinical trials have demonstrated that intensive treatment of hyperglycemia is associated with a decreased risk for the development of DN in type 1 and type 2 diabetic patients [
107‐
110]. In type 1 and type 2 subjects the effect of intensive therapy could be seen many years later [
108,
111]. The effect of the intervention in hyperglycemia in type 1 macroalbuminuric subjects is not so clear [
107,
112,
113]. This became more evident in the EDIC/DCCT follow up study [
108]. In the Kumamoto study, prevention of macroalbuminuria was observed in type 2 DM patients intensively treated [
110].
Recent studies designed to evaluate the benefit of intensive glycemic control in large sets of patients showed a minor protective effect on the development of progression of albuminuria [
61,
114]. In the Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes (ADVANCE) trial, the group in the intensive arm for an average of 5 years showed a small reduction in the number of cases with new-onset microalbuminuria compared to the standard therapy group (23.7 vs. 25.7%) [
61]. No effect was observed in the serum creatinine values [
61]. The same was observed in the Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes (VADT) study [
114]. Patients in the intensive arm for a mean of 5.6 years did not show any benefit regarding changing serum creatinine or GFR values [
114] and a minor effect on albuminuria levels was observed [
114].
Treatment of hypertension leads to an important risk reduction in cardiovascular and microvascular events. In the UKPDS, a reduction from 154 to 144 mm Hg on systolic BP reduced the risk for the development of microalbuminuria by 29% [
115]. BP targets for patients with DM are lower (130/80 mm Hg) than those for patients without DM [
116]. In the Hypertension Optimal Treatment (HOT) study a reduction of diastolic BP from 85 to 81 mm Hg resulted in 50% reduction in the risk of cardiovascular events in diabetic but not in non-diabetic patients [
117]. In the presence of microalbuminuria the treatment of hypertension, irrespective of the agent used, produced a beneficial effect on albuminuria [
118].
The choice of anti-hypertensive agents to use is in some way not a problem in clinical practice, because to reach the BP goals the majority of patients will need several agents. However, due to the known renoprotective effect of ACE inhibitors and ARB, these agents (see below) should be used initially associated with a diuretic.
Renin-Angiotensin System (RAS) Blockade
ACE inhibitors could be used in normotensive subjects to prevent or postpone the development of microalbuminuria [
122]. The aim of ACE inhibitors and ARBs use is not only to diminish the risk for the development of micro- and macroalbuminuria [
123‐
125] but also to decrease the occurrence of cardiovascular events [
124]. However, a recent 5 year multicenter randomized controlled trial involving 285 normoalbuminuric, normotensive patients with type 1 DM failed to show any improvement in biopsy parameters with losartan (100 mg daily) or enalapril (20 mg daily) compared to placebo [
126]. Surprisingly, the 5-year cumulative incidence of microalbuminuria was 17% with losartan, significantly greater than with placebo (6%, P = 0.01). The enalapril group had a similar incidence of microalbuminuria (4%, P = 0.96) in comparison to the placebo group [
126].
RAS blockade with ACE inhibitors or ARB confers an additional benefit on renal function. This renoprotective effect is independent of BP reduction [
118,
127]. These drugs decrease UAE and the rate of progression from microalbuminuria to more advanced stages of DN. A meta-analysis of 12 trials in non-hypertensive microalbuminuric type 1 diabetic patients showed that ACE inhibitors decreased the risk of progression to macroalbuminuria by 60%, and increased the chances of regression to normoalbuminuria [
128]. Therefore, the use of ACE inhibitors or ARB is recommended for all microalbuminuric patients, even if normotensive [
14]. ARBs were also effective in reducing the development of macroalbuminuria in microalbuminuric type 2 diabetic patients [
127,
129].
The aggressive treatment of hypertension has a strong beneficial effect in reducing GFR decline in proteinuric type 1 diabetic patients [
130]. This reduction in GFR decline was predicted by reduction in albuminuria [
131]. According to the MDRD trial, the lower the BP the greater the preservation of renal function in non-diabetic patients [
132]. Patients with proteinuria >1 g/day and renal insufficiency had a slower decline in renal function when BP was <125/75 mm Hg [
132]. Addition of ACE inhibitors in proteinuric type 1 [
133] or ARB in macroalbuminuric type 2 [
134,
135] diabetic patients has a beneficial effect in decreasing proteinuria and reducing renal function decline. The effect of ARBs on protein excretion could be noted within 7 days after starting the treatment, and may persist after [
136]. It seems to be independent of BP reduction [
127] and has a dose response effect beyond the doses needed to control BP [
137]. An acute increase in serum creatinine up to 30 to 35% that stabilizes within 2 months might occur and it is not a reason to stop the treatment [
138]. Increase in serum creatinine above these values should raise the possibility of renal-artery stenosis [
138,
139]. Another limitation to the use of ACE inhibitors is hyperkalemia, especially among those with renal insufficiency [
138]. Acute hyperkalemia (>5.5 mEqL) is an indication to stop these medications. Therefore, albuminuria, serum creatinine and potassium should be checked monthly in the first 2 to 3 months after starting treatment with ACE inhibitors or ARB [
138,
139].
ACE inhibitors and ARB interrupt the RAS at different levels, and the combination of these classes of drugs (RAS dual blockade) has been proposed [
140] as an alternative to treat DN. It has been suggested that this association would have an additive effect on renoprotection. The combination of ARB and ACE inhibitors are effective in reducing UAE ratio in hypertensive patients with type 2 DM when compared to each drug alone. However, this is also associated with lower BP values in the group that used both drugs [
140,
141]. A recent large trial (ONTARGET) in diabetic and nondiabetic subjects showed that the association of the two classes of drugs had a major effect on decreasing proteinuria but not on GFR decline or mortality [
142]. In fact, a worse effect on GFR and mortality was observed. Analyzing the subgroups, the increased mortality came from the less sick subjects. Among diabetic subjects no increased mortality was observed, but also no benefit from the dual blockage was observed [
142]. The VA NEPRHON-D study aimed to evaluate this issue is patients with type 2 DM [
143].
Another step that has been proposed to be blocked is the aldosterone action. Adding the aldosterone antagonist - spironolactone - to ARBs [
144] or ACE inhibitor [
145] is also more effective in reducing UAE and BP in type 2 diabetic patients than each drug alone. A recent meta-analyses that included diabetic and non-diabetic subjects demonstrated that the addition of aldosterone antagonists in patients already on ACE inhibitors and ARBs reduces proteinuria in chronic kidney disease [
146]. This was not associated with an improvement on GFR, but increases the risk of hyperkalemia. Long-term effects of these agents on renal outcomes, mortality, and safety need to be determined [
146].
More recently, the dual blockage of the renin-angiotensin-aldosterone system with aliskiren, a direct renin inhibitor, and losartan at maximal recommended dose (100 mg daily) showed a greater reduction in proteinuria (20%) compared to losartan and placebo [
147]. The effect does not seem to be due to anti-hypertensive effect. However, this was a short duration study (12 weeks) and long term studies are needed. The ongoing trial ALTITUDE might answer some of these questions [
148]. This placebo controlled, randomized trial intends to follow-up about 8600 subjects during two years and compare the effect of aliskiren added to standard treatment (ACE or ARBs) [
148]. The results will be available by 2012.
Hyperglycemia treatment peculiarities
The treatment of DM is not the aim of the present review, but a few special remarks could be made regarding the treatment of hyperglycemia in a patient with renal disease (Table
3).
Table 3
Treatment of hyperglycemia in the patient with type 2 diabetes mellitus and chronic kidney disease
| Hepatic metabolism: 100%. Excretion: bile and feces 50% and urine 50% | -1.5% | High (active metabolites) | Avoid | Avoid | Avoid |
| Excretion: metabolites 90% in urine and feces. 10% excreted without metabolization | -1.5% | Low | Can be used | Can be used | Can be used (adjustments) |
Glimepyride | Hepatic metabolism 100%. Excretion: urine 60% and feces 40% | -1.5% | Low | Can be used | Can be used | Use with care |
| Hepatic metabolism: 100%. Excretion: 10% urine and 90% feces | -1.0% | Low | Can be used | Can be used | Use with care. Adjust dose |
| Hepatic metabolism: 85%. Excretion: urine 83% and feces 10%. 15% excreted inactive in urine | -0.7% | High (active metabolites) | Use with care | Use with care | Avoid if possible |
| Excretion: urine 34%, feces 51% and <2% in urine in the free or active metabolic form | -0.6% | Low | Can be used | Can be used | Avoid |
| Hepatic metabolism and excretion in the urine, of rather inactive metabolites in the urine 64% and feces 23% | -0.6 to 1.5% | Low | Can be used | Can be used | Can be used |
| Hepatic metabolism and excretion in urine of rather inactive metabolites in the urine 15% and feces 85% | -0.6 to 1.5% | Low | Can be used | Can be used | Can be used |
| Excretion: urine 87% and feces 13%, in an unaltered form. | -0.7% | Low | Can be used | Can be used. Reduce dose 50% | Can be used. Reduce dose 75% |
Vildagliptine | Excretion: urine: 85% and feces 15%. | -0.7% | Low | Can be used | Can be used | Not recommended |
| Metabolism and renal excretion | -1.0%** | Low | Can be used | Not recommended | Not recommended |
Metformin is the standard therapy for patients with type 2 DM and will only be briefly discussed here. Metformin is contraindicated when serum creatinine is above 1.5 mg/dl in men and 1.4 mg/dl in women due to the increased risk of lactic acidosis [
149]. However, these values are being questioned [
150]. In these creatinine ranges, some subjects will be using metformin on chronic renal disease stages II and III [
151].
Sulfonylureas and their metabolites, except glimepiride, are eliminated via renal excretion and should be used with caution in patients with GFR [
152]. Glibenclamide is a potent drug and has been known for a long time. It is low cost and available in the public health system. However, it presents a high risk of hypoglycemia. It has active metabolites that increase in patients with decreased GFR, and its pharmacological action is such that the use of glibenclamide is not recommended from stage 3 onwards [
153,
154]. Among the sulfonylureas there is also glipizide which carries a lower risk of hypoglycemia being and alternative on this situation [
154]. Glipizide can be used in chronic renal disease stages 3 and 4. It could still be used in stage 5, with a therapeutic adjustment. Glimepiride is a third generation sulfonylurea with a slightly higher cost and a lower risk of hypoglycemia. However, it is believed that it has a few active metabolites filtered by the kidneys what could be potentially related to higher risk of hypoglycemia compared to glipizide.
Repaglinide [
155] and nateglinide [
156] have a short duration of action, are excreted independently of renal function and have a safety profile in patients with renal impairment. These drugs, like the sulfonylureas, are insulin secretagogues, but they act in different cellular membrane channels, and this brings some pharmacological properties such as quick initial action, non-prolonged action and greater effect on post-prandial glycemia. A flexible aspect of this drugs making therapeutic management easier is the lower risk of hypoglycemia because of the different connection of the membrane channels. But one side effect described similar to observed with the sulfonylureas is weight gain. Its cost is higher than that of sulfonylureas, but theoretically it has a less deleterious effect on beta cells. Among the glinides, the first choice would be repaglinide because of the low risk of hypoglycemia, and it can be used in stage 3 and stage 4 [
155,
157]. Data in the literature are not sufficient to indicate the use of this drug in chronic renal disease stage 5. Nateglinide would be at a disadvantage because it is less potent, and it has active metabolites that can increase the risk of hypoglycemia in subjects with decreased GFR [
158,
159].
Acarbose is a drug that is not potent to reduce HbA1c. However, as its pharmacological action principle is the inhibition of enzyme alpha glycosidase in the small bowel, reducing glucose absorption in the gastrointestinal tract, it is a useful drug to adjust post-prandial hyperglycemia. The metabolism of this drug is practically 100% gastrointestinal, part is excreted in the urine and most of it in the feces, and a small form is excreted in the form of the active metabolite [
153,
160]. The concern of using acarbose in subjects with chronic kidney disease is the accumulation of these metabolites that may lead to hepatic lesions. Thus, acarbose would be contraindicated in subjects with chronic renal disease. There are insufficient data in the literature to use this drug with a creatinine greater than 2 mg/dl. It could be considered up to stage 3, and it should be avoided in stages 4 and 5 [
153,
160].
Glitazones, represented by rosiglitazone and pioglitazone, act through the PPR gamma system and are insulin sensitizer drugs that increase the muscle uptake of glucose and diminish the atherogenic profile of the DM patient, and could be used in renal failure [
161,
162]. Rosiglitazone has been shown to decrease UAE in type 2 diabetic patients as compared to glyburide, suggesting a beneficial effect in the prevention of renal complications of type 2 DM [
163]. This antiproteinuric effect occurs also in nondiabetic disease [
161,
164,
165]. The side effects include anemia, water retention, weight gain and potential hepatotoxicity due to the accumulation of its metabolites. Recently, cardiovascular safety and the risk of increased incidence of fractures have been discussed [
166,
167]. Both would present a low risk of hypoglycemia and could theoretically be used in the different stages of chronic renal disease without adjusting the dose [
168].
A recent meta-analysis suggests beneficial effects of glitazones, with improvement of dyslipidemia in DM, internal carotid intima layer thickness reduction, improved fibrinolysis, and a direct action of the PPR gamma system at glomerular, tubular and vascular levels [
169]. In theory, all these actions (hemodynamic, anti-inflammatory, anti-proliferative and metabolic) would be beneficial actions in nephropathy [
169].
In relation to fractures, a recent meta-analysis showed that in the female population there has been up to two-fold increase in the incidence of fractures including both hip and vertebral fractures [
170]. Since a uremic patient has already an increased osteometabolic risk, a drug that would increase the incidence of fractures should be questioned in these patients.
Two representatives of the DPP-4 inhibitors are available, vildagliptin and sitagliptin. These drugs inhibit the dipeptidyl peptidase-4 enzyme which, in turn, prevents degradation of the GLP-1 which remains active longer. Thus they lead to the reduction of fasting and post-prandial glycemia, without a risk of hypoglycemia. The gliptins suppress the high release of glucagon and are neutral as regards weight. The side effects include airway infection and transaminases elevation. The standard dose is 100 mg, orally, in a single daily dose. Sitagliptin secretion occurs mostly in urine and an adjustment in the dose is recommended according to the stage of renal disease: 50 mg for stage 3 and 25 mg for stages 4 and 5 [
171,
172]. Vildagliptin also is predominantly excreted in the urine. It is unnecessary to adjust the dose in patients with mild or moderate renal failure (50 mg orally, bid). The use of vildagliptin is not recommended, according to the directions that accompany medications, in patients with severe renal failure, patients who are already on dialysis or some other renal substitution therapy.
Exenatide is a GLP-1 analog. Subcutaneous applications (beginning at 5 μg bid for 30 days and then 10 μg bid) should be performed up to one hour before meals twice a day. It is a drug that reduces weight, which may be an advantage in managing the diabetic patient. The major side effects are nausea and vomiting, what occasionally an individual cannot tolerate using it. It is metabolized and excreted by the kidneys. It presents a low risk of hypoglycemia and can be used in stage 3, and it is not recommended in stages 4 and 5 due to the increased risk of side effects [
173].
However, when the renal function is highly compromised, metformin, exenatide and gliptins are contraindicated, and insulin secretagogues are usually not very effective, since these patients have low endogenous production of insulin. Therefore, most patients should be treated with insulin [
153]. We should remember that the half life of insulin is changed as soon as the individual begins to have a major renal function impairment. Pharmacokinetics is modified, and the insulin will have a slightly longer profile. This may make it difficult to manage the day to day situation, in peculiar situations on different days, i.e., the individual who is undergoing a dialysis session may feel bad and change his diet on that day. We should be able to rationalize more with the flexibility of doses here, which is often rather difficult for the patient and the physician.
These individuals certainly will have a greater propensity to hypoglycemia, so we have to be more careful and remember that hypoglycemia may be one of the complications implicated in the increased cardiovascular mortality of these patients. We should also keep in mind that therapeutic goals should be individualized.
Dietary intervention
There are several modalities for a dietary intervention in DN, whether changing protein content or through the manipulation of lipid content. However, few have their efficacy shown based on long term randomized clinical trials.
In patients with type 1 DM, in different stages of renal disease, protein restriction in the diet has shown that it can reduce the decline of renal function and albuminuria. According to a meta-analysis of studies performed with type 1 DM patients and clinical nephropathy, dietary protein restriction retards DN progression [
174]. However, several of these studies were randomized with a crossover design, and the maximum time of follow up was 36 months. Besides, in these studies there was no evidence of benefit on hard outcomes such as mortality or risk of end stage chronic renal failure. A randomized controlled clinical trial with patients with type 1 DM and DN followed for four years, showed that a diet with a moderate protein restriction (0.9 g/kg/day) was associated with a 76% reduction of the risk of end stage chronic renal failure or death [
175].
In patients with type 2 DM this benefit has not been well established. There are few studies with type 2 DM patients addressing this issue, showing no benefit on renal function, probably due to lack of compliance with the diet and short follow-up [
176]. A recent meta-analysis performed with eight studies including patients with type 1 and 2 DM showed a benefit of protein restriction on proteinuria reduction, but not on GFR reduction [
177]. The American Diabetes Association recommends moderate protein restriction (0.8-1.0 g/kg/day) for patients in the initial stages of DN, and a reduction to 0.8 g/kg/day for patients in a more advanced stage of this complication [
27].
Interventions in the dietary lipid content has also been suggested, especially by manipulating the type of meat in the diet. Substituting red meat by chicken meat in the diet over the short term proved be able to reduce UAE, and also the serum levels of total cholesterol, LDL and apolipoprotein B in patients with type 2 DM and micro and macroalbuminuria [
89,
178]. Recently it was also observed that the beneficial effect of this dietary intervention on renal function was similar to the use of enalapril for a 12-month period in patients with type 2 DM [
179]. This effect is probably related to the lower saturated fat content and greater proportion of polyunsaturated fatty acids, observed in chicken meat compared to red meat. Long term studies are needed to confirm this favorable effect.