Prevention And Treatment Strategies

Significant progress has been made in recent years in understanding the pathophysiology, prevention, and treatment of diabetic nephropathy. Median survival after the onset of nephropathy has increased from 6 to 15 years (56). The basis for the prevention of diabetic nephropathy is the treatment of its known risk factors: hyperglycemia, hypertension, smoking, high protein diet, and dyslipidemia (Table 1).

Table 1 Measures Influencing Progression of Diabetic Nephropathy

• Glycemic control

• Tight blood pressure control

• Low protein diet

• Lipid-lowering agent

• Cessation of cigarette smoking

Glycemic Control

Two major clinical trials, the diabetes control and complications trial (DCCT) (57), and the United Kingdom prospective diabetes study (UKPDS) (58), convincingly demonstrated that intensive glycemic control reduces the risk of developing microalbuminuria and nephropa-thy. It was also noted that the patients randomized to strict glycemic control had a long-lasting reduction of 40% in the risk for development of microalbuminuria and hypertension 7 to 8 years after the end of the DCCT (59).

Fioretto and her colleagues have shown regression of glomerular and tubular basement membrane thickening and reduction of mesangial matrix 10 years after solitary pancreas transplant in patients with type 1 diabetes and microalbuminuria (60). These changes were associated with a reduction in the UAE from 103 mg/day at baseline to 30 mg/day after 5 years and 20 mg/day after 10 years. The above structural changes were not seen at 5 years.

The effect of a strict glycemic control on the progression from micro- to macroal-buminuria and on the rate of renal function decline in macroalbuminuric patients is still controversial. Both the DCCT study and the Microalbuminuria Collaborative Study Group did not show reduction in the rate of progression to macroalbuminuria in patients with type 1 diabetes and microalbuminuria (57,61).

In general, the goal for glycemic control is to keep blood glucose level as close to normal as possible without causing significant hypoglycemia. The American Diabetes Association (ADA) recommended HbA1 c to be < 7% (62).

Intensive Blood Pressure Control

Multiple studies have shown the impact of good blood pressure control on prevention and progression of diabetic nephropathy. About 40% of type 1 and 70% of type 2 diabetic patients with normoalbuminuria have blood pressure level > 140/90 mm Hg (63). In the UKPDS, a reduction from 154 to 144 mm Hg of systolic blood pressure reduced the risk for the development of microalbuminuria by 29% (64).

As reviewed by Parving, in both type 1 and type 2 diabetic patients with overt diabetic nephropathy, blood pressure reduction, whether with ACE inhibitors or other antihyper-tensive medication, reduces albuminuria, delays progression of nephropathy, postpones renal insufficiency, and improves survival (65). Although slowing of the progression of renal function has been achieved by using other antihypertensive medications, the RAS has become the target of the most effective strategy for both hypertension control and, independently, for reduction of the pathophysiologic abnormalities that lead to renal protein leak in diabetic nephropathy (66).

In the landmark captopril study of type 1 diabetics, the ACE inhibitor significantly reduced the progression of diabetic nephropathy. Proteinuria decreased and the endpoints of doubling of the serum creatinine, ESRD, or death were reduced by 50% (67). Later on, the

EUCLID study, which was done in 18 European centers, randomized type 1 diabetic patients with normo- or microalbuminuria to treatment with an ACE inhibitor (lisinopril) or placebo (68). After 24 months, there was a significant difference favoring the lisinopril cohort both in terms of mean UAE and in the ratio of transition from normo- to microalbuminuria. Angiotensin receptor blockers (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 (69). Additionally, a 38% reduction in UAE was observed, with 34% of patients reversing to normoalbuminuria. Recent studies have indicated benefit from dual blockade of the RAS by ACE inhibitors plus ARBs as noted by greater reduction in proteinuria and blood pressure in both type 1 and type 2 diabetic patients (70-72). 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 (73). Therefore, the use of either ACE inhibitors, ARBs, or combination of both is recommended as a first-line therapy for type 1 and type 2 diabetic patients with microalbuminuria, even if they are normotensive.

Current ADA recommendations are to lower blood pressure to 130/80 mm Hg in normoalbuminuric and to 126/70 mm Hg for proteinuric diabetic patients (74).

Low Protein Diet

It has long been known that protein restriction is effective in alleviating the symptoms of uremia and delaying the need for dialysis (75). Beyond symptomatic relief, a low protein diet is advocated to slow the decline of renal function (76,77). The proposed mechanism for slowing the progression of renal disease is reduction in hyperfilteration that occurs in the remaining nephrons after renal injury. In 5 year prospective study of patients with type 1 diabetes, ESRD or death occurred in 27% of patients on the usual protein diet as compared with 10% on a low protein diet (78) with a comparable glycemic and blood pressure control in both groups.

Although a clear benefit of dietary protein restriction has not been established in a large randomized prospective trial, current recommendation is dietary allowance of 0.8 g/kg/day of protein, accounting for 10% of total calories, with further restriction as GFR falls.

Lipid-Lowering Agents

Hyperlipidemia is commonly seen in patients with both type 1 and type 2 diabetes mellitus. A number of experimental studies have suggested a link between hyperlipidemia and the development of glomerulsclerosis (79,80). In both type 1 and type 2 diabetes, only a few prospective and controlled studies have shown a correlation between hyperlipidemia and worsening of renal function.

Thomas et al. prospectively followed 152 patients with type 1 diabetes for 8 years to examine the association of dyslipidemia to progression of nephropathy. In patients with microalbuminuria, progression was independently associated with triglycerides content of VLDL, and intermediate-density lipoprotein. In patients with macroalbuminuria, a significant decline in the renal function was independently associated with poor glycemic control, hypertension, and LDL size (81). Hadjadj et al. have also found similar findings when they prospectively followed 297 patients with type 1 diabetes without ESRD for 7 years. High triglycerides levels were an independent predictive factor of both renal and retinal complications. After adjusting for systolic blood pressure, glycemic control, stages of complications at baseline, and diabetes duration, the relative risk for progression was 2.01 (95%, CI: 1.07-3.77) for nephropathy and 2.3 (95%, CI: 1.03-5.12) for retinopathy for patients having serum triglyceride in the highest tertile, compared to the others (82).

Although large prospective trials of the effect of treatment of dyslipidemia on progression of diabetic nephropathy are not yet reported, some evidence indicates that lipid reduction by antilipidemic agents preserves GFR and decreases proteinuria in diabetic patients (83-84). A meta-analysis of lipid-lowering therapy on progression of renal disease assessed 13 prospective controlled trials, 7 of which were exclusively in diabetic patients

(85). Lipid lowering was associated with a lower rate of decline in renal function compared to controls (P = 0.008) inducing beneficial effects equivalent to ACE inhibition in preservation of renal function. As for other component of renoprotection, longitudinal prospective trials are needed to validate the value of lipid-lowering agents. However, as cardiovascular disease is the number one cause of death in diabetic patients with nephropathy, optimizing lipid control is now a standard of care.

Cessation of Cigarette Smoking

Several studies have established the linkage between cigarette smoking and progression of diabetic nephropathy (86-89). Chase et al. assessed the effect of cigarette smoking on diabetic renal and retinal complication in 359 type 1 diabetic patients. The prevalence of increased albumin excretion rate was 2.8 times higher in smokers than in those who do not smoke. Even after correction for glycohemoglobin level and duration of diabetes, smoking was an independent risk factor for development and progression of diabetic nephropathy

(86). Chuahirum et al. reported type 2 diabetic patients who smoked had a faster decline of renal function than nonsmokers (88,89). As is true for pulmonary and cardiovascular disease, quitting smoking should be the therapy of preventive measures for nephropathy in diabetic patients.

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