Slowing progression of renal dysfunction in patients with diabetes

Risk factors for diabetic kidney disease

The main risk factor for DKD is an increasing duration of diabetes, however, it may be present at diagnosis if the patient has had undetected type 2 diabetes for some time.⁵ DKD typically develops after ten years in people with type 1 diabetes.⁵

A large study in the southern region of New Zealand found that almost half of people aged over 20 years with diabetes had an estimated glomerular filtration rate < 60 mL/min/1.73m² or albuminuria, i.e. CKD.⁶

Māori and Pacific peoples with diabetes are more severely affected by kidney disease

Māori and Pacific peoples are more likely to have CKD with moderately to severely increased albuminuria than people of European ethnicity.⁶ People of Pacific ethnicity have a 12 times higher, and Māori six times higher, rate of starting treatment for end-stage renal disease than people of European ethnicity.⁴ Among people starting dialysis, diabetes is the underlying cause of renal failure in 74% of patients of Pacific ethnicity, compared to 68% of Māori and 24% of Europeans.⁴ However, people of Māori or Pacific ethnicity are less likely to receive a transplant as their first treatment for end-stage renal disease than people of European ethnicity.⁴

Factors determining susceptibility, development and progression

Once a person has diabetes, modifiable and non-modifiable factors determine the future risk of developing kidney disease, the onset and the rate of renal decline (Table 1):²

Hyperglycaemia and hypertension are the two most important modifiable risk factors for DKD.⁷

Table 1: Risk factors for chronic kidney disease in patients with diabetes²

Test renal function at least once a year

Patients with diabetes should have their renal function tested at least once a year as part of their annual diabetes review.⁸ Renal testing should include:⁹

• Albumin:creatinine ratio (ACR), from a first void urine sample if possible
• eGFR, which will be automatically generated when a serum creatinine is requested

More frequent testing, e.g. six-monthly, may be appropriate for people with multiple risk factors for DKD, e.g. Māori ethnicity, frequent use of NSAIDs and hypertension, and for those with established DKD (see below).

An increased ACR result should be repeated after two weeks to exclude alternative causes, e.g. a urinary tract infection, menstruation, NSAID use, high protein diet, acute febrile illness, heavy exercise in previous 24 hours or cardiac failure. Regardless of the patient’s eGFR, moderate to severe albuminuria (Table 2) is associated with an increased risk of renal decline, cardiovascular disease and mortality (see: “Albuminuria and decreased eGFR are markers of cardiovascular risk”).⁵

Table 2: Staging of albuminuria¹⁰

^* Severely increased albuminuria is also referred to as proteinuria or overt diabetic kidney disease when persistent

Encourage a healthy lifestyle

A healthy lifestyle is important for all people and those with diabetes or at high risk of developing diabetes may be able to reduce their risk of developing DKD by focusing on:

• A healthy diet, including reducing salt intake to control blood pressure and maximise the benefits of any antihypertensive medicines, and avoiding high protein diets (see below)
• Increased physical activity
• Smoking cessation where appropriate

In patients at high risk of developing type 2 diabetes, e.g. with an HbA_1c level of 46–49 mmol/mol, initiating metformin should be considered as an adjunct treatment in addition to changes in diet and activity levels.¹⁶ Metformin should be initiated in all patients at, or soon after, diagnosis of type 2 diabetes unless they have contraindications, in which case an alternative oral glucose-medicine can be used.¹⁷

For further information on dietary regimens, see: “Weight loss: the options and the evidence”.

For further information on preventing or delaying type 2 diabetes in patients at high risk, see: “A rising tide of type 2 diabetes in younger people: what can primary care do?”.

Tight glycaemic control can preserve renal function

A HbA_1c target of 48–53 mmol/mol achieves the greatest reduction in microvascular risk, e.g. nephropathy, retinopathy and neuropathy for people with diabetes.^{5, 17} This target is most appropriate for:

• Younger people^*
• Newly diagnosed people
• People with type 2 diabetes managed with lifestyle and metformin alone

Large studies in people with type 1 and type 2 diabetes show that early intensive glycaemic control results in a lasting protective effect with a reduced risk of moderate albuminuria of approximately one-third after 9–12 years, compared to standard care.²

^* Excluding children with type 1 diabetes where a target of < 58 mmol/mol is recommended¹⁸

A less stringent target of 53–58 mmol/mol balances the benefits of glycaemic control against the risks of treatments.^{5, 17} Glycaemic targets need to be individualised to account for adverse effects, e.g. hypoglycaemia, co-morbidities such as cardiovascular disease, frailty and patient preference.¹⁹

A higher target of 58-64 mmol/mol may be appropriate if the benefits of a tighter target are outweighed by the risks. In terms of microvascular risk management, reducing HbA_1c in patients with marked hyperglycaemia, e.g. > 80 mmol/mol, to a more moderate level, e.g. < 65 mmol/mol, is thought to offer the greatest benefit.⁵

For information on glucose-lowering medicines, see: “Optimising pharmacological management of HbA_1c levels in patients with type 2 diabetes: from metformin to insulin”.

For information on glycaemic control in older people, see: “Dialling back treatment intensity for older people with type diabetes”.

Further information on glycemic control in type 1 diabetes is available from: “Understanding the role of insulin in the management of type 1 diabetes”

Initiate an ACE inhibitor or an ARB to preserve renal function

An ACE inhibitor or an ARB is recommended for all patients with diabetes with:^{8, 20}

• Blood pressure ≥ 130/80 mmHg regardless of renal function; or
• Albuminuria, i.e. persistent ACR > 3 mg/mmol, even if normotensive

N.B. An ACE inhibitor or an ARB is not recommended for the primary prevention of DKD in patients with diabetes who are normotensive with normal ACR and eGFR.¹

ACE inhibitors and ARBs inhibit the renin-angiotensin-aldosterone system which preserves renal function and slows the progression of DKD by two mechanisms:³

1. Lowering blood pressure
2. Limiting vasoconstriction of the post-glomerular arteriole to reduce intraglomerular pressure

Of the ACE inhibitors that are fully subsidised in New Zealand there is no clear evidence that any one is superior to another in preventing the onset or progression of DKD. Candesartan or losartan are both reasonable choices if an ARB is prescribed rather than an ACE inhibitor, e.g. the patient develops a cough following initiation of an ACE inhibitor.²¹ Losartan is the preferred ARB if the patient has gout due to its serum urate-lowering ability.²² ACE inhibitors and ARBs are generally started at a low dose and titrated to the maximum tolerated dose within the approved range for patients with DKD (see: www.nzf.org.nz for details).²³

Test eGFR, ACR and serum potassium prior to, and five to ten days after, initiation of an ACE inhibitor or an ARB.²⁴ ACE inhibitors and ARBs are renoprotective, however, treatment may result in an increase in serum creatinine and potassium and a corresponding decrease in eGFR due to a reduction in intraglomerular pressure.³ Guidelines recommend considering an alternative explanation, e.g. hypovolaemia, nephrotoxicity or bilateral renal artery stenosis, if the patient’s eGFR decreases by more than 30%.²⁰ Depending on the clinical circumstance it may, however, be appropriate to intervene at a level less than 30%. Treatment options include reducing the dose by half and/or withdrawing treatment if serum creatinine levels remain elevated.

For further information on prescribing ACE inhibitors see: “Prescribing ACE inhibitors: time to reconsider old habits”.

Setting the blood pressure target

The optimal blood pressure to preserve renal function in people with diabetes is < 130/80 mmHg, assessed at least annually.²⁰ Managing blood pressure is essential in preserving renal function in all people with diabetes.³ Approximately 80% of people with type 2 diabetes have hypertension, therefore the two conditions often need to be treated simultaneously.²⁰

Individualised blood pressure targets need to be appropriate for the patient’s clinical circumstance and a less stringent target may be better for some people. For example, those at an increased risk of falls such as older frail people with diabetic neuropathy, especially if there is a history of postural hypotension or hypoglycaemia.²⁴

Calcium channel blockers are the second-line antihypertensive

A low threshold for initiating a second antihypertensive in patients with diabetes is generally recommended. A calcium channel blocker, e.g. amlodipine or felodipine, is an appropriate second-line antihypertensive in this situation as its concurrent use with an ACE inhibitor or an ARB is likely to provide greater renoprotection than an ACE inhibitor or an ARB alone.²⁵ ACE inhibitors and ARBs should not be initiated in combination as this may accelerate renal deterioration and increase adverse effects without reducing the patient’s cardiovascular risk.²⁶

Managing hyperlipidaemia

Hyperlipidaemia is a risk factor for DKD.³ The need for lipid-lowering treatment is generally guided by the patient’s five-year cardiovascular risk:²⁴

• Discuss the benefits and harms of lipid-lowering medicines with all patients with a five-year cardiovascular risk of 5–15%
• Prescribe a lipid-lowering medicine to:
  • All patients with a five-year cardiovascular risk ≥ 15%, including those with diabetes and eGFR < 45 mL/min/1.73m²
  • All patients with a total cholesterol to HDL-cholesterol ratio of eight or more

For further information on managing lipids, see: “Cardiovascular disease risk assessment in primary care: managing lipids”.

Minimise the need for nephrotoxic medicines

Optimise management of co-morbidities that increase the need for nephrotoxic medicines, e.g. gout and osteoarthritis. One-quarter of people with gout in New Zealand also have diabetes and this figure rises to one-third in Māori and Pacific peoples.²⁷ NSAIDs are also used more frequently by Māori and Pacific peoples with gout, compared to New Zealand Europeans with gout.²⁸ If patients with gout adhere to urate-lowering treatment and serum urate levels are treated to target, gout flares will be virtually eliminated for many patients within two years and NSAIDs should not be required.²⁹

For further information on the management of gout, see: “Managing gout in primary care”.

Table 3: Recommended frequency of renal monitoring for patients with diabetes as determined by renal function, adapted from KDIGO (2013).⁸

^*Or more frequently depending on clinical need

ACE inhibitors or ARBs should continue to be taken at the maximum tolerated dose within the approved dose range to preserve renal function in people with DKD, i.e. persistent albuminuria and/or eGFR < 60 mL/min/1.73m².³

There is, however, no evidence that intensive glycaemic control improves renal outcomes in patients once DKD is established.³ A less stringent glycaemic target may therefore be appropriate if a patient develops DKD due to the risk of hypoglycaemia associated with some glucose-lowering medicines, particularly in patients with an eGFR < 30 mL/min/1.73m².¹⁰ Alternatively, if a patient already has kidney disease and they are subsequently diagnosed with diabetes a low dose of a glucose-lowering medicine may be appropriate when treatment is initiated. Glycaemic control should not necessarily be relaxed for all patients who develop DKD though as there may still be benefits if the risk of hypoglycaemia can be managed, e.g. in some younger patients.

The following points may be relevant for oral glucose-lowering medicines in patients with type 2 diabetes and DKD^*:^19,23,30

• Metformin remains the first-line glucose-lowering medicine, unless contraindicated (CrCl <15 mL/min) or not tolerated, however, dosing may need to be reduced, i.e. 1 g daily maximum if creatinine clearance 30–60 mL/min or 500 mg daily if creatinine clearance 15–30 mL/min
• Vildagliptin dosing may need to be reduced, e.g. 50 mg daily maximum if eGFR < 50 mL/min/1.73m²
• Pioglitazone undergoes hepatic metabolism and dose adjustments are not generally required in patients with renal dysfunction but use is not advised in patient on renal dialysis
• Sulphonylureas are not recommended for patients with renal dysfunction due to the risk of hypoglycaemia

As renal clearance declines, people taking insulin may need less to achieve glycaemic control. A reduced dose of insulin also decreases the risk of hypoglycaemia.

^* Sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists reduce DKD progression in people with type 2 diabetes and are recommended internationally as the second-line glucose-lowering medicines for patients with DKD.⁵ Medicines in these classes have been approved for use in New Zealand but none are currently subsidised.

Controlling protein intake can slow the progression of diabetic kidney disease

The optimal level of protein intake is approximately 0.8 g/kg/day for people with DKD as this is associated with improvements in renal function.^{5,31 *} Higher levels of protein intake, i.e. > 1.3 g/kg/day, are associated with increased albuminuria, more rapid loss of renal function and increased cardiovascular mortality in people with diabetes.⁵ Reducing protein intake below 0.8 g/kg/day is unlikely to slow renal decline or decrease cardiovascular risk and is not recommended.⁵ It is not known if a low protein diet reduces the risk of developing DKD. In general dietary patterns that are high in plant and sea foods and low in processed foods, e.g. the Mediterranean diet, are more likely to slow progression of DKD.³² Referral to a dietitian may be appropriate for patients with diabetes who require additional nutritional support.

^*For an 80 kg person this equates to 64 g of protein which is approximately 300 g of fish, 200 g of chicken breast or 225 g of lean steak. Further information on the protein content of food is available from: https://nutritionfoundation.org.nz/nutrition-facts/nutrients/protein

Diabetic kidney disease increases the risk of acute kidney injury

People with diabetes are at increased risk of AKI, compared to those without diabetes, and the risk is even higher in those with DKD.⁵ Approximately 10% of patients hospitalised with AKI require kidney replacement therapy and mortality rates of 50% are reported for patients with this severity of injury.³³

AKI can have many causes but the most common involve a reduction in blood flow to the kidney, e.g. hypovolaemia caused by diarrhoea, vomiting, haemorrhage, sepsis or disturbed vasoregulation due to NSAIDs, particularly if the patient is also taking an ACE inhibitor/ARB and a diuretic, i.e. the “triple whammy”.

Early administration of intravenous fluids, typically isotonic saline, is recommended to reduce further kidney injury and assist recovery in patients with, or at high risk of, AKI due to volume depletion.³³

Maintain hydration and discuss a “sick day” plan

Patients with DKD should avoid volume depletion by maintaining adequate fluid intake, particularly if they are unwell or during hot weather. Provide written instructions of what to do if vomiting or diarrhoea develops, including:

• Maintaining an adequate fluid intake, aiming for a pale coloured urine
• Avoiding NSAIDs, e.g. use paracetamol instead
• Being aware of the symptoms of dehydration, e.g. increased thirst, dry mucous membranes, lethargy and weight loss
• Knowing which medicines may need to be temporarily withdrawn or require dose adjustments, e.g. metformin, dabigatran, gabapentin, atenolol and opiates
• Seeking medical attention if their condition deteriorates

Reduce the risk from nephrotoxic medicines

Patients taking an ACE inhibitor/ARB and a diuretic should be specifically warned of the risks of using NSAIDs and should avoid purchasing over-the-counter NSAIDs. Regular medicine reviews are recommended to avoid inadvertent concurrent prescribing of an ACE inhibitor/ARB, a diuretic and a NSAID. If this combination of medicines is required in a patient with DKD renal function should be monitored more frequently.

For further information on the triple whammy, see: “Avoiding the triple whammy in primary care: ACE inhibitor/ARB + diuretic + NSAID”.

When to consider referral to a nephrologist

Management in primary care is appropriate for the majority of patients with DKD, particularly those with a stable eGFR and controlled albuminuria and blood pressure.⁹ Discussion with or referral to a nephrologist is appropriate in the following situations when DKD may be progressing:⁹

• An unexplained decline in eGFR > 15% in three months
• An eGFR < 45 mL/min/1.73m² and falling, although health pathways/referral criteria in some regions in New Zealand specify < 30 mL/min/1.73m²
• Severely increased albuminuria that is increasing, i.e. ACR > 30 mg/mmol, especially in a younger patient

Ideally, a renal ultrasound would be performed before referral to a nephrologist but this may not be possible in all regions.⁹

Nephrology referral criteria varies by region. The bestpractice chronic kidney disease decision support module contains referral criteria for each DHB. For further information, see: www.bestpractice.net.nz/feat_mod_PCS.php