The Prevention of Nephropathy in Diabetic Patients

Primary prevention includes early detection of diabetes, glycemic control, screening for microalbuminuria, control of hypertension and smoking cessation, while key issues in secondary prevention are glycemic control, reduction of hypercholesterolemia, control of hypertension, smoking cessation, use of ACE inhibitors and possible restriction of dietary protein (Walling 2000).

There are several pathologic processes that contribute to diabetic nephropathy, including glomerular hypertrophy, sclerosis and nephron loss (Walling 2000). In the beginning stage, hyperglycemia increases the glomerular filtration rate and causes glomerular hypertrophy, and is already established in 40 percent of patients at the time of diagnosis of diabetes (Walling 2000). The microalbuminuric stage develops roughly five years after diagnosis in patients with type 1 diabetes but may occur earlier in patients with type 2 diabetes (Walling 2000). Up to 300 mg of albumin may be excreted daily (Walling 2000). Good glycemic control and an introduction of angiotensin-converting enzyme (ACE) inhibitors can retard the progression of nephropathy at this stage, while at more advanced stages of diabetic nephropathy, overt proteinuria, hypertension, and reduction in creatinine clearance develop (Walling 2000). At this stage, patients rapidly progress to require dialysis or transplantation (Walling 2000).

Nephropathy is a common complication of diabetes and is characterized by the development of proteinuria, culminating in end-stage renal disease with a particularly high risk of cardiovascular morbidity and mortality (Thornalley 2003). Tight control of blood glucose (mad blood pressure) decreases the risk of developing nephropathy, however, it is not always achievable due to the limitations of current drug therapy (Thornalley 2003). A study published in the August 01, 2003 issue of Diabetes, suggest that “high-dose thiamine repletion suppressed the development of incipient nephropathy in experimental diabetes in which effects on the PKC, glycation, and oxidative stress pathways were involved” (Thornalley 2003). Researchers found similar effects on human mesangial cells in hyperglycemic culture in vitro (Thornalley 2003). The primary intervention was the prevention of thiamine deficiency and induction of TK expression with consequent activation of the reductive PPP shunt (Thornalley 2003). The effects were achieved by increasing the dietary availability of thiamine to diabetic rats by as little as 20 times the minimum daily allowance, yet this was sufficient to prevent thiamine deficiency (Thornalley 2003). Thiamine deficiency exacerbated the development of diabetic nephropathy, thus the researchers proposed that clinical diabetic subjects should avoid becoming thiamine deficient, even weakly so, and that high-dose thiamine repletion should be considered for therapy to prevent the development of clinical diabetic nephropathy (Thornalley 2003).

Diabetic nephropathy is more prevalent among African Americans, Asians, and Native Americans than Caucasians (Zelmanovitz 2005). Moreover, among patients starting renal replacement therapy, the incidence of diabetic nephropathy doubled from 1991-2001, however, the rate of increase has slowed down (Zelmanovitz 2005). The reason for the slow down is probably due to the adoption in clinical practice of several measures that contribute to the early diagnosis and prevention of diabetic nephropathy, which thereby decreases the progression of established renal disease (Zelmanovitz 2005). A ten-year follow-up revealed the risk of diabetic nephropathy was 29 times greater in patients with type 2 diabetes with UAE values > 10 (micro)g/min, and the same held true for patients with type 1 diabetes (Zelmanovitz 2005). This favors the concept that the risk associated with UAE is a continuum, as is the case with blood pressure levels (Zelmanovitz 2005). .

Treatment of hypertension dramatically reduces the risk of a cardiovascular and microvascular event in patients with diabetes, in fact, hypertension is common in diabetic patients, even when renal involvement is not present (Zelmanovitz 2005). About 40 percent of type 1 and 70 percent of type 2 diabetic patients with normoalbuminuria have blood pressure levels > 140/90 mmHg (Zelmanovitz 2005). In the UKPDS, a reduction from 154 to 144 mmHg on systolic blood pressure reduced the risk for the development of microalbuminuria by 29 percent (Zelmanovitz 2005). Blood pressure targets for patients with diabetes are lower, 130/80 mmHg, than those for patients without diabetes (Zelmanovitz 2005). In the Hypertension Optimal Treatment (HOT) study, a reduction of diastolic blood pressure from 85 to 81 mmHg resulted in a 50 percent reduction in the risk of cardiovascular events in diabetic but no nondiabetic patients (Zelmanovitz 2005).

The role of ACE inhibitors in the prevention of diabetic nephropathy in patients with type 1 diabetes has not been defined (Zelmanovitz 2005). The use of perindopril during 3 years in normotensive normoalbuminuric type 1 diabetic patients delayed the increase in albuminuria, and in patients with type 2 diabetes, ACE inhibitors and ARBs both diminish the risk for diabetic nephropathy and reduce the occurrence of cardiovascular events (Zelmanovitz 2005). In the MICRO-HOPE (Heart Outcomes Prevention Evaluation) study,10 mg/day of ramipril decreased the risk of overt nephropathy by 24 percent and the risk of cardiovascular heath in patients with type 2 diabetes who were 55 years of age with one additional cardiovascular risk factor by 37 percent (Zelmanovitz 2005).

Ramipril also reduced UAE at 1 year and at the end of the study (Zelmanovitz 2005).

In microalbuminuric type 1 and type 2 diabetic patients, numerous studies have shown that treatment of hypertension, irrespective of the agent used, produced a beneficial effect on albuminuria (Zelmanovitz 2005). Renin-angiotensin system (RAS) blockade with ACE inhibitors or ARBs confers an additional benefit on renal function, this effect is independent of blood pressure reduction and may be related to decreased intraglomerular pressure and passage of proteins into the proximal tubule (Zelmanovitz 2005).

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