Practical Diabetes Care, 3rd Ed., Excerpt #13: Diabetic Renal Disease Part 2 of 5

Macroalbuminuria

Macroalbuminuria is defined as:
• urinary albumin excretion > 300 mg per 24 hours;
• AER > 200 µg/min;
• ACR > 20 mg/mmol (USA > 300 mg/g);
• persistent stick-positive proteinuria (1 to 3+) is invariable.

Nephrotic syndrome

In the IDNT study of irbesartan in diabetic nephropathy (2001), more than 40% of patients had the nephrotic syndrome, defined as:
• total urinary protein > 3.5 g/day;
• urinary albumin > 2.2 g/day;
• ACR > 2.2 g/g (250 mg/mol).

Traditionally, the syndrome also includes:
• hypoalbuminemia (serum albumin < 35 g/L);
• hypercholesterolemia (total cholesterol > 6.7 mmol/L, 260 mg/dL) or statin use;
• peripheral oedema, or use of a loop diuretic [6].

Definitional minutiae apart, proteinuria of this degree carries a poor prognosis, both renal and cardiovascular, with a risk of rapid deterioration in GFR and high mortality, as in non-diabetic renal disease. Because of the high cardiorenal risk, and because with vigorous treatment a certain proportion can be brought into remission (see below), it is important to identify these patients as early as possible, and to establish joint management with the renal team.

Thyroid function in nephrotic syndrome
Protein-bound thyroid hormone loss can be massive in heavy proteinuria. TSH secretion is stimulated, and although patients are clinically euthyroid, thyroid function tests may suggest early hypothyroidism, i.e. TSH 5–10 mU/L, low-normal free T4 (10–15 pmol/L). This phenomenon is well known in children, but less recognized in adults [7]. It does not respond to L-thyroxine treatment. The converse is important: if this thyroid profile emerges, then check urinary protein levels before embarking on further thyroid investigations.

Diagnosis of microalbuminuria

Urinary albumin measurements have high biological variability, but ACR is less variable than 24-hour urinary albumin measurements (13% vs. 27%). Nevertheless, for diagnostic purposes the recommendation remains that a positive screening test for microalbuminuria (usually ACR) should be followed up with three timed urine samples over the next 6 weeks. If two or three samples are positive, then the diagnosis is confirmed. If a timed urine sample is used for screening, then only two confirmatory tests are required. This difficult procedure is particularly important in younger normotensive type 1 patients, who may be committed unnecessarily to long-term angiotensin blockade treatment. Common sense must be used here: stick-positive proteinuria with a single macroalbuminuric timed sample is sufficient. Albumin in urine is stable at room temperature for 7 days (and up to 30 days at 4°C), so multiple specimens can be stored for a single delivery to the laboratory.

‘Renoprotection’ in normotensive non-microalbuminuric patients

There is a widespread belief that because of the benefits of angiotensin blockade treatment in microalbuminuria and macroalbuminuria, ‘renoprotection’ with these agents might reduce the risk of normotensive normoalbuminuric patients developing microalbuminuria. This situation frequently occurs in type 1 diabetes, but the DIRECT-Renal study (2008) in which patients were treated with high-dose candesartan for 5 years did not prevent microalbuminuria [8]. Good glycemic control (HbA1c 7.0%, 53 mmol/mol or lower) is the only reliably effective preventive measure in type 1 patients, reducing the incidence of microalbuminuria in DCCT by 30–40%.

In type 2 diabetes, RCTs are less clear. In the BENEDICT study, treating hypertensive patients (mean BP 150/87 mmHg) with the ACE-i trandolapril 2 mg daily reduced the risk of progressing from normoalbuminuria to microalbuminuria by about 50% over 4 years [9]. This benefit was not seen with high-dose candesartan (32 mg daily) in the DIRECT-Renal study, either in normotensive patients (mean BP 123/75 mmHg) or those with relatively well-controlled hypertension (mean BP 140/80 mmHg). However, normotensive type 2 patients with persistently negative microalbuminuria are unusual (and may have late-onset type 1 diabetes), and many type 2 patients will have other indications for angiotensin blockade (hypertension, established macrovascular disease or risk factors for it).

Management of microalbuminuria

Type 1 diabetes: the glycemic approach
Microalbuminuric type 1 patients are hypertensive relative to normoalbuminuric patients, though many will not have blood pressure that reaches the criterion level for either hypertension (BP > 140/90 mmHg) or even pre-hypertension (120–140/80–90 mmHg; see Chapter 11). Glycemic control is still very important, and CSII should be offered where available to motivated individuals not achieving HbA1c below 7.0% (53 mmol/mol) on an intensified insulin regimen. Smoking is an independent risk factor for microalbuminuria (as in type 2 diabetes) and should be actively targeted. Aspirin or lipid-lowering treatment is of no value. Angiotensin blockade treatment is usually considered essential, but spontaneous regression of microalbuminuria is frequent, particularly if:

• HbA1c is reasonable (e.g. < 8%, 64 mmol/mol);
• systolic blood pressure is below 115 mmHg;
• total cholesterol under 5.1 mmol/L (198 mg/dL) and triglycerides under 1.64 mmol/l (145 mg/dL), which they are likely to be in most type 1 patients;
• microalbuminuria is of short duration [10].

In patients with low-grade microalbuminuria (e.g. ACR 3–5 mg/mmol, 26–44 mg/g) it is therefore reasonable to intensify glycemic control, target cessation of smoking and monitor ACR every 3–6 months to assess trends in AER before starting angiotensin blockade, particularly in women of childbearing age. Treatment, if started, must be titrated to the highest recommended dose, postural symptoms permitting (but, intriguingly, ACE-i treatment is not consistently associated with regression of microalbuminuria, another reason to consider improving glycemic control as primary management).