T2 Diabetes: Target Albuminuria and Blood Pressure

The RENAAL Study (Reduction of End Points in Non-Insulin Dependent Diabetes with the Angiotensin II Antagonist Losartan) continues to give us critical direction in the management of the cardiovascular and renal risk factors prevalent in the diabetic demographic.¹

The most common cause of ESRD worldwide is type 2 diabetes mellitus.² The RENAAL study demonstrated that compared with placebo, losartan-an angiotensin receptor antagonist-significantly reduced:

. The doubling of serum creatinine (risk reduction, 25%)
. The development of ESRD (risk reduction, 28%)
. The time to first hospitalization for heart failure (risk reduction, 32%)

Note, however, that target blood pressure was the same in the losartan and placebo groups: alternative antihypertensives (none that were active on the renin-angiotensin-aldosterone axis) were used to reach target blood pressure (calcium channel blockers, diuretics, alpha and beta blockers, and central agents).

Also, glucose control was no different in either group.

If not BP and tight control, then elevated urine albumin
So, if it was not solely a blood pressure below target or tighter diabetic control that benefited this diabetic cohort, what else might have?

Although controlling blood pressure slows the progression of renal disease and mitigates other vascular risk factors, RENAAL should help us focus on the risks contingent on an elevated urine albumin (>300 mg/gm or 500 mg total).

After publication of the RENAAL Study in 2001, a number of other publications have further mined the initial data. One review developed a Risk Score to predict outcomes in patients with T2DM and nephropathy.³ The higher the hazard ratio, the higher the risk of ESRD in a diabetic person with that variable.

The hazard ratio for each independent variable was:
. 14.7 for the albumin creatinine ratio,
. 9.2 for serum creatinine,
. 5.5 for hemoglobin (lower as a consequence of the anemia of chronic renal disease)
. 10.2 for serum albumin level (lowered by urinary protein loss or poor nutrition).

When we test for urine albumin/creatinine ratios, we are obtaining a screen that correlates strongly with progressive renal disease that may culminate in dialysis dependence. In fact, another post-RENAAL summary observed that albuminuria is an independent target for renal protective therapy (with ACEIs and ARBs). For each 50% reduction in albuminuria in patients on losartan in the first 6 months of treatment, there was a 45% decrease risk for ESRD on follow up, an 18% decreased risk for in cardiovascular morbidity and mortality, and a 27% reduction the risk for heart failure.⁴

(See next page for "Take-Home Do's and Don'ts")

Some “take home dos and don’ts” from RENAAL?
 

1. Follow guidelines and obtain urine albumin and creatinine measurements in your diabetic patients. A value >300mg albumin/gm of creatinine is abnormal and is associated with a greater functional decline in GFR.

2. Always treat blood pressure aggressively with an ARB as the backbone of therapy with targets of 130/80 mm/hg or 125/75 mm/hg in persons with >1 gm protein over 24 hours.

3. Do not use both an ARB and an ACEI together.
 

4.  Do not forget other aspects of diabetic care, such as retinopathy. Patients with retinopathy at baseline enrollment in RENAAL had a 22% higher risk of ESRD or death on follow up!⁴

Primary care physicians are strategically positioned to combat the epidemic of T2 diabetes complicated by cardiovascular and renal disease. Attention to a few easily obtained details (BP, urine albumin, and other primary care screens) can protect these patients from serious complications.

References:

1. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and Nephropathy. N Engl J Med. 2001;345:861-869.
2. Keane WF, Zhang Z, Lyle PA, et al. Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: the RENAAL Study. Clin J Am Soc Nephrol. 2006;1:761-767.
3. Eijkelkamp WBA, Zhang Z, Remuzzi G, et al. Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the Reduction in Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Trial. J Am Soc Nephrol. 2007;1540-1546.
4. Shahinfar S, Lyle PA, Zhang Z, et al. Losartan: lessons learned from the RENAAL Study. Expert Opin Pharmacother. 2006;7:623-630.