Albuminuria: When urine predicts kidney and cardiovascular disease
ABSTRACTAlbuminuria is common. Traditionally considered a precursor to diabetic nephropathy, it has now been directly linked to adverse cardiovascular outcomes and death, independent of other risk factors. In this review, we compare the measures of albuminuria, examine the evidence linking it to renal failure, cardiovascular disease, and death, and provide recommendations for its testing and management.
KEY POINTS
- Albuminuria is best measured by the albumin-to-creatinine ratio.
- In several studies, albuminuria has been independently associated with a higher risk of death, cardiovascular events, heart failure, stroke, and progression of chronic kidney disease.
- Despite strong evidence linking albuminuria to adverse outcomes, evidence is limited in favor of routinely screening for it in the general population.
- Evaluating and managing albuminuria require understanding the limits of its clinical measures, controlling other risk factors for progression of renal disease, managing it medically, and referring to a specialist in certain situations.
THE CASE FOR TREATING ALBUMINURIA
Reduced progression of renal disease
Treating patients who have proteinuric chronic kidney disease with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) can reduce the risk of progression of renal failure. However, it is unclear whether this benefit is the result of treating concomitant risk factors independent of the reduction in albuminuria, and there is no consistent treatment effect in improving renal outcomes across studies.
Fink et al,51 in a meta-analysis, found that chronic kidney disease patients with diabetes, hypertension, and macroalbuminuria had a 40% lower risk of progression to end-stage renal disease if they received an ACE inhibitor (relative risk [RR] 0.60, 95% confidence interval [CI] 0.43–0.83). In the same meta-analysis, ARBs also reduced the risk of progression to end-stage renal disease (RR 0.77, 95% CI 0.66–0.90).
Jafar et al,52 in an analysis of pooled patient-level data including only nondiabetic patients on ACE inhibitor therapy (n = 1,860), found that the risk of progression of renal failure, defined as a doubling of serum creatinine or end-stage renal disease, was reduced (RR 0.70, 95% CI 0.55–0.88). Patients with higher levels of albuminuria showed the most benefit, but the effect was not conclusive for albuminuria below 500 mg/day at baseline.
Maione et al,53 in a meta-analysis that included patients with albuminuria who were treated with ACE inhibitors vs placebo (n = 8,231), found a similar reduction in risk of:
- Progression to end-stage renal disease (RR 0.67, 95% CI 0.54–0.84)
- Doubling of serum creatinine (RR 0.62, 95% CI 0.46–0.84)
- Progression of albuminuria (RR 0.49, 95% CI 0.36–0.65)
- Normalization of pathologic albuminuria (as defined by the trialists in the individual studies) (RR 2.99, 95% CI 1.82–4.91).
Similar results were obtained for patients with albuminuria who were treated with ARBs.53
ONTARGET.54 In contrast, in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial, the combination of an ACE inhibitor and an ARB showed no benefit in reducing the progression of renal failure, and in those patients with chronic kidney disease there was a higher risk of a doubling of serum creatinine or of the development of end-stage renal disease and hyperkalemia.
Also, in a pooled analysis of the ONTARGET and Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) trials, a 50% reduction in baseline albuminuria was associated with reduced progression of renal failure in those with a baseline ACR less than 10 mg/g.55
Improved cardiovascular outcomes
There is also evidence of better cardiovascular outcomes with treatment of albuminuria. Again, it is uncertain whether this is a result of treating risk factors other than albuminuria with ACE inhibitors or ARBs, and there is no parallel benefit demonstrated across all studies.
LIFE.47,48 In the Losartan Intervention for Endpoint Reduction in Hypertension trial, survival analyses suggested a decrease in risk of cardiovascular adverse events as the degree of proteinuria improved with ARB therapy.
Maione et al,53 in a meta-analysis including 8,231 patients with albuminuria and at least one other risk factor, found a significant reduction in the rate of nonfatal cardiovascular outcomes (angina, myocardial infarction, revascularization, stroke, transient ischemic attack, or heart failure) with ACE inhibitors vs placebo (RR 0.88, CI 0.82–0.94) and also in 3,888 patients treated with ARBs vs placebo (RR 0.77, CI 0.61–0.98). However, the meta-analysis did not show that ACE inhibitor or ARB therapy reduced rate of cardiovascular or all-cause mortality.
Fink et al,51 in their meta-analysis of 18 trials of ACE inhibitors and four trials of ARBs, also found no evidence that ACE inhibitor or ARB therapy reduced cardiovascular mortality rates.38
The ONTARGET trial evaluated the combination of an ACE inhibitor and ARB therapy in patients with diabetes or preexisting peripheral vascular disease. Reductions in the rate of cardiovascular disease or death were not observed, and in those with chronic kidney disease, there was a higher risk of doubling of serum creatinine or development of end-stage renal disease and adverse events of hyperkalemia.56 And although an increase in baseline albuminuria was associated with worse cardiovascular outcomes, its reduction in the ONTARGET and TRANSCEND trials did not demonstrate better outcomes when the baseline ACR was greater than 10 mg/g.55
WHO SHOULD BE TESTED?
The benefit of adding albuminuria to conventional cardiovascular risk stratification such as Framingham risk scoring is not conclusive. However, today’s clinician may view albuminuria as a biomarker for renal and cardiovascular disease, as albuminuria might be a surrogate marker for endothelial dysfunction in the glomerular capillaries or other vital vascular beds.
High-risk populations and chronic kidney disease patients
Nearly all the current guidelines recommend annual screening for albuminuria in patients with diabetes and hypertension (Table 2).7,10–13 Other high-risk populations include people with cardiovascular disease, a family history of end-stage renal disease, and metabolic syndrome. Additionally, chronic kidney disease patients whose estimated GFR defines them as being in stage 3 or higher (ie, GFR < 60 mL/min/1.73m2), regardless of other comorbidities, should be tested for albuminuria, as it is an important risk predictor.
Most experts prefer that albuminuria be measured by urine ACR in a first morning voided sample, though this is not the only option.
Screening the general population
Given that albuminuria has been shown to be such an important prognosticator for patients at high risk and those with chronic kidney disease, the question arises whether screening for albuminuria in the asymptomatic low-risk general population would foster earlier detection and therefore enable earlier intervention and result in improved outcomes. However, a systematic review done for the United States Preventive Services Task Force and for an American College of Physicians clinical practice guideline did not find robust evidence to support this.51
OUR RECOMMENDATIONS
Who should be tested?
- Patients with chronic kidney disease stage 3, 4, or 5 (GFR < 60 mL/min/1.73m2) who are not on dialysis
- Patients who are considered at higher risk of adverse outcomes, such as those with diabetes, hypertension, a family history of end-stage renal disease, or cardiovascular disease. Testing is useful for recognizing increased renal and cardiovascular risk and may lead clinicians to prescribe or titrate a renin-angiotensin system antagonist, a statin, or both, or to modify other cardiovascular risk factors.
- Not recommended: routine screening in the general population who are asymptomatic or are considered at low risk.
Which test should be used?
Based on current evidence and most guidelines, we recommend the urine ACR test as the screening test for people with diabetes and others deemed to be at high risk.
What should be done about albuminuria?
- Controlling blood pressure is important, and though there is debate about the target blood pressure, an individualized plan should be developed with the patient based on age, comorbidities, and goals of care.
- An ACE inhibitor or ARB, if not contraindicated, is recommended for patients with diabetes whose ACR is greater than 30 mg/g and for patients with chronic kidney disease and an ACR greater than 300 mg/g.
- Current evidence does not support the combined use of an ACE inhibitor and an ARB, as proof of benefit is lacking and the risk of adverse events is higher.
- Refer patients with high or unexplained albuminuria to a nephrologist or clinic specializing in chronic kidney disease.
