风清扬
Progression of Diabetic Nephropathy Slowed With Early Detection of Albuminuria

September 30, 2010 (Stockholm, Sweden) — A study of more than 11,000 adults with hypertension and type 2 diabetes, presented here at the European Association for the Study of Diabetes 46th Annual Meeting, showed that the lifetime risk for nephropathy and its progression might be greater than previously thought. In addition, results showed that the use of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) was not optimal in this population, indicating that there might be room for improvement in strategies to reduce the burden of disease.

Epidemiologist Suma Vupputuri, PhD, MPH, from Kaiser Permanente Center for Health Research/Southeast in Atlanta, Georgia, said that estimates that one third of diabetic patients develop nephropathy are from a time when glycemic thresholds for the diagnosis of diabetes were higher than today, and before aggressive treatment was shown to reduce renal complications.

She said because nephropathy is a major cause of cardiovascular disease and end-stage renal disease, it is important to understand the progression from normal levels of albumin excretion to micro- and macroalbuminuria, and to define the risk factors associated with nephropathy progression.

The researchers studied type 2 diabetes patients with hypertension (n = 11,562) who were 18 years or older and for whom there were urine albumin-to-creatinine ratios (UACR) documented in 2001, 2002, or 2003, and at least 1 additional UACR 3 to 8 years later.

The baseline stages of nephropathy were defined by the UACR: a ratio below 30 μg/mg was considered normal, from 30 to 299 μg/mg indicated microalbuminuria, and 300 μg/mg or above indicated macroalbuminuria. Progression was defined as the first UACR value recorded in a stage higher than that seen at the baseline. Patients were censored if they died or left the health plan.

Over 89 months of follow-up, the incidence of progression of nephropathy was highest for people with normal baseline UACRs, followed by patients with microalbuminuria, and then macroalbuminuria (94.6, 44.1, and 6.7 per 1000 patient-years, respectively).

"Among patients with normal albumin at baseline, those who progressed to a higher stage of nephropathy were in general older, had a longer duration of diabetes, had higher mean blood pressures, and had higher HbA1cs [glycated haemoglobin]," Dr. Vupputuri said. The patients with microalbuminuria at baseline who progressed were more likely to be male, had longer durations of diabetes, had higher mean blood pressures, and had higher HbA1c levels. The macroalbuminuria group had risk factors similar to the microalbuminuria group, and had lower glomerular filtration rates (GFRs) and a diagnosis of cardiovascular disease or heart failure.

Across the stratified baseline cohorts, 78% to 91% of patients were receiving antihypertensive agents, and about half were receiving statins. Most were receiving antihyperglycemic drugs (range, 67% to 79%). The use of insulin went up and oral agents down with increasing nephropathy stage.

ACE inhibitor or ARB use ranged from 61% to 67% for all baseline groups, whether they progressed or not, with one notable exception. Of patients with baseline macroalbuminuria who progressed, ACE inhibitor or ARB use was only 38%.

From the 3 Cox regression models that identified risk factors for time to progression for each baseline cohort, it emerged that ACE inhibitor or ARB use was not a significant factor for patients with normal albumin levels or microalbuminuria at baseline.

However, for patients with baseline macroalbuminuria, the use of these drugs conferred a multivariate hazard ratio (HR) of 0.53 (95% confidence interval [CI], 0.29 - 0.95), meaning their use reduced the risk for progression by 47%. Similarly, age conferred a 21% benefit per 5 years (HR, 0.79 per 5 years; 95% CI, 0.66 - 0.95), as did estimated GFR, with a 65% risk reduction for every increase of 10 mL/min per 1.73 m2 (HR, 0.35; 95% CI, 0.27 - 0.48).

Dr. Vupputuri summarized by saying that of the entire baseline cohort, 41% had prevalent micro- or macroalbuminuria, and 68% with a normal starting level developed micro- or macroalbuminuria.

Predictors of progression of nephropathy included age, race (being African American was somewhat protective), diabetes duration, systolic and diastolic blood pressure, HbA1c level, body mass index, estimated GFR, ACE inhibitor/ARB use, and cardiovascular disease.

A limitation of the study is its possible lack of generalizability; it was restricted to patients with diabetes, hypertension, and health insurance who had multiple determinations of UACR. Furthermore, estimates of risk for progression could have been biased by patients who died before their nephropathy might have progressed. Finally, individual variation in albumin excretion and serum creatinine production could have influenced the results.

Dr. Vupputuri concluded that the progression of diabetic nephropathy found here was higher than previously reported. "The use of ACE [inhibitors] and ARBs was lower than expected in this population," she said. "Our study suggests that successful strategies to prevent or slow the progression of nephropathy are needed and that these may effectively reduce the burden of disease."

Session moderator Leszek Czupryniak, MD, PhD, associate professor of diabetology and internal medicine at the University of Lodz in Poland, said other limitations of the study are the fact that the investigators had no information with which to correlate the drugs being used by individual patients with their outcomes, nor did they have information on concomitant diseases.

Nonetheless, he praised the study for following such a large cohort longitudinally according to the degree of albuminuria, obtaining data not previously available.

"What was interesting in the study is that a lot of people develop early kidney damage, but then very few of them progress to end-stage renal disease," Dr. Czupryniak said. "The more practical conclusion would be that, first of all, don't be afraid as a patient if your doctor [tells you] that you have microalbuminuria. . . . The second thing is — and it's an indirect implication of the study — that we do have measures to stop the kidney damage at that level."

He cited the fact that almost half the people with normal albumin excretion developed microalbuminuria, but only 6% progressed to macroalbuminuria, and a very tiny fraction (0.09%) developed end-stage renal disease. "We are able to maintain patients at an early level of kidney damage for years," he said.

"The study really shows that if [these patients had] normal albumin excretion, basically your kidneys work normally. You can progress within 7 or 8 years to microalbuminuria very easily. . . but people who already had macroalbuminuria, then the progression rate was very, very low," Dr. Czupryniak noted. Once albuminuria is detected, "definitely more aggressive prevention measures [should be] taken," adding that, "microalbuminuria is a reversible state." Drug, diet, and lifestyle interventions can help to limit the rate of nephropathy progression.

He strongly advises physicians to screen patients for albuminuria; it is not only a sign of kidney damage, it is a sign of generalized vasculopathy, including cardiovascular disease, that can be slowed or halted with aggressive pharmacologic treatment. But he cautioned that 1 measurement is not enough to make a diagnosis of microalbuminuria, and the test should be positive on at least 2 of 3 occasions, preferably at least 1 month apart.

"It's easy to develop microalbuminuria, but then it's also easy to stop it at this level," Dr. Czupryniak said.