The main functions of albumin are to maintain plasma oncotic pressure via its negatively charged surface and colloidal nature, provide nutrition to renal tubular cells, and serve as an antioxidant. Hepatocytes produce approximately 10-15 g of albumin daily, which is regulated by the interstitial colloidal pressure. Albumin exits the blood and is reabsorbed by the lymphatic system at a rate of 4.5% per hour.
There are many barriers to albumin within the nephron’s glomerular filtration system. At physiological pH, the glomerular capillary wall and endothelial cells repel albumin, as they are all negatively charged. The glomerular basement membrane (GBM) is a porous system, but normally these exits are too small to permit passage of albumin. Additionally, the megalincubulin complex degrades albumin in the nephron, specifically the proximal convoluted tubule. The underlying function is to preserve amino acids for further use but is also another method of restricting albumin’s passage.
Through the dysfunction of the GBM filtration barrier, albumin can be secreted into the urine, and the amount that is present is important. The current definition of microalbuminuria (MA) is an amount of urinary albumin greater than the normal value, but also lower than what is detected by a conventional dipstick. Thus, microalbuminuria’s range of urine albumin excretion (UAE) rate is 30 to 300 mg/d. This value derives from studies that evaluated adults but could also apply to the pediatric population. Macroalbuminuria, on the other hand, is classified as greater than 100 mg/12h or 300mg/d. The diagnosis of diabetic kidney disease requires a person with type 1 or 2 diabetes to have a persistently elevated albuminuria (>300mg/d), diabetic retinopathy, and the absence of other kidney diseases. Finally, proteinuria is increased urinary excretion of any type of protein.
The current diagnosis of microalbuminuria also includes patients who have testing with a urinary albumin/creatinine ratio (UACR), where the range is between 2 to 20 mg. By including creatinine, it corrects the value for urine concentration and volume. However, other factors can affect the level of UACR, including gender, race, blood pressure, time of day, muscle mass, and amount of food, water, and salt intake. Thus, the UACR can vary by up to 40% daily. In addition to the individual variability, one should be cautious that males, African Americans, Asians, smokers, higher muscle mass, urinary tract infection, and genital leakage have an elevated UACR at baseline. Due to the considerable variation, one should obtain three UACR measurements that are each one month apart.
Microalbuminuria develops from a dysfunction of the GBM to allow 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 GBM’s negative charge and allowing excessive amounts of albumin to leak out. Advanced glycosylation end-products can also chelate with the proteins of both the GBM and mesangial matrix, thereby neutralizing albumin’s negative charge. Additionally, hyperglycemia initiates the glycation of GBM and epithelial cells’ podocyte receptor causing GBM charge selectivity dysfunction.
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. 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. 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.
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. Females had a higher prevalence of 9.7%, whereas males had 6.1%. Moreover, evidence shows that the prevalence increases with age. Regarding the age groups of 20 to 49, 50 to 69, and >70 years, the prevalence of microalbuminuria was 5.8, 11.4, and 22.7%.
Microalbuminuria has been associated with type 1 and type 2 diabetics. 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. In patients with uncontrolled hypertension, microalbuminuria was seen in 47.4% of patients; whereas, in patients with controlled blood pressure was 36.7%.
Developing microalbuminuria arises when the GBM barrier, 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 tubular under-reabsorption.
Dysregulated enzymatic metabolism of the extracellular matrix is the pathogenesis behind developing endothelial damage. 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.
There are structural changes at the level of GBM, as described above, with 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.
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 appear on histology.
Microalbuminuria, in itself, has not been associated with causing specific symptoms. However, due to its link with diabetes, obesity, hypertension, and cardiovascular events, patient history and physical examination should focus on evaluating these complications. Specifically, paying attention to any personal or family history of kidney, cardiac, and systemic diseases could reveal pertinent information. Additionally, diabetic patients 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.
The gold standard diagnostic test is a 24-hour urine collection as it has the lowest variability, but it is labor-intensive. As described above, the UACR corrects for urine concentration and volume but can vary through other factors. The urine spot collection, on the other hand, changes depending on the urine volume. Other alternatives have undergone development, but they have similar sensitivities to the 24-hour collection. These are immunoturbidimetry, immunonephelometry, enzyme-linked immunosorbent assays, immunoassay with latex bodies, radial immunodiffusion, and fluroimmunoassay.
As per the National Kidney Foundation and European Society of Hypertension, in high-risk patients, screening with a UACR is required to evaluate for microalbuminuria and potential complications. The high-risk patient population consists of the elderly, African Americans, Asians, diabetics, hypertensives, and a family history of chronic kidney disease (diagnosed at older than 60 years). However, screening the general population still requires further evaluation to determine if it is beneficial.
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 type 2 diabetics and diabetic nephropathy, the recommendation is also every year, but it should start following the initial diagnosis.
Laboratory investigations should include basic metabolic panel (to evaluate for decreased GFR, increased creatinine, and electrolyte imbalances) and complete white count (for leukocytosis). Other ones to consider obtaining are blood sugars, hemoglobin A1c, lipid panel, and troponins. Additionally, ultrasound is an option to look for signs of kidney 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.
If microalbuminuria is present, aggressive measures should ensue with the ultimate goal of decreasing the risk of cardio-metabolic complications. The first-line treatment is lifestyle modifications to control diabetes and hypertension. Although it seems trivial, this can save retinal function, prevent further kidney damage, decrease stroke risk, and decrease microvascular complications. For type 2 diabetics 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. Interestingly, eating chicken, instead of red meat, saw a urinary albumin excretion decrease of 46% along with decreasing total cholesterol and apolipoprotein B in type 2 diabetic patients with microalbuminuria.
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 benefits and the least side effects. Angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or beta-blocker vasodilators can reduce blood pressure. Although many clinicians commonly believe that ACE inhibitors and ARBs are interchangeable in the treatment method, some data does not support the effectiveness of ARBs. In patients younger than 50 years, the blood pressure goal should be 120/70-75 mmHg, whereas it is slightly higher at 125 to 130/80 to 85 mmHg in those older than 50. Moreover, ACE inhibitors are useful in diabetic patients, even without hypertension. They have a reno-protective effect of decreasing mesangial expansion and preventing the onset of glomerulosclerosis. The other anti-hypertensives help manage hypertension but have some to minimal effect in delaying the progression of kidney disease.
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), pimagedine (a second-generation inhibitor of advanced glycation). Additionally, ruboxistaurin, a protein kinase C-beta inhibitor, has been implicated in decreasing UAE. Increased vascular endothelial growth factor (VEGF), which regulates vascular permeability and angiogenesis, has been linked with microalbuminuria in type 2 diabetic patients. Thus, VEGF inhibitors could be helpful in patients with microalbuminuria. Glycosaminoglycans, such as sulodexide, can also decrease albuminuria. Statins, on the other hand, have a well-documented effect in reducing the risk of cardiovascular disease, but its role in decreasing urinary albumin excretion is still controversial. Due to its cardioprotection, it merits inclusion in the treatment regimen.
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. Finally, the level of microalbuminuria can serve as an indicator of treatment response, especially in patients with hyperinsulinemia, insulin resistance, and hypertension.
Microalbuminuria can present in various diseases, including kidney-related and non-kidney related. 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. Furthermore, increased toll-like receptor 4 was associated with microalbuminuria and diabetic kidney disease. Thus, the hypothesis is that inflammation activated further disease progression.
Moreover, microalbuminuria coinciding with third-trimester pregnancies could indicate the future sequelae of pre-eclampsia.
The main reason to test the UAE level is to evaluate the patient for possible future complications. However, clinicians 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.
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 the physician and patient undergo rapid action to prevent further complications, such as macroalbuminuria, diabetic kidney disease, proteinuria, and chronic kidney disease.
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 people with diabetes, it is only two-fold. The risk of cardiovascular events is even higher for patients with macroalbuminuria versus microalbuminuria. Thus, screening and treatment compliance during MA could prevent macroalbuminuria and even death. The UACR range for microalbuminuria starts 2 mg/day, but data shows that the risk between increased UAE and cardiovascular disease can begin even at 1 mg/day.
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.
With progressive disease, patients can develop macroalbuminuria, diabetic kidney disease, and proteinuria. 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.
Due to the possible complications with microalbuminuria, when it is present on labs, one should order further laboratory workup to evaluate the cardiac, renal, and systemic systems. If these values are also concerning, one should consider consulting nephrology or cardiology. When the clinician diagnoses type 2 diabetes, they should refer the patient to nephrology and ophthalmology.
The evaluation and treatment of microalbuminuria require the involvement of the patient. They should understand the importance of compliance with follow-up visits, screening guidelines, lifestyle modifications, and medication regimen.
Along with patient education, physicians must understand the drastic implications of microalbuminuria. Strongly advising their patients to be compliant with the recommendations has been shown to prevent future complications, decrease morbidity and mortality, and improve quality of life.
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