Assignment

The Abnormal Albuminuria Syndrome in Diabetes

Proteinuria (albuminuria) is a condition of having too much protein in the urine which results from damage within the kidneys.

Proteinuria in diabetes will usually be the result of either long term hyperglycemia (high blood sugar levels) or hypertension (high blood pressure).

Pathophysiology:

Three main mechanisms involved in proteinuria(as albumin is smaller so, albuminuria)

1.Afferant arteriolar dialatation:

It is secondry two many, but two Main mechanisms

i: Advance glycosylated enzyme; During long standing hyperglycaemic state in diabetes mellitus, glucose forms covalent adducts with the plasma proteins through a non-enzymatic process known as glycation. Protein glycation and formation of advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with some other diseases such as rheumatoid arthritis, osteoporosis and aging.

ii: Increase protein kinase C which in turn increase vusculsr permeability and hence increase filtration and slbuminuria

2.Efferant Arteriolar constriction;

Due to hyperglycemia itself and also secondry to afferent arteriolar dialatation there is Activation of Renin Angiotensin Aldosteron System (RAAS) that leads efferent constriction

3.Glomerulosclerosis secondry to increase filtration and hence increase pressure in Bawmen’s capsule

Which Laboratory Method Should We Use?

Traditionally, the dipstick test was used to detect protein in

The urine. The test is semiquantitative, however, and insensitive to detect reliably albumin concentrations in ranges <300 mg/d albumin. At present, various antibody-based methods are used to measure lower levels of urinary albumin. These include RIA, nephelometry, immunoturbidimetry, and ELISA. It is beyond the scope of this review to evaluate these different techniques in detail. Recently, an HPLC method was developed by which not only immunoreactive but also immunounreactive albumin is measured . Using this method, more patients are found to have an albumin excretion in the microalbuminuric range . Whether patients who are detected as having microalbuminuria by HPLC are equally at risk for progressive renal and cardiovascular disease as those who are detected by the traditional antibody-based methods has yet to be determined. Whichever method is chosen, it is preferable to measure albumin in fresh samples . These methods all require laboratory facilities. Antibodybased dipstick tests for microalbuminuria also are available . Although only semiquantitative, these tests have the advantage that they can be used easily by the general practitioner or the patient at home. A recent study in hypertensive patients found a sensitivity of 88%, a specificity of 80%, a positive predictive value of 69%, and a negative predictive value of 92%. The development of point-of-care testing systems may provide in the near future a quantitative urine albumin value within seconds.

Which Sample Should We Collect?

For the diagnosis of microalbuminuria, a 24-h urine collection is the gold standard. Because of the effort involved, it is not the method of choice for screening. The second best is a timed overnight urine collection. Again, because this requires collection of urine over a given time period, this may be acceptable for screening specific patient groups such as patients with diabetes or hypertension, but it is less feasible for population screening. The next best is a first-morning urine sample. This

Has the advantage over a spot-urine sample because it is always performed at the same time of the day, and it is least influenced by hydration status and physical activity of the patient, reducing the variability that is caused by these factors.

This may be a good choice for population screening if the patient is asked to mail a urine sample, as was done in the PREVEND study . In clinical practice, however, a spot-urine sample is collected when the patient visits either the general practitioner or the health care office, where the screening takes place. Some of the variability in timing of collection can be overcome by correcting urinary albumin concentration for urinary creatinine concentration. Taking these considerations together, the best approach is to

Use a spot-urine sample (either the first-morning void or at the time of the visit to the medical office) as a prescreening. The patients whose urine is found positive then either should deliver two more samples to confirm whether the first value indeed was abnormal or, preferably, should collect two 24-h urine samples. This latter approach was tested in the PREVEND study. After using just one first-morning urine sample for measurement of urinary albumin concentration, patients with a urinary albumin concentration above a certain cutoff were invited for two 24-h urine collections. It was suggested that a cutoff value of 10 mg albumin/L could be used for mass screening to identify individuals who are more likely to have a UAE >30 mg/24 h .

A healthy albumin to creatinine ration is defined as:

Men : less than or equal to 2.5 mg/mmol

Women : less than or equal to 3.5 mg/mmol

Screening:

Patients with diabetes should be screened annually for DKD. Initial screening should commence:

5 years after the diagnosis of type 1 diabetes; or From diagnosis of type 2 diabetes.

Screening should include:

Measurements of urinary ACR in a spot urine sample;

Measurement of serum creatinine and estimation of GFR.

An elevated ACR should be confirmed in the absence of urinary tract infection with 2 additional first-void specimens collected during the next 3 to 6 months.

Microalbuminuria is defined as an ACR between 30-300 mg/g.

Macroalbuminuria is defined as an ACR > 300 mg/g.

2 of 3 samples should fall within the microalbuminuric or macroalbuminuric range to confirm classification.

In most patients with diabetes, CKD should be attributable to diabetes if:

Macroalbuminuria is present;

Or Microalbuminuria is present in the presence of diabetic retinopathy,

In type 1 diabetes of at least 10 years’ duration.

Other cause(s) of CKD should be considered in the presence of any of the following circumstances:

Absence of diabetic retinopathy

Low or rapidly decreasing GFR

Rapidly increasing proteinuria or nephrotic syndrome

Refractory hypertension

Presence of active urinary sediment

Signs or symptoms of other systemic disease

Or>30% reduction in GFR within 2-3 months after initiation of an ACE inhibitor or ARB

Definitions of nephropathy, based upon albuminuria

Relative likelihood of diabetic kidney disease (DKD) by CKD stage and albuminuria

Causes of a false positive test for albuminuria

Vigorous exercise

Urinary tract infection

Presence of blood, e.g. menses

Concentrated urine (less likely using ACR)

Causes of a false negative test for albuminuria

Dilute urine (less likely using ACR).

Treatment for diabetic renal disease

Treatments can usefully be considered under the headings of glycaemia (and other metabolic corrections), blood pressure, cardiovascular risk factors, and diet.

Glycaemia

Both the DCCT/EDIC and the UKPDS studies confirmed that good glycaemic control can prevent the development of microalbuminuria. There are conflicting data on the role of glycaemic control in the progression of established nephropathy, although, as a rule, patients with worse control do less well and have a greater incidence of concomitant complications, such as retinopathy and neuropathy. As GFR declines, insulin clearance by the kidneys is reduced, so doses may need adjustment. In addition, as most patients with overt nephropathy will also have a long duration of diabetes, they will be at greater risk of hypoglycaemic unawareness. These two factors make hypoglycaemia a real risk, so target HbA1c may need to be higher than for those without nephropathy.

A small study of pancreas transplantation in type 1 patients with established nephropathy and glomerulosclerosis showed that prolonged normoglycaemia for >10 years resulted in a reversal of matrix accumulation and GBM thickening. This demonstrates that the pathology may take as long to reverse as it does to develop and that nothing short of normoglycaemia may suffice for the resolution of established disease.

Blood pressblood pressure

There are no data supporting a role of antihypertensive therapies (specifically agents which block the renin–angiotensin system ras) in the prevention of nephropathy in normoalbuminuric, normotensive people with type 1 or type 2 diabetes. Once blood pressure rises above 140/90mmhg in type 1 and 160/90mmhg in type 2, there are trial data showing that ras-blocking agents can prevent the development of microalbuminuria and overt nephropathy. These studies have not been of a sufficient duration to demonstrate any impact on esrd rates. Once overt nephropathy has developed, ace inhibitors in type 1 and angiotensin ii receptor blockers (arbs) in type 2 diabetes have been shown to reduce the numbers developing esrd, more so than other antihypertensive therapies. These drugs remain the cornerstone of treatment of blood pressure in nephropathy. Diabetes and renal guidelines suggest a target blood pressure of <130/80mmhg in patients with nephropathy.

Cardiovascular risk factors

The high rates of cv disease and the unfavourable lipid profiles seen in people with nephropathy make these attractive targets. In the heart protection study (mainly type 2 patients), there was a reduction in cv events by around 25%, but few had nephropathy. Recently, the sharp trial reported a significant reduction in risk for cv events of 17% in over 6,000 people with pre-dialysis ckd randomized to simvastatin/ezetimibe vs placebo. Lipid-lowering to a target ldl cholesterol of <2mmol/l should be undertaken in all people with diabetes and ckd. No consistent effect of lipid-lowering has been shown on the rate of loss of gfr or albuminuria. Smoking rates are higher in those with nephropathy, compared to those without, and there are some data that cessation can help preserve renal function as well as cv risk.

Multifactorial intervention (including glycaemic control, ace inhibitors, aspirin, lipid-lowering, smoking cessation, weight reduction, exercise, and antioxidant therapy—the steno 2 trial) has been shown to reduce cv morbidity and mortality in 80 people with type 2 diabetes and microalbuminuria. Thus, a broad clinical approach to management should be undertaken in all with diabetes and ckd.

Diet

High dietary protein has been shown to damage the kidney in experimental diabetes. In type 1 diabetes, protein restriction can reduce rate of loss of gfr, albuminuria, and mortality in people with established nephropathy. The data are less strong in type 2 diabetes. A dietary protein content <0.8g/kg is suggested, but patients find long-term adherence to be difficult. As with all patients with ckd, people with diabetes may develop anaemia, hyperphosphataemia, vitamin d deficiency, and hyperkalaemia, particularly in stage 4. All of these may require expert dietary and nephrology input and should prompt referral

Criteria for referral for specialist review (take into account patient’s wishes, serious comorbidities, and age)

CKD stage 4 or 5 (eGFR <30mL/min/1.73m2).

Rapid decline of GFR (eGFR decline >5mL/min/1.73m2 >10mL/min/1.73m2/5 years).

Microscopic or macroscopic haematuria and/or active urinary sediment.

Signs of other systemic disease, such as SLE or systemic sclerosis. Blood pressure outside target despite four or more drugs at optimum titration.

Heavy proteinuria (>1g/day or protein:creatinine ratio >100mg/ mmol or ACR >70mg/mmol).

Family history of genetic causes of kidney disease (e.g. polycystic kidneys).

Suspected renal artery stenosis.

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