Microalbuminuria

Etiology

Microalbuminuria develops from a dysfunction of the GBM permitting albumin to enter the urine. The enzyme N-deacetylase is necessary to form heparan sulfate, which is how the GBM derives its negative charge. Furthermore, inadequate control of blood sugars inhibits this enzyme, reducing the negative charge on GBM and allowing excessive amounts of albumin to leak out.[4] Advanced glycosylation end-products can also neutralize the negative charge of albumin by binding with the proteins of both the GBM and mesangial matrix.[6] Additionally, hyperglycemia initiates the glycation of GBM and podocyte receptors interfering with the charge on GBM.[1][2][6]

The current hypothesis, known as the ‘Steno hypothesis,’ is that systemic vascular endothelial dysfunction initiates the development of microalbuminuria and cardiovascular disease, as there is a strong correlation between these three variables.[2][3][7][8] Therefore, having comorbidities that cause endothelial damage is considered a risk factor. These include increased age, insulin resistance, dyslipidemia, obesity, hypertension, decreased physical activity, and smoking.[5] Some studies predict a genetic component linking together microalbuminuria, atherosclerosis, and even nephropathy. An increased UAE rate was seen among patients with a deletion-deletion polymorphism of the ACE gene.[6]

Epidemiology

A study evaluating microalbuminuria in 22,244 patients (aged 6 to 80 years) reported a prevalence of 7.8%, especially in those older than 40 years. Women had a higher prevalence of 9.7%, whereas men had 6.1%.[2] Moreover, evidence shows that the prevalence increases with age. Regarding the age groups of 20 to 49, 50 to 69, and more than 70 years, the prevalence of microalbuminuria was 5.8%, 11.4%, and 22.7%.[7]

Microalbuminuria has been associated with patients who have type 1 or type 2 diabetes. For patients with type 1, the prevalence of microalbuminuria within the first three years after diagnosis is only 6%; however, after five years, it is 41%. In type 2, the prevalence is 20 to 25% for newly diagnosed and long-standing diabetics.[8][9] In patients with uncontrolled hypertension, microalbuminuria was seen in 47.4% of patients, whereas, in patients with controlled blood pressure, it was 36.7%.[10]

Pathophysiology

Microalbuminuria arises when GBM, a complex sieve, leaks an increased amount of albumin. The proposed mechanism is a combination of glomerular size enlargement, GBM thickening, mesangial expansion, and podocyte foot process effacement. Microalbuminuria can also occur via inadequate tubular reabsorption.[2][7]

Dysregulated enzymatic metabolism of the extracellular matrix is the pathogenesis behind developing endothelial damage.[3][8] Thus, at vascular places other than just the renal system, the albumin can either leak out of or enter the vessel wall. When this happens, albumin can stimulate inflammation, lipid accumulation, and atherosclerosis, which eventually could form fixed albuminuria and decreased kidney function.[7]

Histopathology

There are structural changes at the level of GBM that lead to microalbuminuria. However, these are heterogeneous and may even be present in patients with normoalbuminuric diabetes. The GBM alterations are typically seen in type 1 diabetes but not type 2.[8]

Furthermore, researchers found no correlation between increased GBM permeability and any histological changes. Since the majority of the GBM dysfunction is through altered charge selectivity, not size, it would not appear on histology.[2][8]

History and Physical

History Taking

Microalbuminuria, in itself, has not been associated with any specific symptoms. However, due to its link with diabetes, obesity, hypertension, and cardiovascular events, providers should focus on history and physical examination to assess for these complications. Specifically, paying attention to any personal or family history of renal, cardiac, and systemic diseases could reveal pertinent information. Additionally, patients with diabetes may present with symptoms of cardiac disease, vision difficulties, and urinary tract disorders. On physical exam, it is particularly important to evaluate for elevated blood pressure, abnormal cardiac exam, carotid pulse for bruits, and lower extremity swelling.[11]

The majority of patients do not have any symptoms, and microalbuminuria is picked up on routine laboratory testing that is carried out to evaluate systemic diseases, such as diabetes mellitus or hypertension, or when a well-person examination is conducted.[12]

As microalbuminuria occurs mostly in the absence of any serious underlying renal disease, more benign and common causes of microalbuminuria should be considered first. The following questions should be asked:

• Is this transient - This may be because of physical exertion and fever

• Is this orthostatic - Typically seen in tall, thin adolescents or people younger than 30 years, there is an association with severe lordosis; normal renal function and albuminuria are frequently less than 1 g/24 hours[13]

• Is nonrenal disease causing it, such as severe cardiac failure, sleep apnea - Normal renal function and albumin loss is less than 1 g/24 hours

• Are there any symptoms suggestive of nephrotic syndrome or significant glomerular pathology 

• Are there any changes in the appearance of urine, such as red/smoky, frothy; is there any correlation of this to a respiratory tract infection

• Is there ankle, periorbital, labial, or scrotal edema

• Has the patient ever been diagnosed with high blood pressure

• Is there a history of high cholesterol levels in the patient's blood

• Has the patient ever had a diagnosis of a multisystem disease or another glomerulopathy

• Is there a past or family history of any renal disease

• If the patient has diabetes mellitus, for how long; are there any complications, such as retinopathy

• Is a family history of diabetic nephropathy present

• Are there any multisystem inflammatory diseases present, such as systemic lupus erythematosus (SLE) or rheumatoid arthritis

• Are there symptoms like joint discomfort, skin rash, bone pain, fever, weight loss, night sweats, or Raynaud syndrome

• Is the patient on any medication, including herbal remedies

• Are there any past medical illnesses, such as jaundice, malaria, tuberculosis, syphilis, or endocarditis

• Is the patient at risk of HIV infection or hepatitis

Physical Examination

• Assessment of intravascular volume status is important - Take erect and supine blood pressure and pulse, examine the jugular venous pulse, and listen to heart sounds

• Examine for extravascular volume status - Look for edema, which may not be present in microalbuminuria; if there is a more significant loss, then weight gain and pleural effusions can be seen

• Assess the patient for the presence of systemic features, such as joint swelling or deformity, retinopathy, rash, signs of chronic liver disease, organomegaly, cardiac murmurs, and lymphadenopathy

• Look for complications of protein loss, such as venous thrombosis, although these may not be seen in microalbuminuria

Evaluation

The gold standard diagnostic test for the detection of microalbuminuria is a 24-hour urine collection as it has the lowest variability, but it is labor-intensive.[3][4] As described above, the UACR corrects urine concentration and volume but can vary due to other factors. The urine spot collection, on the other hand, changes depending on the urine volume.[3][5] Other alternatives have undergone development, but they have similar sensitivities to the 24-hour collection. These are immunoturbidimetry, immunonephelometry, enzyme-linked immunosorbent assays, immunoassays with latex bodies, radial immunodiffusion, and fluoroimmunoassay.[3][4]

As per the National Kidney Foundation and the European Society of Hypertension, in high-risk patients, screening with a UACR is required to evaluate for microalbuminuria and its potential complications. The high-risk patient population consists of the elderly, African Americans, Asians, patients with diabetes, patients with hypertension, and patients with a family history of chronic kidney disease (diagnosed at older than 60 years).[1][3][14] However, screening the general population still requires further evaluation to determine if it is beneficial.[14]

Furthermore, the American Diabetes Association recommends that this screening be repeated every year for type 1 diabetes (if the diagnosis is older than five years ago). As for patients with type 2 diabetes and diabetic nephropathy, the recommendation is also every year, but it should start following the initial diagnosis.[1]

Laboratory investigations should include a basic metabolic panel (to evaluate for decreased GFR, increased creatinine, and electrolyte imbalances) and a complete white count (for leukocytosis). Other blood tests to be considered for the assessment of associated conditions are blood sugars, hemoglobin A1c, lipid panel, and troponins. Additionally, ultrasound is an option to look for renal and urinary abnormalities. Renal biopsies are rare because of the procedural side effects, and there are no evidence-based recommendations for indications to acquire one.[11]

Evaluation of microalbuminuria is carried out in outpatient clinics unless there is a complication. All patients with impaired renal function or evidence of glomerulopathy should be seen by a nephrologist. The urine dipstick can primarily detect albumin. Albuminuria is observed in glomerular proteinuria. Some factors can lead to false-positive results, such as the recent use of iodinated radiocontrast agents, gross hematuria, and alkaline urine. The normal content of urinary protein is less than 150 mg/day.

Screening for microalbuminuria can be carried out by doing early morning spot protein or urinary albumin-to-creatinine ratio. If there is significant proteinuria a 24-hour urine collection must be done. This ratio or spot albumin can also be used for follow-up. If the ratio increases significantly, it becomes advisable to do the 24-hour urine collection.[15][16][17]

Proteinuria/microalbuminuria can be transient. To determine whether it is transient in nature, the following steps should be taken:

• Urinalysis and microscopy on 3 separate occasions

• Albumin-to-creatinine ratio in a random spot urine sample

• Urinalysis of an early-morning urine sample before any physical activity

To establish whether it is a case of orthostatic proteinuria, the following should be performed:

• Urine microscopy

• Urine collection on two occasions - Daytime (between 7 am and 11 pm) and overnight (between 11 pm and 7 am) 

In order to determine the cause of albuminuria as the underlying glomerular disease, the following should be done:

• Urine microscopy – Presence of dysmorphic red blood cells/casts

• 24-hour urine collection for the quantification of albumin excretion

• Serum creatinine, blood glucose, albumin, and cholesterol

• Autoantibody panel - If indicated by the clinical picture, test for antinuclear antibody (ANA), antistreptolysin O titers, anti-DNA antibodies, antineutrophil cytoplasmic antibodies (ANCA), cryoglobulins, anti-glomerular basement membrane (anti-GBM) antibodies, and complement levels (C3 and C4) 

Imaging studies in albuminuria may include the following:

• Renal ultrasonography – To establish glomerular disease as the cause of microalbuminuria, it is imperative to look at the echogenicity and size of the kidneys[18]

• Chest X-ray or computed tomography (CT) scan – If guided by the clinical picture

Treatment / Management

If microalbuminuria is present, aggressive measures should ensue with the ultimate goal of decreasing the risk of cardio-metabolic complications.[1] The first-line treatment is lifestyle modification to control diabetes and hypertension. Although it seems trivial, this can save retinal function, prevent further kidney damage, decrease the risk of cerebrovascular accidents, and reduce microvascular complications.[5] For patients with type 2 diabetes with microalbuminuria, reports indicate that a normal protein diet of (0.8 g x kg)/(bodyweight x day) was optimal, not a low protein diet.[19] Interestingly, eating chicken instead of red meat saw a reduction in urinary albumin excretion of 46%, along with decreasing total cholesterol and apolipoprotein B in type 2 diabetic patients with microalbuminuria.[11]

Maintaining an A1c of less than 7% has been shown to decrease the risk of developing not only microalbuminuria but also macroalbuminuria. The evidence shows that rosiglitazone and insulin have the best outcomes and the least side effects.[11] Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), or vasodilatory beta-blockers can reduce blood pressure. Although many providers commonly believe that ACE inhibitors and ARBs are interchangeable in the treatment method, some data do not support the effectiveness of ARBs.[5] These classes of drugs have an effect on reducing proteinuria, separate from their antihypertensive effect.[20] In patients younger than 50 years, the blood pressure goal should be 120/70-75 mm Hg, whereas it is slightly higher at 125-130/80-85 mmHg in those older than 50. Moreover, ACE inhibitors are useful in patients with diabetes, even without hypertension. They have a reno-protective effect of decreasing mesangial expansion and preventing the onset of glomerulosclerosis.[6][11][21] The other anti-hypertensives help manage hypertension but have minimal effect in delaying the progression of kidney disease.[3][22] Normalization of blood pressure in hypertensive patients results in a decrease in intraglomerular pressure and albuminuria.[23](A1)

If treatment with an ARB or ACE inhibitor does not sufficiently control proteinuria in patients with chronic kidney disease, further control of proteinuria can be done by adding mineralocorticoid receptor antagonists (MRA), such as spironolactone or eplerenone. However, MRAs are associated with an increased risk of hyperkalemia. A new agent, finerenone, which is a nonsteroidal MRA, decreased proteinuria while causing lower rates of hyperkalemia.[24](A1)

Immunosuppressants, such as cyclophosphamide and azathioprine, should be used in patients who have progressive renal insufficiency or who have vasculitic changes on renal biopsy.[25]

Several experimental drugs show promising evidence but require further studies to evaluate if they decrease the long-term cardiovascular disease associated with microalbuminuria. For one of the groups, the mechanism is by decreasing protein glycation. These medications are thiamine, ALT-711 (a cross-link breaker of advanced glycation), and pimagedine (a second-generation inhibitor of advanced glycation). Additionally, ruboxistaurin, a protein kinase C-beta inhibitor, has been implicated in decreasing UAE.[11] Increased vascular endothelial growth factor (VEGF), which regulates vascular permeability and angiogenesis, has been linked with microalbuminuria in patients with type 2 diabetes. Thus, VEGF inhibitors could be helpful in patients with microalbuminuria.[8] Glycosaminoglycans, such as sulodexide, can also decrease albuminuria.[3] Statins, on the other hand, have a well-documented effect in reducing the risk of cardiovascular disease, but their role in decreasing urinary albumin excretion is still controversial. Due to its cardioprotection, it merits inclusion in the treatment regimen.[3]

When considering the associated comorbidities with microalbuminuria, the treatment recommendations should also include weight loss, aspirin, and maintaining low-density lipoprotein cholesterol of less than 100.[11] Finally, the level of microalbuminuria can serve as an indicator of treatment response, especially in patients with hyperinsulinemia, insulin resistance, and hypertension.[1][3]

In terms of specific treatments, sodium-glucose co-transporter 2 (SGLT2) inhibitors, such as canagliflozin and empagliflozin, have gained popularity not only in the management of diabetes mellitus but also in reducing the development or further worsening of albuminuria.[26] A meta-analysis observed that combination therapy with SGLT2 inhibitors and other hypoglycemic agents helps reduce albuminuria.[27](A1)

Non-dihydropyridine calcium channel blockers (NDCCBs), such as diltiazem and verapamil, decrease proteinuria more than dihydropyridine calcium channel blockers (DCCBs) because NDCCBs affect both the afferent and efferent arteriole.[28][29](A1)

Endothelin activation has an association with renal inflammation and fibrosis. Endothelin A (ETA) receptor blockade leads to the dilation of the glomerular capillaries, reducing albumin permeability. Endothelin B (ETB) reduces arterial pressure by decreasing salt and water reabsorption from the kidneys. Experimental ETA-selective antagonists, such as avosentan and atrasentan, have been shown to decrease proteinuria.[30][31](A1)

Differential Diagnosis

Microalbuminuria can present in various diseases, kidney-related and non-kidney related.[6] Notably, it has been proposed to be an acute phase reactant and subsequently increases during inflammation, especially ischemia, reperfusion, burns, trauma, sepsis, and surgery. Organ-specific inflammatory conditions that have correlations with microalbuminuria are periodontitis, obstructive respiratory disease, hepatitis, bowel disease, pancreatitis, rheumatoid arthritis, and psoriasis.[4][5][7] Furthermore, increased toll-like receptor 4 is found to be associated with microalbuminuria and diabetic kidney disease. Thus, the hypothesis is that inflammation activates further disease progression.[32]

Moreover, microalbuminuria coinciding with third-trimester pregnancies could indicate the future sequelae of pre-eclampsia.[4]

Prognosis

The main reason to test the UAE level is to evaluate the patient for possible future complications. However, providers should not merely view microalbuminuria as a kidney damage marker but as a predictor of kidney dysfunction progression rate and reflect the effect of systemic disorders on the kidney.[1]

It is well known that the glomerular filtration rate (GFR) is useful in staging chronic kidney disease. In comparison to microalbuminuria, GFR is a pure kidney damage marker. Several studies have demonstrated that there is a continuous correlation between microalbuminuria and developing end-stage renal disease. Therefore, when presented with a patient with a reduced GFR classified under stage 3 or 4, the patient with microalbuminuria should be considered very high risk instead of high risk as per the GFR. This classification ensures that prompt action is taken to prevent further complications, such as macroalbuminuria, diabetic kidney disease, proteinuria, and chronic kidney disease.[5]

Microalbuminuria has links with a high rate of atherosclerotic cardiovascular events (such as coronary artery disease, stroke, and peripheral vascular disease) and subsequently increased morbidity and mortality. The evidence reveals in adults, it is a four to six-fold increase, whereas, in patients with diabetes, it is only two-fold.[3][5][6][9] The risk of cardiovascular events is even higher for patients with macroalbuminuria versus microalbuminuria. Thus, screening and compliance with the treatment of microalbuminuria could prevent macroalbuminuria and even death.[3][6] The UACR range for microalbuminuria starts at 2 mg/day, but data shows that the risk between increased UAE and cardiovascular disease can begin even at 1 mg/day.[3]

Among patients with essential hypertension, microalbuminuria can predict kidney function decline, coronary artery stenosis, and hypertensive retinopathy. Importantly, the latter two are reversible with adequate treatment.[5]

Complications

With progressive disease, patients can develop macroalbuminuria, diabetic kidney disease, and proteinuria.[1] The level of serum albumin is unable to predict the nutritional status of a patient. However, during states of extreme starvation, serum albumin is low, and urine albumin is high.

Other complications of proteinuria are:

• Pulmonary edema, which is attributable to fluid overload

• Acute kidney injury secondary to intravascular depletion and progression of kidney disease

• Increased risk of cardiovascular diseases

• Increased risk of vascular thromboses, such as renal vein thrombosis

• Increased risk of bacterial infections