Info

Proteinuria

>200

>30

>300

urinalysis for microalbumin should be part of routine surveillance in diabetes, but a positive finding must be repeated to confirm, and infection excluded as well. A sample should then be sent to the laboratory to measure the ratio more accurately, or alternatively a 24-hour urine collection for albumin can be arranged.

Investigation of suspected nephropathy

Nephropathy is a well recognised and not uncommon complication in diabetes, usually starting with albuminuria that progresses over time. However, other causes of kidney disease might affect someone with diabetes, and there are many potential causes of proteinuria. So the initial question is whether the diagnosis can be made based on the clinical presentation, or whether further investigations including renal biopsy are justified.

Patients with diabetes who develop microalbumin and who are detected through routine surveillance will not need invasive investigations at this stage. They should have a midstream specimen of urine (MSU) taken to exclude infection, and provided this is sterile and acellular it is safe to continue follow-up on the assumption that they have stage II (incipient) nephropathy (see Table 12.1).

Those with actual proteinuria (detectable on conventional urinalysis suggesting a urinary albumin concentration >200mg/l) should similarly have infection, pyuria and haematuria excluded through MSU. It may be worth measuring albumin excretion through a 24-hour urine collection, to provide a baseline for future progression. Such patients should also have an ultrasound examination of the renal tract, to support the clinical examination in excluding unexpected pathology such as a tumour. For those with renal impairment, ultrasound also helps to exclude obstructive causes, particularly in men, who may have prostatic enlargement, or in either sex as a result of autonomic neuropathy causing chronic urinary retention (Box 12.4).

A blood test for C-reactive protein and antinuclear factor is worthwhile in patients with proteinuria. Routine biochemistry should reveal normal serum albumin levels. A patient with low albumin levels and oedema (nephrotic syndrome) is likely to have a different cause for their proteinuria (see Box 12.4). If the cause is diabetic nephropathy, at the point where proteinuria becomes detectable on conventional stix, it is likely that the e-GFR will be at least borderline, if not actually abnormal.

Box 12 .4 Abrupt onset of proteinuria is never due to diabetes

Patients not following the typical pattern of presentation may have another cause of renal disease that might benefit from other types of treatment. Other causes are more likely to affect type 2 patients, as they tend to be commoner with increasing age

Patients with proteinuria due to diabetic nephropathy usually also have retinopathy. If this is not present then other causes of renal disease need considering (Box 12.5).

Anaemia occurs relatively early in diabetic nephropathy compared with other causes of kidney disease, so it is not unusual for this anaemia to be symptomatic at the point where the urea and creatinine are not particularly high.

Patients with renal artery stenosis may be identified if a decline in renal function (sometimes dramatic) occurs after commencing ACE inhibitors. A vascular bruit may be evident on auscultating the abdomen. Such patients should be referred for imaging of the renal arteries and may benefit from interventions to improve renovascular function including angioplasty.

Box 12 .5 Who needs other investigations?

• Type 1 patients developing proteinuria without having been through a microalbuminuria stage

• Pyuria or haematuria on MSU

• Family history of other renal disease

• Absence of retinopathy

• Nephrotic syndrome

• Features of nephritis: haematuria, raised C-reactive protein

• Those showing an abrupt decline in renal function following ACE inhibition

Histological features of diabetic nephropathy

Renal biopsy

Renal biopsy is carried out via a posterior approach through the lumbar musculature, under local anaesthetic, and guided by ultrasound. In preparation, patients should have clotting function and platelet count checked, and be fasted for 6 hours. Macroscopic haematuria frequently occurs after this procedure, and is almost always self-limiting.

Figure 12.2 Diabetic glomerulosclerosis with Kimmelstiel-Wilson nodules.

Histology

The typical histological signs of diabetic nephropathy are diabetic glomerulosclerosis with mesangial expansion and thickening of the basement membrane. The classical features evident in the later stages are Kimmelstiel-Wilson nodules, associated with hyalinisa-tion of the efferent and afferent arterioles (Figure 12.2).

Primary prevention

Diabetic nephropathy is essentially a microvascular complication, but as indicated above, it may trigger macrovascular processes as well that promote its further progression. This 'vicious cycle' should encourage not only early intervention but also prevention if possible. The most effective means of achieving this are through:

• Glycaemic control

• Blood pressure control

Smoking cessation

These should be offered to all patients with diabetes, but treatment targets should be tightened when the early stages of nephro-pathy develop. In patients with no current signs of nephropathy, targets need to be balanced against other issues including quality of life and risks of over-treatment. This particularly applies to elderly patients and those whose life-expectancy is already limited.

Treatment of diabetic nephropathy

The patient with established nephropathy is not only at risk of end stage renal failure but also of cardiovascular complications including myocardial infarction. A high proportion of patients with proteinuria have co-existing coronary artery disease, which may be asymptomatic. It is also likely that other microvascular disease is present, and almost all have co-existing retinopathy.

Secondary prevention

The mainstay of treatment of diabetic nephropathy is secondary prevention through tight blood pressure and glycaemic control, lipid management and smoking cessation if appropriate (Box 12.6). Patients entering the symptomatic stage should be referred and managed by a nephrologist in addition to any follow-up occurring in primary care. Good communication between primary and secondary care is important to achieve the best outcomes and the best use of specialist expertise.

Box 12.6 Treatment targets in diabetic nephropathy

Treatment targets in diabetic nephropathy should be individually tailored, but generally aim for:

Blood pressure <130/80

Total cholesterol <4.0mmol/l and LDL <2.0mmol/l

Non-smoker status

In established nephropathy with proteinuria, it is safe to assume the patient has widespread microvascular and macrovascular (including coronary artery) disease

Angiotensin converting enzyme inhibitors (ACEIs)

Angiotensin converting enzyme inhibitors (Box 12.7) have been shown to reduce progression of diabetic nephropathy, and should be offered to all patients with any degree of albuminuria, even if the blood pressure is normal. They reduce the risk of end stage renal failure requiring dialysis or transplantation, and improve all-cause mortality. Patients may fail to tolerate ACEIs for a number of reasons. Cough is a relatively common side effect and requires substitution of the drug with an angiotensin 2 receptor blocker. These drugs have also been shown to reduce progression to end stage renal failure, but not all-cause mortality, and ACEIs are still the preferred option if tolerated (Box 12.8).

Box 12.7 Currently available Angiotensin converting enzyme inhibitors (ACEIs) and Angiotensin 2 receptor blockers

ACEIs

Angiotensin 2 receptor blockers

Ramipril

Candesartan

Lisinopril

Valsartan

Enalapril

Losartan

Captopril

Irbesartan

Trandolapril

Telmisartan

Quinapril

Eprosartan

Perindopril

Olmesartan

Cilazapril

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