A Review of the Prevention and Treatment of Microalbuminuria in Normotensive Type 2 Diabetes
Megha P. Patel, MD
Brookdale Department of Geriatrics and Palliative Medicine at the Icahn School of Medicine at Mount Sinai, New York, New York
B. Brent Simmons, MD
Associate Professor, Department of Family, Community, and Preventive Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania
Patel MP, Simmons BB. A review of the prevention and treatment of microalbuminuria in normotensive type 2 diabetes. Consultant. 2019;59(7):195-198.
ABSTRACT: Type 2 diabetes mellitus (T2DM) has become the leading cause of nephropathy in the United States. Diabetic kidney disease affects a large percentage of persons with diabetes in their lifetime, and its progression is associated with significant health care costs and decreased quality of life. Microalbuminuria is a well-established early marker for cardiovascular and kidney disease and is associated with increased morbidity and mortality even in healthy individuals. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers both have been shown to reduce microalbuminuria across a wide cohort of patients and therefore are first-line agents for treatment of hypertension and kidney disease in persons with T2DM. However, the role of these medications in the setting of normotensive T2DM with and without microalbuminuria is less clear. This article reviews the guidelines for treatment and prevention of microalbuminuria in T2DM and the evidence from recent research.
KEYWORDS: Type 2 diabetes mellitus, diabetic kidney disease, microalbuminuria, normotensive
Type 2 diabetes mellitus (T2DM) has become the leading cause of nephropathy in the United States. Diabetic kidney disease (DKD) eventually affects up to 40% of persons with T2DM.1,2 It is associated with increased health care costs and causes a significant burden on quality of life.2 Albuminuria, which is any level of protein found in the urine, is an indicator of kidney disease. Approximately 5% to 10% of patients with a new diagnosis of T2DM already have some degree of albuminuria.3
Patients with T2DM and albuminuria have a poor prognosis, since albuminuria indicates a generally rapid decline of the estimated glomerular filtration rate (eGFR) and development of cardiovascular disease.4 The diabetic patient with albuminuria is at 2 to 4 times increased risk of death from cardiovascular causes. Patients with T2DM and proteinuric kidney disease and no history of previous myocardial infarction (MI) have greater incident MI rates than patients with a history of MI, with hazard ratios (HRs) ranging from 1.20 to 2.22.5 The higher HRs correspond with higher levels of albuminuria.5 Recently, Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommended a more comprehensive definition of the stages of kidney disease that incorporates levels of albuminuria in addition to eGFR.6-8
Microalbuminuria, which is subclinical albuminuria, is defined as a urine albumin-to-creatinine ratio (UACR) of 30 to 299 mg/g creatinine.8 Greater levels are considered macroalbuminuria or overt/gross albuminuria. Microalbuminuria is associated with hypertension and hyperfiltration (rather than overt nephropathy) and generally appears before a reduction in eGFR.4 It is regarded as an early indicator of kidney disease and the earliest marker of glomerular disease.3,4,9,10 Consequently, microalbuminuria has become a routine measurement to identify early diabetic nephropathy.3,9 The presence of microalbuminuria, independent of other risk factors, carries a relative risk of 2.3 for developing ischemic heart disease and reduces 10-year survival rates from 97% to 91%.11,12 Therefore, it is common medical practice to treat microalbuminuria in patients with T2DM to prevent progression of kidney disease and development of overt albuminuria.
A substantial portion of our understanding of the development of DKD in T2DM is derived from data from persons with type 1 diabetes mellitus (T1DM), who on average develop nephropathy within 20 years of disease onset.4,7,10 Despite similar pathophysiology, the risk of developing nephropathy in T2DM is less predictable.2-4 The predictive value of microalbuminuria leading to macroalbuminuria is much lower in T2DM because of excess mortality from cardiovascular disease causes. Risk factors such as ethnicity and the presence of concurrent comorbidities such as hypertension, cardiovascular disease, sleep apnea, and obesity affect protein excretion, as well.8,13
EVALUATION AND DIAGNOSIS
All patients with T2DM and patients with comorbid hypertension should be screened for microalbuminuria at least annually. According to the American Diabetes Association (ADA) guidelines, due to biologically varying levels of urinary albumin excretion, a patient should only be considered to have microalbuminuria after 2 of 3 UACR specimens collected within a 3- to 6-month period are 30 mg/g creatinine or higher.8 Other primary causes of kidney damage should be absent. Conditions such as infection, exercise, fever, congestive heart failure, hypertension, elevated blood glucose, and menstruation often cause transient changes in albumin excretion.
UACR is best measured using spot urinary specimens. Other methods such as 24-hour urine collection are cumbersome and do not add accuracy to these measurements. It is important that urine albumin be measured with creatinine to avoid false-negative and false-positive rates, since albumin levels fluctuate with hydration status.
It is important to note that the absence of albuminuria does not exclude the possibility of nephropathy. As the prevalence of diabetes increases in the United States, the number of people with reduced eGFR without albuminuria has also been on the rise.14-16 A cross-sectional study showed that 55% of type 2 diabetics with chronic renal insufficiency did not have microalbuminuria.16 Normoalbuminuria with reduced eGFR is more likely in older and female patients. It is postulated that renal parenchymal disease, rather than classic glomerulosclerosis as seen in T1DM, may be the cause of renal insufficiency, as well as age-related renal senescence, interstitial fibrosis, and vascular disease.16 Certainly in some cases, alternative causes of kidney disease must be considered, particularly with rapidly declining eGFR, urine sediment with red or white blood cells or casts, rapidly increasing albuminuria, or nephrotic syndrome. These findings warrant a referral to a nephrologist for further workup.
GUIDELINES AND TREATMENT
It is well established that optimal glycemic control is the first step in preventing the development of microalbuminuria and consequent DKD. Patients with diabetes and comorbid hypertension must also maintain blood pressure control.17 Likewise, patients who are overweight or obese should be advised to lose weight, since increased weight is an independent cause of microalbuminuria.
Aside from optimal medical management of diabetes and other comorbid conditions, many studies show that the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) prevents progression of microalbuminuria to overt albuminuria and further kidney damage via renin-angiotensin system (RAS) blockade.18-21 One study that evaluated the time to onset of DKD determined that hypertensive type 2 diabetics with microalbuminuria who were treated with an ARB had a HR of 0.30 compared with placebo.18 A network meta-analysis by Palmer and colleagues showed that type 2 diabetics with hypertension had reduced rates of end-stage renal disease (ESRD) when treated either with combined ACEI and ARB therapy or with ARB monotherapy (odds ratios, 0.62 and 0.77, respectively).22 As such, patients with diabetes and hypertension are commonly treated with ACEIs or ARBs as first-line treatment.
The 2017 ADA guidelines have clear recommendations for treatment of albuminuria in patients with diabetes. In nonpregnant patients with diabetes and hypertension, treatment with an ACEI or ARB is recommended for those with an elevated UACR of 30 to 299 mg/g creatinine.8 Treatment in these groups has been shown to reduce progression of albuminuria and cardiovascular events.23 Specifically, there was a 16% relative risk reduction for progression to overt nephropathy and 25% for combined cardiovascular events.24 Treatment with an ACEI or ARB is strongly recommended for those with UACR of 300 mg/g creatinine or above and/or an eGFR below 60 mL/min/1.73 m2. An ACEI or ARB is not recommended for the primary prevention of DKD in diabetics who have normal blood pressure, normal UACR below 30 mg/g creatinine, and normal eGFR. In patients with albuminuria without hypertension, the ADA recognizes that while ACEIs or ARBs are often prescribed for albuminuria without hypertension, clinical trials have not been performed in this setting to determine whether they improve long-term renal outcomes. Therefore, ACEIs and ARBs are not recommended for patients without hypertension to prevent the development of DKD.8
The KDIGO 2012 guidelines similarly recommend the use of ACEIs or ARBs in diabetic patients with hypertension and chronic kidney disease (CKD). For diabetic patients with CKD and a UACR from 30 to 300 mg/g creatinine, KDIGO suggests the use of an ACEI or ARB. The use of ACEIs or ARBs in patients with albuminuria without hypertension is not specifically addressed.6
The US Preventive Services Task Force has decided not to review the topic of screening for CKD and therefore has no update.25
Large trials have shown that levels of albuminuria may be reduced by treatment with ACEIs and ARBs in overt kidney disease, which is defined by either reduced rate of dialysis or doubling of serum creatinine.9,26,27 However, this pharmacological therapy is not clearly beneficial in the early stages of DKD, particularly in normotensive diabetic patients without microalbuminuria.
The DIRECT studies aimed to identify whether administration of candesartan would affect the incidence of microalbuminuria or the rate of change of microalbuminuria in T1DM or T2DM.28 Results showed that RAS blockade across all groups, including normotensive type 2 diabetics, did not prevent microalbuminuria. The rate of change in albuminuria, while statistically significant, had a negligible (0.11 µg/min) absolute risk reduction with unclear clinical significance. Both the placebo and treatment arms for T2DM had similar adverse effect rates; however, there was a slightly higher rate of serious adverse events in the candesartan group compared with the placebo group (32% vs 28%). This study also had major limitations. The study was powered to retinal endpoints rather than renal endpoints, and both primary and secondary endpoints (new microalbuminuria and rate of change in albuminuria, respectively) were not patient-oriented outcomes. Furthermore, most of the patients were white. Outcomes such as diabetic nephropathy would require a much longer study, since it takes decades of diabetes to cause DKD. Overall, the patients who were recruited were healthier than those in other studies discussed here and therefore were at lower risk for microvascular complications.
The TRANSCEND study aimed to assess the long-term effects of telmisartan vs placebo in patients with high vascular risk, including diabetic patients with end-organ damage without macroalbuminuria.29 Primary outcomes included cardiovascular events, and therefore the study was powered to these events. Secondary outcomes included dialysis or doubling of serum creatinine levels. Results showed that telmisartan reduced the risk of microalbuminuria, macroalbuminuria, or both by 11.4% vs 14.8% in the placebo group. However, the reduction of albuminuria was not associated with less progression of kidney disease, and therefore the study concluded that microalbuminuria may not be a reliable marker for subsequent worsening of kidney disease in patients with vascular disease. Thus, the study did not show strong evidence that ARBs can prevent clinically significant renal disease in patients without albuminuria.
The ROADMAP study compared the use of olmesartan in the delay of microalbuminuria in T2DM.30 While this study showed that olmesartan reduces time to onset of microalbuminuria, with no adverse effects on renal outcomes, the study did not continue as long as would be necessary to assess renal endpoints. Furthermore, this study showed that a blood pressure reduction below 120/70 mm Hg was associated with a statistically significant increase in cardiovascular-related death in the treatment group among patients with known heart disease.
In the MICRO-HOPE studies, diabetic patients with cardiovascular risk factors were randomly assigned to ramipril, vitamin E, or placebo groups.24 The study was ended early due to clear cardiac benefit shown in the ramipril treatment group. However, the substudy evaluating renal endpoints showed that 7% of participants on ramipril vs 8% on placebo developed overt nephropathy. These conclusions were limited by the fact that the substudy did not have high enough power to be able to detect effects in different subgroups, such as those who were hypertensive vs normotensive.
A more recent Cochrane meta-analysis reviewed the use of antihypertensives for preventing DKD.31 The authors found that compared with placebo, ACEIs reduced the risk of new-onset microalbuminuria, macroalbuminuria, or both. Similar benefits were seen in patients with and without hypertension; however, these results were not statistically significant. ACEIs were shown to reduce mortality compared with placebo; however normotensive patients were not separated from this group analysis. Few patients in the cited studies progressed to ESRD or had a doubling of serum creatinine level; therefore, no significant difference was seen in patients treated with ACEIs or placebo. In regard to primary prevention of DKD in normotensive, normoalbuminuric patients, the study concluded that ACEIs may be beneficial in diabetic patients who can tolerate ACEI therapy. However, the available studies have not proven that prevention of microalbuminuria will actually lead to a reduction in kidney failure given the slow rate of decline of kidney function. Furthermore, this meta-analysis combined patients with T1DM and T2DM. Additionally, it did not separate normotensive from hypertensive patients, and multiple classes of antihypertensives were included.
A meta-analysis by Persson and colleagues focused on studies that included only normoalbuminuric type 2 diabetics who were exclusively treated with ACEIs or ARBs.32 The primary outcome was the development of microalbuminuria or macroalbuminuria. Secondary outcomes included all-cause mortality, cardiovascular mortality, and morbidity. The analysis favored the use of ACEIs or ARBs in prevention of microalbuminuria, with a number needed to treat of 25 to prevent 1 case of microalbuminuria. All-cause mortality was insignificantly reduced. The other secondary endpoints could not be assessed because numbers were too small. Furthermore, the studies analyzed did not address adverse effects adequately, and normotensive and hypertensive patients could not be separated in the analysis.
It is clear that diabetic patients with hypertension should be treated with an ACEI or ARB to help prevent the onset of microalbuminuria and subsequent progression of kidney disease. However, the treatment of normotensive, normoalbuminuric type 2 diabetics is less clear. Most studies primarily look at cardiovascular outcomes in these patients, and normotensive patients are not separated. Even the effect on cardiovascular outcomes has been shown to be either marginally beneficial or even harmful.
Although some studies use microalbuminuria as a surrogate renal outcome to help assess the progression of kidney disease, not all patients ultimately progress to overt kidney disease, making the clinical utility of primary prevention even more difficult to assess. In addition, adverse effects such as hypotension or acute kidney injury are not adequately addressed with the regular use of an ACEI or ARB, which is concerning for a normotensive diabetic patient with normal kidney function.
More studies need to be performed in this population with clearer assessment of adverse effects. Therefore, given the results of studies that have been performed thus far, the evidence is insufficient for the primary prevention of kidney disease in normotensive, normoalbuminuric type 2 diabetics.
Megha P. Patel, MD, is at the Brookdale Department of Geriatrics and Palliative Medicine at the Icahn School of Medicine at Mount Sinai in New York, New York.
B. Brent Simmons, MD, is an associate professor in the Department of Family, Community, and Preventive Medicine at Drexel University College of Medicine in Philadelphia, Pennsylvania.
- MacIsaac RJ, Ekinci EI, Jerums G. Markers of and risk factors for the development and progression of diabetic kidney disease. Am J Kidney Dis. 2014;63(2 suppl 2):S39-S62.
- Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Am J Kidney Dis. 2014;64(4):510-533.
- Chen S, Khoury C, Ziyadeh FN. Pathophysiology and pathogenesis of diabetic nephropathy. In: Alpern RJ, Caplan MJ, Moe OW, eds. Seldin and Giebisch’s The Kidney. Vol 2. 5th ed. New York, NY: Academic Press; 2013:2605-2632.
- Mogensen CE. Microalbuminuria, blood pressure and diabetic renal disease: origin and development of ideas. Diabetologia. 1999;42(3):263-285.
- Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375(9731):2073-2081.
- Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1-150.
- Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non–insulin-dependent diabetes mellitus: a systematic overview of the literature. Arch Intern Med. 1997;157(13):1413-1418.
- American Diabetes Association. Standards of medical care in diabetes—2017. Diabetes Care. 2017;40(suppl 1):S11-S12
- Heerspink HJL, Kröpelin TF, Hoekman J, de Zeeuw D; Reducing Albuminuria as Surrogate Endpoint (REASSURE) Consortium. Drug-induced reduction in albuminuria is associated with subsequent renoprotection: a meta-analysis. J Am Soc Nephrol. 2015;26(8):2055-2064.
- Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud U, Keen H. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet. 1982;1(8287):1430-1432.
- Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, et al. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation. 2004 Jul 6;110(1):32-35.
- Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion: an independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.
- Palaniappan L, Carnethon M, Fortmann SP. Association between microalbuminuria and the metabolic syndrome: NHANES III. Am J Hypertens. 2003;16(11 pt 1):952-958.
- de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss NS, Himmelfarb J. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA. 2011;305(24):2532-2539.
- MacIsaac RJ, Tsalamandris C, Panagiotopoulos S, Smith TJ, McNeil KJ, Jerums G. Nonalbuminuric renal insufficiency in type 2 diabetes. Diabetes Care. 2004;27(1):195-200.
- Kramer HJ, Nguyen QD, Curhan G, Hsu C-y. Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA. 2003;289(24):3273-3277.
- Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA. 2015;313(6):603-615.
- Parving H-H, Lehnert H, Bröchner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345(12):870-878.
- Ruggenenti P, Fassi A, Ilieva AP, et al; Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J Med. 2004;351(19):1941-51.
- O’Hare P, Bilbous R, Mitchell T, O’Callaghan CJ, Viberti GC; Ace-Inhibitor Trial to Lower Albuminuria in Normotensive Insulin-Dependent Subjects Study Group. Low-dose ramipril reduces microalbuminuria in type 1 diabetic patients without hypertension: results of a randomized controlled trial. Diabetes Care. 2000;23(12):1823-1829.
- Chaturvedi N; EUCLID Study Group. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet. 1997;349(9068):1787-1792.
- Palmer SC, Mavridis D, Navarese E, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet. 2015;385(9982):2047-2056.
- Patel A; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370(9590):829-840.
- Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355(9200):253-259.
- Moyer VA; US Preventive Services Task Force. Screening for chronic kidney disease: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2012;157(8):567-570.
- Brenner BM, Cooper ME, de Zeeuw D, et al; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861-869.
- Lewis EJ, Hunsicker LG, Clarke WR, et al; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851-860.
- Bilous R, Chaturvedi N, Sjølie A, et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann Intern Med. 2009;151(1):11-20.
- Mann JFE, Schmieder RE, Dyal L, et al; TRANSCEND (Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease) Investigators. Effect of telmisartan on renal outcomes: a randomized trial. Ann Intern Med. 2009;151(1):1-10.
- Haller H, Ito S, Izzo JL Jr, et al; ROADMAP Trial Investigators. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011;364(10):907-917.
- Lv J, Perkovic V, Foote CV, Craig ME, Craig JC, Strippoli GFM. Antihypertensive agents for preventing diabetic kidney disease. Cochrane Database Syst Rev. 2012;12:CD004136.
- Persson F, Lindhardt M, Rossing P, Parving H-H. Prevention of microalbuminuria using early intervention with renin-angiotensin system inhibitors in patients with type 2 diabetes: a systematic review. J Renin Angiotensin Aldosterone Syst. 2016;17(3):1470320316652047.