Definition and introduction

Microclbuminuria is traditionally defined as an increase in urinary albumin too subtle to be measured by chemistry sticks for total protein. With improved methodology, these low levels of albumin (20-200 ug/min, 30-300 mg/24h or 20-200 mg/l) can now be measured.

Microalbminuria is considered a clinically improtant indicator of deteriorating renal funcation in diabetic and hypertensive patients. In these patients, the microalbuminuria phase is followed by progressive incarease in urinary protein excretion and declining glomerular filtration rate, This results in chemistry stickpositive proteinuria, known as overt nephropathy or macroproteinuria.

Without treatment, the patient will develop uraemia and require referral to end-stage renal-failure programmes such as dialysis or transplantation. Microalbuminuria has also proved to be a strong independent predictor of atherosclerotic disease, cardiovascular mortality and overall mortality. Increased urinary albumin excretion signals an increase in the transcapillary escape rate of albumin and is therefore a marker of microvascular disease.

Onset of microlbuminuria (increase in urinary albumin excretion beyond the lower limit of microalbminuria) is the most significant single predictor of progressive microvascular disease and macrovascular disease (nephropathy, atherosclerosis, coronary disease, retinopathy). The association of microlbuminuria with cardiovascular disease might be explained by endothelial dysfunction, hypertension abnormalities in lipid metabolism, insulin resistance and protein glycosylation. THe exact mechanisms responsible for these associations have been elucidated to some extent but many remain to be characterised.

Pathogenesis

General

The development of microalbuminuria probably involves both metabolic and haemodynamic factors affecting renal microcirculation. On the one hand, sustained hypertension is known to cause transcapillary escape of proteins, such as albumin, by increasing the intraglomerular pressure. On the one hand, metabolic disorders directly affect the glomerular basement membranes and their permselectivity, thereby altering glomerular function and, ultimately, causing golmerular sclerosis. These separate mechanisms are differently emphasised in different diseases, which should be taken into account in planning therapy.

Haemodynamic aspects

Glomerular hydrostatic Pressure is normally regulated by the relative vasoconstriction-vasodilation of the blood vessels leading to and from the glomerulus (afferent and efferent arterioles).

Defects of this authoregulatory function may lead to increased glomerular hydrostatic pressure and increased urinary albumin excretion or microalbuminuria. In salt-sensitive hypertension, salt intake disturbs renal blood flow, resulting in raised intraglomerular pressure. Indeed, salt sensitivity is more common among groups of hypertensive patients with an increased susceptibility to develop renal failure (black, obese, elderly and diabetic patients).

Figure2. Picture showing the glomerulus with permeable walls. The afferent arterioles feed the blood into the Bowman's capsule to be filtered. The glomerulus filters the blood, and the efferent arterioles transport the filtered blood capsule to the medula. The glomerular fitrate pass down the tubule and reaches eventually the bladder.

Metobolic aspects

As diabetes mellitus is a state chronic hyperglycaemia, it is proble that glucose contributes to diabetic nephropathy. Urinary albumin excretion is dependnt on both renal haemodynamics and the permselectivity of he glomerular basement membrance. Microalbuminuria could also be due to a loss of the anionic charge of the glomerular basement membrane. THis has been observed in diabetic patients, in whom advanced glycosylation end neutralise the concurrent increase in the transmembrane passage of albumin. In type 1 with the deposits of AGE products. The risk of microalbuminuria has been found to increase with the amount of glycosylated haemoglobin HbAc, in blood. Recent studies have also indicated an association between microlbumin uria and impaires glomerular charge selectivity in healthy individuals.

Metabolic syndrome

Microalbuminuria often occurs together with the metabolic syndrome consisting of hyperinsulim aemia and insulin resistance, increased triglyceride and decreased high-density lipoprotein (HDL) levels, hyperglycaemia for diabetes but they have also been observed in nondiabetic and prediabetic individuals.

THe roles of hypertension and hyperglycaemia in this context have been discussed above, whereas the exact causal relationships between the other factors and microalbumuminuria have not been established. It is known, howerever, that all of these factors are independently associated with microalbuminuria and progressive renal disease. THe metabolic syndrome as an entity has also been albuminuria in diabeti patients.

Table 2. Charaterisation of Metabolic syndrome

Hyperinsulinanaemia

Insulin resistance

Serum triglcerides

Serum HDL cholesterol

Blood glucose

Hypertension

Clinical significance

General

The measurement of albumin excretion gives an estimate of glomerular integrity (Including the function of tubular reabsorption). It is not clear whether m microalbuminuria itself contributes to the deterioration of renal function, but recent evidence suggests that it could in fact be purely a manifestation of nephropathy. Nevertheless, microalbuminuria is a reliable indicator of a risk of progressive renal and cardiovascular disorders. In addition, a decrease in microalbuminuria indicates a positive response to the chose line of therapy.

Microalbuminuria is a reliable risk indicator for renal and cardiovascular disorders. By measuring microalbuminuria one can monitor the patients's response to the chosen line of therapy.

Diabetes mellitus

The appearance of microalbuminuria is the first sign of nephropathy. Patients with persistent microalbuminuria are referred to as having incipient nephropathy. Hyperfiltrations is the first detectable alteration in renal funcation in the course of diabetic renal disease and occurs sson after the emergence of microalbuminuria. Urinary albumin excretion persistently exceeding 20ug min represents a 20-fold increased risk for the development of clincally overt renal disease in patients with type 1 or 2 diabetes.

Furthermore, increased urinary albumin excretion precedes and is highly predictive of diabetic nephropathy, end-stage renal disease and advanced nephropathy in type 1 diabetes. Half of patients with type 1 diabetes with overt nephropathy develop end-stage renal disease within 10 years and over three-quarters within 20 years.

Microalbuminuria precedes and is highly predictive of diabetic nephropathy and end-stage renal disease.

Without specific treatment,20-40% of type 2 diabetic patients with microalbuminuria progress to overt nephropathy but only~20% developend-stage renal disease within 20 years of the onset of overt begins to fall, the speed of the decrease is highly variable from one individual to another, but there may be no overall difference patients with type 2 diabetes.

In addition to being the first manifestation of nephropathy, albuminuria is a prognostic marker for greatly increases cardivascular morbidity and mortatlity in patients with microalbuminuria should be screened for vascular disease and receive active therapy to reduce all cardiovascular risk factors, including lowering of blood cholesterol. The joint occurrence of microalbuminuria and the components of the metabolic syndrome is particularly common among patients with type 2 albumin excretion is a strong independent predictor of progressive renal disease, atherosclerotic disease, cardiovascular mortality and overall mortality. Conversely insulin resistance has been suggested to predict an elevation in urinary albumin excretion and to precede microalbuminuria. Interestingly, approximately 20% of patients with type 2 diabetes and end-stage renal disease have a nondiabetic from of renal disease caused by other components of the metabolic syndrome.

Albuminuria is a prognostic marker for increased cardiovascular morbidity and mortality in patients with type 1 or 2 diabetes.

Patients with microalbuminuria should receive active therapy to reduce all cardiovascular risk factors, including lowering of blood cholesterol.

The clinical challenge lies in identifying the high risk individuals and developing effective measures to prevent end-stage renal disease. This is highly relevant, as type 2 diabetes may be preventable, and good control of blood glucose and blood pressure has been founf to prevent renal complications in the two main types of diabetes. As mentioned above, the effectiveness of anyrenoprotective treatment may be evaluated by monitoring the rate of urinary albumin excretion.

Reduced proteinuria is strongly correlated with reduced progression to end-stage renal disease.

Table 3. Stages of diabetic nephropathy.

Stage	Characteristics
Normoalbuminuria	Urinary albumin excretion normal(<20ug/min)
Microalbuminuria Incipient diabetic nephropathy	Urinary albumin excretion increases (20-200 ug/min) Persistent microalbuminuria (microalbuminuria in at least two out of three measurements within 6months) hyperfiltration, blood pressure elevation
Early overt diabetic nephropathy	Clinical proteinuria (urinary albumin excretion>200ug/min in two out of three measurements with in 6 months or dipstick-positive proteinuria). Hypertension.
Advanced diabetic nephropathy	Progressive proteinuria Hypertension Declining glomerular filtration rate (decreased creatinine clearance)
End-stage renal disease	Uraemia Nephrotic syndrome Need for renal replacement therapy (transplantation or dialysis)

Hypertension and cardivovascular disease

There is an association between hypertension and albumin excretion even in the absence of diabetes. As in diabetes, only 40% or less of patients with essential hypertension develop microalbuminuria, and these are not necessarily the ones with the highest blood pressure levels. Hypertensive patients who develop microalbuminuria often have salt-sensitive hypertension, a habit of smoking and several metabolic and haemodynamic abnormalities belonging to the metabolic syndrome. The detection of microalbuminuria in essential hypertension is imporatant in that it identifies a subgroup of hypertensive individulas at higher risk of targetorgan damage. This allows measures to be undertaken fot the prevention of complications such as hypertensive nephropathy.

Hypertensive individuals should be screened for microalbuminuria to identify those at higher risk of target-organ damage.

Microalbuminuria has been found to be associated with cardiovascular risk factors, cardiovascular events and mortality even in nondiabetic subjects. The prevention and treatment of cardiovascular diseases is an adequate management of diabetes, especially in patients with type 2 diabetes. Available evidence suggests that although risk factors such as hypertension and hypercho lesterolaemia are known to cause cardiovascular diseases, microalbuminuria may in fact be a better indicator of established microvascular damage and a better predictor of cardiovascular events. Studies have found a direct relationship between urinary albumin excretion and fasting insulin levels, on the one hand, and angiographic evidence of coronary artery disease, on the other. In nondiabetic patients, microalbuminuria probably reflects not renal but more generalished vascular damage.

In nondiabetic patients, microalbuminuria is associated with cardiovascular risk factors and increased mortality.

Additional implications

Pre-eclampsia in pregnancy.

The incidence of pre-eclampsia is substantially increased in diabetic pregnancies, leading to higher maternal and perinatal morbidity and mortality. Prepregnancy microalbuminuria has been suggested to predict pre-eclampsia in patients with type 1 diabetes. In high-risk pregnant women without diabetes, microalbuminuria has been found to be highly predictive of hypertensive complications and signigicantly correlated with birth weight.

Cancer chemotherapy

Nephrotoxicity is an adverse effect of certain anticancer drugs, and suceddful treatment of malignant disease can in fact be limited by such toxicity. Chemotherapy-induced renal dysfunction generally involes damage to renal vasculature or structures, heamolytic uraemic sundrome and prerenal perfusion deficits. Microalbuminuria has been considered a senitive indicator of glomerular damage, whereas serum cystatin C measurements appear to be a sensitive method of detecting early reduction in glomerular filtration rate. Microalbuminuria has been reported to be useful in detecting early glomerular damage during cisplatin therapy. Ifosamide regimens have also been monitored using urinary protein excretion measurements. Detection of early impairment in renal function allows more precise adjustment of the doses of chemotherapeutic agents.

Acute infectious nephritis

The use of tests for microalbuminuria have also been proposed for long-term follow-up after episodes of acute infectious nephritis.

Screening, Monitoring and treatment

Method

Screening for microalbuminuria can be performed by three methods. (1) measurement of albumin concentration in first-void morining urine or measurement of the albumin-to-creatinine ratio in a random spot; (2) 24-hour urine collection with creatinine measurement, allowing simultaneous determination of creatinine clearance; and (3) timed (e.G. 4-hours to overnight) urine collection. THe first method is often found to be the easiest to carry out at a doctor's office and generally provides accurate information. Firstvoid or other morning collections are preferred because of the diurnal variation in albumin excretion. If such timing cannot be used, it is nevertheless important to observe uniform timing when collecting samplles from the same individual. Specific assays are needed to detect microalbuminuria because standard hospital laboratory assays for urinary protein are not sufficiently sensitive. Microalbuminuria is said to be present if urinary albumin excretion is>30mg/24h, which is equivalent to 20 ug/min or 20 mg/1 (Table 1).

Variability and interference

The rate of urinary albumin excretion depends significantly on physiological parameters and is also rather sensitive to interfering factors. The intraindividual variation (CV%) in urinary albumin excretion is 30-50% and the corresponding diurnal variation (CV%) is 50-100%.

Table 4. Definitions of abnormalities in albumin excretion.

Category

24-h collection

(mg/24h)

Timed collection

(ug/min)

Spot collection

(ug/mg creatinine)

Normal

Microalbuminuria

Clinical albuminuria

<30

30-299

>300

<20

20-199

>200

<30

30-299

>300

Because of variability in urine albumin excretion, two of three speciments collected within a 3-to6- month period should be abnormal considering a patient to have crossed one of these diagnostic thresholds. Exercise within 24h, infection, fever, congestive heart failure, marked hyperglycemia, marked hypertension, pyuria, and hematuria may elevate urinary albumin excretion over baseline values.

In diabetic nephropathy patients 20-50% average increases from night to day-time in albumin excreation has been reported. Samples should not be collected after exertion, in the presence of urinary tract infection, during acute illness, immediately after surgery or even after an acute fluid load. Furthermore, tubular and postrenal causes of albuminuria need to be borne in mind Upright posture, diuresis, short-term hyperglycaemia, exercise, urinary tract infections, marked hypertension, heart failure and acute febrile illness can cause transient elevations in urinary albumin excretion. Tests for microalbuminuria should be done on at least two to three occasions, two of which should be positive to permit a diagnosis of microalbuminuria.

Diagnosis of microalbuminuria is based on two to three positive microalbuminuria tests on different occasions.

Diabetes

All patients with type 1 or type 2 diabetes should be annually screened for microalbuminuria If a positive result for microalbuminuria is obtained in a type 1 diabetic, the patients is obtained in a type 1 diabetic, the patient's treatment should be intensified to diminsh urinary albumin excretion and to half further deterioration or renal function (Figure 1).

In type 2 diabetics, microalbuminuria is a significant indicator of increased cardiovascular risk. The level of microalbuminuria should be measured every two to three months until a plateau is reached. The action required after the detection of microalbuminuria in a diabetic patient consists of four approaches, as explained below.

The level of diagnosed microalbuminuria should be measured every two to three months.

Figure3. Screening for microalbuminuria

*In type 1 diabetes, screening for microalbuminuria should begin after 5 years disease duration.

Reprinted with permission from the American Diabetes Association

Actions after deection of microalbuminuria

First, the effective management of blood glucose concentration is fundametal. Hyperglycaemia is believed to directly damage the glomerular basement membranes by inducing AGE product formation. According to several major trials, retinopathic, nephropathic and possibly neuropathic complications can be reduced by lowering blood glucose levels with intensive therapy The UK Prospective Diabetes Study trial (UKPDS) achieved a median HbAc of 70%, compared with a median HbAc of 7.9% with conventional therapy, and a 25% reduction in the overall microalbuminuria complication rate.

Second, hypertension should be optimally treated. The target blood pressure for diabetic patients with microalbuminuria is 125-130/75-80 mmHg, and these demanding targets should be rigorously pursued. The UKPDS showed that lowering bllod pressure to a mean of 144/82 mmHg significantly reduced strokes, diabetes-related deaths, heart failure, microvascular complications and visual loss. Angiotensin-converting enzyme (ACE) inhibitors, which have been found to decrease urinary albumin excretrion, are currently considered to be the first line of medication in hypertensive patients with diabetes. According to several major trials, ACE inhibitors are effective in not just decreasing blood pressure and proteinuria but also in slowing down the deterioration of glomerular filtration rate in microalbuminuric and protinuric patients. The greater antiproteinuric actio of AGE inhibitor as compared with other antihypertensive agents appears to be due to selective vasodilation of the offerent glomerular arterioles and a consequent decrease in intraglomerular hydrostatic pressure. However, a direct effect of these drugs on the permselectivity of the glomerular basement membrance cannot be ruled out. In cases wehere a satisfactory blood pressure response is not obtained by an AGE inhibitor alone, Diuretics and / or calcium channel blockers amy be added to the therapeutic regimen.

Thired, the patient should be encouraged to give up smoking. Smoking carries an additional independent risk of both diabetic and nondiabetic progressive renal disease, as well as worsening patients' prognosis. Smoking is also associated with an increased risk of microalbuminuric and doubling of the rate of progression to end-stage renal disease, whereas stopping smoking has been reported to reverse these processes.

Foutth, the intake of dietary protein should be restricted because such a dietary modification appears to significantly decrease urinary albumin excretion in type 1 diabetes and to slow the rate of decline of renal function. THis is best achieved in co-operation with a nutritionist.

Table 5. Summary of actions after detection of microalbuminuria.

Measures to halt the progression of microalbuminuric	Target
1. Effective control of gluvose matabolism
2. Effective treatment of hypertensionwith ACE inhibitors and, as reguires with diuretics and calvium vhannel blockers	Bllod pressure target 125-130/75-80mmHg
3. Stopping smoking
4. Intake of dietary protein should be restricted

Hypertension

The detection of microalbuminuric in essential hypertension is important in that it identifies a subgroup of hypertensive individuals at higher risk of target-organ damage. These patients typically have several proven and modifiable risk factors for vascular and metabolic complications, such as obesity, hyperlipidaemia and glucose introlerance. Therefore, efforts should be aimed at treating the primary disease as effectively as possible (target blood pressure 130/180mmHg). Research evidence makers ACE inhibitors the first line of medication in this context. ACE inhibitors have been demonstrated to significantly reduce progression from macroproteinuria to overt proteinuria and from nephropathy to end-stage renal disease even in patients without diabetes. They have also been shown to reduce the risk for cardiovascular events without increasing diabetes-related adverse effects (c.f. the unfavourable effects of calcium channel blockers and beta blockers on glycaemic control.

Correction of the other above-mentioned abnormalities by lifestlye modification and/or pharmacological means, together with the management of blood pressure, is effective in reducing the incidence of nephropathy, diabetes and cardiovascular disease.

Patients with hypertension and macroproteinuria should aim for pressure levels of 130/80 mmHg.

ACE inhibitors significantly reduce progression from macroproteinuria to evert proteinuria. Reduction in urinary albumin excretion has been conclusively associated with improved prognosis regarding development of nephropathy and other micro-and macrovascular complication.

In contrast to diabetes, there are so far no exact guidelines on the course of action in the case of macroproteinuria in nodiabetic hypertension. It has yet to be established whether correction of macroproteinuria as such affords further protection against cardiorenal complications. Nonetheless, macroproteinuria should alert the physician to search for other risk factors and use effective therapies to reduce the chances of those risks resulting in clinical manifestations.

Economic aspects

Nearly 33% of patients with diabetes mellitus develop renal complications, including end-stagedevelop renal failure. in the United States, diabetic kidney disease is the most common cause of end-stage renal failure. These patients may require dialysis or renal transplantation, both of which are expensive and may signigicantly impair the patient's quality of life. The cost of screening for macroproteinuria has been calculated to be $2.06 billion per year. In contrast, the cost of treating diabetic patients for renal disorders substantially exceeds this amount ($3.4 billion per year). Evaluating diabetic paients for macroproteinuria produces substantial cost benefits in addition to the obvious benefits to patients in preventing this common complication of diabetes.

It is cost-beneficial to screen diabetics for macroproteinuria.

Conclusion

Tests for macroproteinuria may be considered some of the most practial, effective and inexpensive tools for managing diabetes and hypertension in general practice. In diabetic patients, macroproteinuria teste should be used in parallel with HbA1c measurements to optimise the monitoring and treatment of the disease. In hypertensive patients, with or without diabetes, macroproteinuria testing should be used to detect patients at increased, risk for physician to the probability of additional risk factors and to monitor the efficacy of treatment. In a wider context, the onset and ectent of macroproteinuria may be used for early detection of subclinical deterioration of renal function and as an indicator of incipient progressive renal disease. Early detection of renal impairment allows the physician to implement more effective renoprotective strategies. It is improtant to realise that control of macroproteinuria invariably reduces the likehood of developing end-stage renal disease.