Diabetes-related chronic kidney disease

Kidney disease associated with diabetes is the single leading cause of kidney failure.⁵ 

CKD occurs in one in four women with type 2 diabetes and in one in five men with type 2 diabetes,⁶ and is more common in Aboriginal and Torres Strait Islander people.⁷ 

Some non-European groups (eg South-east Asian, African American, Afro-Caribbean, Māori peoples) have high rates of end-stage diabetic nephropathy, possibly, but not entirely, due to later or delayed diagnosis and suboptimal care.⁸ 

There is strong evidence that treatment in the early stages of CKD reduces the progression of kidney damage, morbidity and mortality. Therefore, people with type 2 diabetes should be screened and retested regularly to detect early indications of kidney damage and to monitor the effects of treatment. Detection of CKD involves a ‘kidney health check’, which comprises of blood pressure measurement, blood measurement of eGFR plus uACR. This check should be done annually in people with diabetes or hypertension or in Aboriginal and Torres Strait Islander peoples aged over 18 years.⁹ (Refer to the National Aboriginal Community Controlled Health Organisation (NACCHO) and The Royal Australian College of General Practitioners (RACGP) National guide to preventive healthcare for Aboriginal and Torres Strait Islander people.) 

Diagnosis of the cause of the CKD is important because people with diabetes may have additional or alternative causes of renal impairment. 

Systolic blood pressure appears to be the best indicator of the risk of CKD in people with type 2 diabetes. However, the optimal and safest lower limit of systolic blood pressure has not been clearly defined and recommendations vary in current guidelines. Kidney Health Australia currently recommends a blood pressure consistently below 130/80 mmHg as a goal for all people with CKD, whereas the Heart Foundation recommends a target below <140/90 mmHg with a systolic blood pressure of <120 mmHg in some patients.^9,10 

For appropriate individual targets for blood pressure, refer to ‘Type 2 diabetes and cardiovascular risk’ and ‘Type 2 diabetes: Goals for optimum management’. 

Independent of diabetes, proteinuria and reduced eGFR have been associated with an increased risk of major cardiovascular disease; the additional presence of type 2 diabetes increases this risk 2.4- to 4.6-fold compared with people without diabetes.¹¹ 

CKD is largely asymptomatic until advanced CKD occurs, so early assessment and diagnosis are critical before the severity of disease is advanced, diagnosed by the persistent presence of elevated urine albumin excretion, low eGFR or other manifestations of kidney damage.

Screening for CKD can be performed by the following two laboratory tests: 

• early morning or spot urine uACR) 
• eGFR (in Australia, eGFR is now automatically calculated from measurement of serum creatinine). 

Any positive uACR needs to be confirmed with a repeated collection performed within three months to ascertain persistent abnormality. Contributors to transient albuminuria should be considered; for example:¹² 

• urinary tract infection 
• decompensated congestive heart failure 
• menstruation 
• acute severe elevation in blood glucose or blood pressure 
• recent major exercise 
• febrile illness. 

Figure 1 provides an algorithm for the initial detection and diagnosis of CKD. 
Figure 1. Algorithm for initial detection and diagnosis of chronic kidney disease (CKD).⁹ 
 

Type 2 diabetes and CKD 

The baseline approach to managing CKD in people with type 2 diabetes is as follows: 

• exclude treatable causes of kidney disease, such as glomerulonephritis, renal artery stenosis, obstructive nephropathy and acute kidney injury due to dehydration 
• perform CVD risk assessment (refer to ‘Type 2 diabetes and cardiovascular risk’) 
• regularly review the choice and dose of medications in order to achieve optimal blood pressure and glycaemic management 
• support lifestyle management in addition to pharmacological management 
• advise on smoking cessation, limiting salt intake, moderate alcohol consumption and weight management 
• pharmacological therapies include: 
  • the use of an ACEi or ARB to the maximally tolerated dose, which, in addition to addressing hypertension, may also assist albuminuric CKD 
  • SGLT2i should be considered according to CKD stage, and a dip in eGFR may occur on initiation, but this stabilises in most patients 
  • the use of a non-steroidal mineralocorticoid receptor antagonist (currently finerenone is available; careful selection in individual patients and the risks of hyperkalaemia may need to be managed with this agent) 
  • lipid-lowering combinations such as statins and ezetimibe need to be considered to address cardiovascular risks 
  • the use of GLP-1 receptor agonists (GLP-1RAs) with evidence of renal benefits may be appropriate in individual patients, noting current Therapeutic Goods Administration indications and Pharmaceutical Benefits Scheme restrictions 
  • avoid the ‘triple whammy’ (refer below) 
• maintain up-to-date immunisations 
• provide adults with diabetes and CKD a ‘sick-day’ medication list that outlines which medications should be withheld during times of acute illness.¹² 

Detailed consideration regarding diabetes medications are as follows. 

• Metformin: use with caution as eGFR decreases. Dose reduction is needed for eGFR 30–60 mL/min/1.73 m2. Metformin should be ceased if eGFR falls below 30 mL/min/1.73 m2 due to a risk of lactic acidosis. 
• Dipeptidyl peptidase-4 inhibitors:¹³ no dose adjustment required for linagliptin in renal impairment due to hepatic metabolism. Reductions in doses of alogliptin, saxagliptin, sitagliptin and vildagliptin are required in patients with eGFR <60 mL/min/1.73 m2 due to pharmacological accumulation without toxicity. Saxagliptin is not recommended in patients with eGFR <15 mL/min/1.73 m2, whereas the other drugs may be used with appropriate dose adjustment.¹⁴ 
• Sulfonylureas:¹³ dose review is required because CKD increases the risk of hypoglycaemia. 
• SGLT2i:^15,16 these require adequate glomerular filtration for glycaemic-lowering efficacy. Dapagliflozin and empagliflozin may be used for glycaemic management, but if eGFR <45 mL/min/1.73 m2 in the case of dapagliflozin and <30 mL/min/1.73 m2 in the case of empagliflozin, then additional therapeutic options may need to be considered. However, non-glycaemic effects in reducing the progression of microalbuminuria and macroalbuminuria, as well as the progression of renal disease and end-stage renal disease, have been demonstrated in recent trials down to an eGFR of 25 mL/min/1.73 m2 for dapagliflozin and 20 mL/min/1.73 m2 for empagliflozin¹⁷ 
• Acarbose:¹³ avoid if the creatinine clearance rate is <25 mL/min. 
• Glitazones: dose adjustment in patients with CKD is not needed.¹³ Glitazones should not be used in people on dialysis, because safety in this patient group has not been established. 
• GLP-1RAs: GLP-1RAs have been shown to improve albuminuria, and semaglutide has demonstrated a positive effect on a composite of kidney and cardiovascular outcomes in albuminuric kidney disease.¹⁸ There is limited experience in the use of dulaglutide and semaglutide in people with end-stage renal disease.^17,19 
• Insulin: regular review of dose is indicated, because CKD increases the risks of hypoglycaemia. 
• Any potentially nephrotoxic medications, such as non-steroidal anti-inflammatory drugs (NSAIDs), should be avoided. 
• Avoid the ‘triple whammy’, which refers to acute nephrotoxicity when people are exposed to the combination of NSAIDs, diuretics and ACEi/ARBs.²⁰ 

Consider referral of people to specialist renal care if they fulfil the criteria in Box 1. Referral to other members of a multidisciplinary team, such as an accredited practising dietitian or a credentialled diabetes educator, may also assist with management and appropriate renal dietary recommendations. 

Resources for general practitioners 

• The Kidney Failure Risk Equation
• KDIGO
• Kidney Health Australia Chronic kidney disease (CKD) management in primary care handbook (5th edition) 
• Kidney Health Australia patient resources 
• Kidney Health Australia resources for Aboriginal and Torres Strait Islander People
• CARI Guidelines