Kidney Dysfunction

• ACE inhibitors
• Blood pressure control
• Blood glucose control
• Cardiovascular risk
• Dietary protein intake

• 25-40% of patients with diabetes will develop diabetic nephropathy within 20-25 years of the onset of diabetes
• One third of patients with nephropathy will progress to develop end stage renal failure (ESRF)
• 20% of people requiring renal replacement therapy in the UK (dialysis or renal transplant) have diabetes
• People with diabetic kidney disease have a significantly increased risk of cardiovascular disease; the risk is increased 2-4 times with early nephropathy (microalbuminuria), 9 times with established proteinuria and 50 times with ESRF
• Tight glucose control, tight blood pressure control and the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) to block the rennin-angiotensin system (RAS) have all been shown to reduce the rate of development and progression of diabetic nephropathy

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• Diabetic nephropathy develops over many years due to progressive damage to the kidneys in patients with diabetes
• It is associated with the development of proteinuria, hypertension and a progressive decline in glomerular filtration rate (GFR)
• If untreated, patients may develop overt renal failure
• Most people with diabetic nephropathy also have evidence of other microvascular complications especially retinopathy
• Diabetic nephropathy is defined as the presence of clinical proteinuria in a person with diabetes who does not have any other renal disease
• Microalbuminuria (increased urinary albumin excretion) is the earliest clinical marker of diabetic nephropathy
• Microalbuminruia should be measured on an early morning urine sample or a timed overnight urine sample but is not detectable by dipstick urine tests
• UTI, intercurrent febrile illness, cardiac failure, strenuous activity, menstruation, uncontrolled blood glucose or blood pressure may cause a false positive result.

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• Early morning urine sample in plain container sent to biochemistry lab for urine albumin:creatinine ratio measurement (ACR), or
• Timed overnight (ON) urine sample for albumin excretion rate (AER)
• If positive for microalbuminuria repeat with two further urine ACR or ON urine collections over 4-6 weeks

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This describes pathological albuminuria in the 30-200mg/l range which is not detectable by chemical ‘dipstix'

Albumin excretion varies with respect to factors such as

• time of day, with rates being lower overnight
• exercise, with rates being increased
• disease such as hypertension which will increase the rate in some patients

To diagnose micoralbuminuria you need:

• At least 2 out of 3 positive urine samples
• Urine albumin:creatinine ratio (ACR) ≥ 2.5 mg/mmol in men or ≥ 3 mg/mmol in women, or
• Urine albumin excretion rate 20-200 mcg/min in timed ON urine, or
• Urine albumin excretion 30-300 mg/24 hours in 24 hour urine collection

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• Urine albumin:creatinine ratio (ACR) > 30 mg/mmol, or
• Urine albumin excretion > 200mcg/min, or
• Urine albumin excretion rate > 300mg/24 hours 300mg24 hours

Note:

Chemical ‘dipstix' can detect urinary protein at a concentration >200mg/l.

• Dipstix urinanalysis is highly specific in detecting glomerular proteinuria in excess of 300mg/dl
• Dipstix urinalysis will not detect microalbuminuria in early diabetic nephropathy (30-300mg/dl).
• If proteinuria is detected then it must be determined:
  • Whether the proteinuria is persistent? (is there a clinical suspicion of UTI? )And the amount of protein excretion
  • A 24 hour urine collection is indicated if there is persistent proteinuria, protein detected on at least three urine sample
• Urine microscopy will help identify proteinuria, microscopic haematuria and proteinuria is suggestive of glomerular disease.
• A positive test should be followed by measurement of 24 hour urinary protein excretion
• The normal range for urinary protein is 60-200mg per day although adolescent males, especially those who play regular contact sports, may excrete up to 300mg per day
• False negative can be caused by urine which is very acid, or which is very dilute (check pH of sample for confirmation of its quality)
• A false positive can be caused by haematuria

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If proteinuria present for the first time exclude Urinary tract infection before progresssing

Blood Glucose Control

In patients with diabetes and normal albumin excretion, a lower blood HbA1c is associated with a lower risk of developing microalbuminuria

This has been shown in both type 1 diabetes (Diabetes Control and Complications Trial) and type 2 diabetes (UKPDS study)

There is no lower threshold for HbA_1c therefore the lowest possible HbA_1c is the target for prevention of nephropathy

Blood Pressure Control

Tight blood pressure control also reduces the risk of developing nephropathy

In the UKPDS, the lower the BP, the lower the risk of developing microalbuminuria

There is no evidence to support a particular class of anti-hypertensive agent for prevention of nephropathy in an individual with normal albumin excretion; the level of BP is the most important factor

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Management of Microalbuminuria and Proteinuria

Angiotensin Converting Enzyme (ACE) Inhibitors

In patients with type 1 diabetes and early nephropathy ACE inhibitors significantly reduce development and progression of microalbuminuria even in those with a normal blood pressure

This effect is independent of reduction in blood pressure

In patients with type 1 diabetes and hypertension with established nephropathy ACE inhibitors significantly reduce progression of nephropathy to ESRF

In patients with type 2 diabetes and microalbuminuria with normal blood pressure ACE inhibitors reduce progression to proteinuria and renal impairment

In patients with type 2 diabetes and hypertension with microalbuminuria or proteinuria angiotensin receptor blockers (ARB) significantly reduce the rate of progression of nephropathy

Blood Pressure Control

Diabetic nephropathy is associated with hypertension and hypertension leads to worsening of nephropathy

Tight blood pressure control can reduce the progression of proteinuria and decrease the rate of decline in GFR in patients with diabetes and incipient or established nephropathy

Adequate control of blood pressure can reduce the rate of fall of GFR from 12ml/min/year to 5ml/min/year

Many patients will need a number of different anti-hypertensive agents to achieve blood pressure targets

An ACE inhibitor or ARB titrated up to the maximum tolerated dose should be the first line choice in a patient with diabetic nephropathy

A calcium antagonist or a  thiazide or loop diuretic or c should be added in next and thereafter, additional anti-hypertensive agents may be added according to individual patient requirements (click here to take you to the hypertension pathway).

Targets for blood pressure control with microalbuminuria or proteinuria:

• < 130/80mmHg or if young patient 120/70

Blood Glucose Control

Poor blood glucose control is associated with the development and progression of diabetic nephropathy

The DDCT and UKPDS studies have shown that good blood glucose control prevents development of microalbuminuria

Studies of good blood pressure control on the progression of established nephropathy have not shown significant benefit, however good blood glucose control in established nephropathy is important in reducing the risk of other microvascular complications and reducing cardiovascular risk

Target HbA_1c with microalbuminuria or proteinuria:

• HbA_1c < 6.5%

Cardiovascular Risk

Patients with incipient or established nephropathy have an increased risk of cardiovascular disease compared with those without nephropathy

As albuminuria rises, cardiovascular risk increases in type 1 and type 2 diabetes

Patients with nephropathy should have aggressive management of other cardiovascular risk factors including lipids, stopping smoking, weight loss

All patients with nephropathy should be prescribed aspirin and a statin

Total cholesterol < 4.0 mmol/l

LDL cholesterol < 2.0 mmol/l

HDL cholesterol > 1.0 mmol/l (men), > 1.3 (women)

Triglyceride < 1.7 mmol/l

Dietary Protein Intake

There is some evidence that reducing dietary protein intake to 1g/kg body weight/day reduces the rate of progression of proteinuria.

• ACE inhibitor or ARB for all patients
• Tight blood pressure control
  • BP < 130/80mmHg
• Tight blood glucose control
• HbA1c < 6.5%
• Aggressive management of cardiovascular risk factors
  • Stop smoking
  • Aspirin 75mg daily
  • Statin
    • Total cholesterol < 4.0 mmol/l
    • LDL cholesterol < 2.0 mmol/l
    • HDL cholesterol > 1.0 mmol/l (men), > 1.3 (women)
    • Triglyceride < 1.7 mmol/l
• Moderate protein intake (with established proteinuria)
  • 1g/kg body weight/day

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Monitoring of Progression

* Stage 1 and 2 chronic kidney disease only apply with other evidence of chronic kidney damage:

• persistent microalbuminuria
• persistent proteinuria
• persistent haematuria
• structural abnormality of the kidneys
• biopsy – proven glomerulonephritis

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Diabetes Renal Clinic

• Who to refer to Diabetes Renal Clinic:
• Any patient with type 1 or type 2 diabetes and one or more of:
  • persistent proteinuria
  • serum creatinine >120µmol/l and < 200µmol/l or eGFR 30-45ml/min.
  • rising creatinine >20% or falling GFR >15% over 12 months
  • eGFR < 90ml/min with persistent microalbuminuria
  • established nephropathy under the care of nephrology but with other diabetes-related complications or management problems
• Who to refer to Nephrology Clinic:
• Any patient with type 1 or type 2 diabetes with one or more of:
  • serum creatinine > 200µmol/l
  • rapidly rising serum creatinine
  • eGFR < 30ml/min
  • features of non-diabetic kidney disease (no retinopathy, haematuria, renovascular disease)

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Urine testing at annual review

Why test urine?

primarily urine is tested to check for protein, which will give an indication of renal function. it is also useful for reviewing glucose control and detecting acute problems such as urinary tract infections and ketoacidosis.

Test for:

• glucose
• blood
• ketones
• protein and/or microalbuminuria

1. Use fresh urine that has not been centrifuged. thoroughly mix the urine sample. the sample should be at room temperature when the test is performed and should not have been standing for more than 2 hours.
2. take a test strip out of the container. close the container again with the original desiccant stopper immediately after removal of the strip. this is important as otherwise the test areas become discoloured due to moisture and incorrect results may be obtained.
3. briefly (about 1 second) dip the strip into the urine making sure that all test areas are moistened.
4. when withdrawing the test strip, wipe the edge against the rim of the vessel to remove excess urine.
5. after 60 seconds compare the reaction colours of the test areas with the colours on the label. compare the 5th (blood) test area with both colour scales as separate colour scales are given for erythrocytes and haemoglobin. any colour changes appearing only along the edges of the test areas, or developing after more than 2 minutes, do not have any diagnostic significance.

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Glucose only usually appears in the urine when the blood glucose level is >10mmol/l. The point at which this occurs is called the renal threshold. Thus urine tests will only demonstrate blood glucose when they are significantly higher than target range. Conversely a negative blood glucose test result will signify that blood glucose levels are less than 10mmol/l but may still remain above target.

Note: age may change the renal threshold. It is common for older people to a higher renal glucose renal threshold often >11mmol/l

Urine tests test for glucose represent what blood glucose levels were in the recent past, they do not measure what level the blood glucose is at the time of the test. It is entirely possible to have a very high urine glucose level and normal blood glucose level. This simply indicates that blood glucose levels were high in the recent past but has returned to normal when the blood glucose test was performed.