Implications of Albuminuria on Kidney Disease Progression

Abstract

Albuminuria is recognized in all hypertension guideline statements as a cardiovascular risk factor and indicator of kidney disease. Recent data also demonstrate a strong association between the presence of microalbuminuria and elevations in C‐reactive protein. Thus, the increased membrane permeability that generates microalbuminuria may be secondary to an inflammatory process. Progression from microalbuminuria (>30 and ≤300 mg albumin/g creatinine) to macroalbuminuria (>300 mg albumin/g creatinine) indicates a worsening of vascular disease and the presence of kidney disease. Recent outcome trials of kidney disease progression have demonstrated the best results among those with reductions in albuminuria in concert with blood pressure (BP) reduction. Thus, use antihypertensive agents that not only lower BP but also lower or normalize albuminuria levels. All recent guideline statements support the use of agents that block the renin‐angiotensin‐aldosterone system as part of a regimen to achieve the BP goal. Further lowering of albuminuria may be achieved by adding either a nondihydropyridine calcium antagonist such as verapamil or diltiazem, or aldosterone receptor blockers. Use of an angiotensin receptor blocker added to an angiotensin‐converting enzyme inhibitor or vice versa can further lower albuminuria by an additional 30%–40%, which is not true of the additional lowering of BP.

There are no outcomes trials in people with stage 1 or stage 2 nephropathy, i.e., glomerular filtration rates >60 mL/min that are positive with regard to slowing the progression of kidney disease, as defined by the doubling of creatinine, development of end‐stage renal disease, or death. There are, however, many trials in people with advanced kidney disease (stages 3 and 4) secondary to either diabetic or nondiabetic causes demonstrating a marked slowing of kidney disease in concert with a reduction in proteinuria (macroalbuminuria) (Table I). ¹ , ² , ³ , ⁴ , ⁵ , ⁶ The definitions of microalbuminuria and macroalbuminuria (proteinuria) are discussed in the paper by Toto ⁷ in this issue, so the reader is referred to that paper for an in‐depth discussion of this topic.

Table I.

A Summary of Studies Demonstrating Positive Outcomes in Concert With Reductions in Proteinuria/Macroalbuminuria

	Baseline GFR	Baseline Albuminuria Level
Nondiabetic
MDRD 20	40	>300 mg/d*
AIPRI 4	52	>300 mg/d*
REIN 5	56	>300 mg/d*
AASK 6	46	≅300 mg/d
Diabetic
Captopril study 3	68	>300 mg/d
Hannedouche et al. 21	51	>300 mg/d
Bakris et al. 22	59	>300 mg/d*
Bakris et al. 23	62	>300 mg/d*
IDNT 2	≅40	>500 mg/d*
RENAAL 1	≅40	>300 mg/d*
GFR=glomerular filtration rate; MDRD=Modification of Diet in Renal Disease study group; AIPRI=Angiotensin‐Converting enzyme Inhibition in Progressive Renal Insufficiency trial; REIN=Ramipril Efficacy In Nephropathy trial; AASK=African‐American Study of Kidney Disease and Hypertension; IDNT=Irbesartan Diabetic Nephropathy Trial; RENAAL=Reduction of Endpoints in Non‐insulin‐dependent diabetes mellitus with the Angiotensin II Antagonist Losartan study; *more than half the patients had close to a gram or more of proteinuria (macroalbuminuria) per day. Clearly all patients had stage ≥3 kidney disease, stage 5 being the initiation of dialysis.

Microalbuminuria is a urinary finding that results from a generalized injury to the endothelium along the vascular tree that includes the kidney. ⁸ It is indicative of an inflammatory process in that transient microalbuminuria occurs in settings such as exercise, fevers, heart failure, and poor glycemic control. ⁹ Thus any value obtained for albuminuria must be evaluated in the context of a stable disease process and absence of the aforementioned factors. The urinary test should also be repeated after 1–2 weeks as per the new recommendations. ⁹ Proper evaluation to assess whether any level of albuminuria or proteinuria is present is summarized in Figure I. ¹⁰

Figure 1.

Annual evaluation of albuminuria

KIDNEY DISEASE PROGRESSION: FOCUS ON PROTEINURIA

It should be remembered that all studies focused on renal outcomes were carried out in people usually with >300 mg/d of proteinuria and a glomerular filtration rate of <60 mL/min. There are three long‐term outcome trials ⁴ , ⁵ , ⁶ in nondiabetic kidney disease and three ¹ , ² , ³ in diabetic kidney disease. In each of these trials, the mean reduction in proteinuria at the trial end was 32%–37% in the treated groups.

Nondiabetic Kidney Outcome Trials

In the Angiotensin‐converting‐enzyme Inhibition in Progressive Renal Insufficiency (AIPRI) ⁴ trial, patients randomized to the angiotensin‐converting enzyme (ACE) inhibitor benazepril achieved a greater slowing in kidney disease progression as compared with placebo, with a 66% risk reduction in disease progression in those randomized to an ACE inhibitor. This group also had a significantly greater reduction in urinary protein compared with the placebo group.

The second trial is the Ramipril Efficacy In Nephropathy (REIN) ⁵ trial of nondiabetic renal disease. Patients who had serum creatinine values of >177 μmol/L (2.0 mg/dL) and >3.0 g/d of proteinuria and were treated in the ACE inhibitor group had a 62% reduction in renal disease progression while individuals with microalbuminuria had only a 22% reduction in renal disease progression over the same 42‐month follow‐up period. In this trial, the greatest benefit was observed in those with the greatest reduction in proteinuria, which occurred in those with the highest levels of proteinuria at the start of the study.

The third trial is in African Americans with renal disease, who have a higher likelihood of developing progressive renal disease and who derive additional renoprotection from blockade of the renin‐angiotensin system (RAS) if adequate blood pressure (BP) lowering is achieved. In the African‐American Study of Kidney Disease and Hypertension (AASK), ⁶ the primary end point was the rate of change in glomerular filtration rate (GFR) (GFR slope), clinical composite outcome of reduction in GFR by ≥50% (≥25 mL/min/1.73 m²) from the baseline, end‐stage renal disease, or death. A group treated with ramipril plus other medications manifested a risk reduction in clinical composite outcomes of 22% (95% confidence interval, l%–38%; p=0.04) as compared with a metoprolol‐based treatment group and 38% (95% confidence interval, 14%–56%; p=0.004) when compared with an amlodipine group. In this trial, prognostic signs that correlated with a slowing of kidney disease progression included: 1) goal BP <130/80 mm Hg; 2) a 30% increase in serum creatinine (baseline <3 mg/dL) within the first 4 months of therapy; and 3) a reduction of >30% from the baseline levels of proteinuria. Moreover, in this trial, the level of proteinuria at any given time was found to correlate with the magnitude of renal disease progression; thus the higher the level of proteinuria, the faster the progression of kidney disease. It is important to note that this was true even on drugs such as ACE inhibitors or angiotensin receptor blockers (ARBs). It should also be remembered, however, that a large percentage of patients received other medications, primarily diuretics to achieve lower BP.

Concomitant therapy of an ACE inhibitor with an ARB has been demonstrated to further reduce proteinuria and improve renal outcomes for both diabetic and nondiabetic renal disease. ¹¹ , ¹² This improvement is independent of further BP reduction. In a recent randomized controlled trial ¹³ of immunoglobulin A nephropathy, only 10 (11%) of 85 patients on a combination treatment of trandolapril and losartan reached the combined primary end point of time to the doubling of the serum creatinine concentration or end‐stage renal disease as compared with 20 (23%) of 85 on trandolapril alone (hazard ratio [HR], 0.38, 95% confidence interval [CI], 0.18–0.63; p=0.018) and 20 (23%) of 86 on losartan alone (HR, 0.40, 95% CI, 0.17–0.69; p=0.016). The 10 individuals with the slowest progression of kidney disease had an additional 35% reduction in proteinuria over the other two groups with the same level of BP control.

Diabetic Kidney Disease

Agents that reduce proteinuria along with BP also reduce progression of diabetic nephropathy. Data from the CDN trial ³ indicate that ACE inhibitors are more effective than other agents in reducing albuminuria among subjects with renal disease and in retarding the decline in GFR and the onset of kidney failure even at similar levels of BP control. In this trial, the group that provided the majority of outcome events were those with the most advanced nephropathy and highest level of proteinuria whose proteinuria was reduced with the treatment.

Trials in type 2 diabetics demonstrate that ARBs are more effective than other antihypertensive classes of antihypertensive agents tested (β blockers, dihydropyridine calcium antagonists [DHP‐CAs]) in delaying the progression of nephropathy in those with decreased GFR (<60 mL/min) and macroalbuminuria (proteinuria). In both the Irbesartan Diabetic Nephropathy Trial (IDNT) ² and the Reduction of Endpoints in non‐insulin‐dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) ¹ study, subjects randomized to irbesartan (or losartan in RENAAL) attained a significant risk reduction in time to dialysis, transplantation, and death when compared with therapies that did not include an ARB. In both of these trials, an ≅35% reduction in proteinuria from baseline was noted (Table II). Keep in mind, however, that, in these trials, an average of three different antihypertensive agents was used, including the randomized drug.

Table II.

A Summary of Outcome Trials (Focus on Time‐to‐Dialysis) in Patients With Diabetic and Nondiabetic Causes of Nephropathy on Progression of Kidney Disease Based on Proteinuria Reduction

Increased Time to Dialysis (30%–35% Proteinuria Reduction)	No Change in Time to Dialysis (no Proteinuria Reduction)
Captopril study 3
AASK 6	Amlodipine arm‐IDNT 2
RENAAL 1	Amlodipine arm‐AASK 6
IDNT 2
IDNT=Irbesartan Diabetic Nephropathy Trial; RENAAL=Reduction of Endpoints in Non‐insulin‐dependent diabetes mellitus with the Angiotensin II Antagonist Losartan study; AASK=African‐American Study of Kidney Disease and Hypertension

Agents that reduce BP without concomitant reductions in proteinuria or macroalbuminuria, such as DHP‐CAs, have not been shown to slow kidney disease progression (Table II). Thus the role of CAs in the absence of ACE inhibitors or ARBs in the treatment of hypertension in advanced kidney disease has been controversial. Disparities exist between the effects of the CA subclasses on proteinuria reduction, an effect that is reflected in renal outcomes. ¹³ Only the non‐DHP‐CAs, verapamil and diltiazem, appear to be consistently effective in reducing proteinuria in advanced diabetic nephropathy with evidence of reduced cardiovascular events in several outcome trials. ¹³ , ¹⁴ On the other hand, DHP‐CAs, when used in the absence of blockers of the RAS, may be associated with increased risks of progressive diabetic kidney disease, as noted in the IDNT ² (Table II).

In IDNT, ² the group randomized to the DHP‐CA, amlodipine had much less reduction in proteinuria when compared with the ARB irbesartan. This greater reduction in proteinuria by irbesartan was associated with far fewer people reaching the dialysis end point, despite similar levels of BP control in each group. It should be appreciated, however, that when combined with ACE inhibitors and/or ARBs, DHP‐CAs do not detract from the benefit of the RAS blockade and further lower BP with the resultant benefit of stroke reduction, as demonstrated in post hoc analyses of the RENAAL trial. ¹⁵ As such, both the American Diabetes Association and the National Kidney Foundation ⁹ , ¹⁶ recommend that DHP‐CAs should not be used in diabetic nephropathy in the absence of ACE inhibitors or ARBs but rather as third‐line therapy after diuretics and RAS blockers. ⁹ , ¹⁶

Caveats

The amount of sodium intake can strongly influence both the lowering of BP and albuminuria of both ACE inhibitors and ARBs. Salt restriction and/or pretreatment with a diuretic can increase the response of RAS blockers, ¹⁷ especially in African Americans. ¹⁸ Diuretics are the oldest class of antihypertensive agents and have consistently demonstrated the ability to reduce cardiovascular mortality, even in patients with diabetes and/or kidney disease. ¹⁹ Moreover, the appropriate use of diuretics mitigate against profound increases in serum potassium seen in people with advanced nephropathy or diabetes with blockers of the RAS.

RECOMMENDATIONS

Documented persistent elevations (two out of three measurements above the reference range) in individuals undergoing treatment for elevated BP, lipid disorders, or both should be retested within 6 months. After diagnosis and evaluation, continued surveillance is recommended to assess progression of renal disease and response to therapy. Agents that block the RAS (ACE inhibitors and ARBs) are preferred initial therapy due to their favorable effects on both BP and albuminuria. Due to their widespread tolerability, they can be dose‐titrated for maximal proteinuria reduction. Diuretics can potentiate the effects of ACE inhibitors/ARBs. Additionally, use of an ACE inhibitor plus an ARB, or either of these agents with an aldosterone receptor blocker, further lowers proteinuria and slows kidney disease progression. If hyperkalemia becomes a problem, appropriately dosed loop diuretics (b.i.d.) should be given. If hyperkalemia remains a problem, then nondihydropyridine CAs should be considered instead of DHP‐CAs in proteinuria reduction, despite the similar BP‐lowering effects.