Diabetic kidney disease

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

type 1 diabetes with nephropathy: not on dialysis

1st line – glycaemic control

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1st line –

glycaemic control

In all type 1 diabetic patients, regardless of whether they are on dialysis or not, treatment with insulin is needed. Insulin is usually given subcutaneously. See Type 1 diabetes.

Patients with type 1 diabetes and chronic kidney disease (CKD) are at risk for hypoglycaemia because of impaired clearance of insulin, and because of impaired kidney gluconeogenesis.

American Diabetes Association guidelines recommend keeping HbA1c at <53 mmol/mol (<7%) for adults with diabetes, noting that setting a glycaemic goal during consultations is likely to improve patient outcomes.[1] Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that individualised HbA1c targets should range from <48 mmol/mol to <64 mmol/mol (<6.5% to <8.0%) for patients with diabetes and CKD not treated with dialysis.[47] Targets in this range have been associated with improvements in survival, cardiovascular (CV) outcomes, and microvascular endpoints, as well as lower risk of CKD progression.[47] Safe achievement of targets at the lower end of this range (e.g., <48 mmol/mol or <53 mmol/mol [<6.5% or <7.0%]) may be facilitated by continuous glucose monitoring or self-monitoring of blood glucose and by selection of glucose-lowering agents that are not associated with hypoglycaemia.[47]

UK guidelines recommend setting individualised HbA1c targets in discussion with the patient. A goal of 48 mmol/mol (6.5%) is appropriate for most adults. A goal of 53 mmol/mol (7.0%) may be used for adults on drugs associated with hypoglycaemia.[83]

Intensive lowering of blood glucose with the goal of achieving near-normoglycaemia has been shown in large, randomised studies to delay the onset and progression of albuminuria and slow estimated glomerular filtration rate (eGFR) decline in people with type 1 and type 2 diabetes.[1][69][70][71][72][73][74][75][76][77] [ ] Less stringent goals may be appropriate for very young children, older adults, people with frailty, people with a history of severe hypoglycaemia, and those with limited life expectancies, advanced microvascular or macrovascular complications, or comorbid conditions.[1] Treatment goals need to be individualised, taking into account age, disease progression, and macrovascular risk, as well as the patient's lifestyle and disease management capabilities.[80] The main harm associated with lower HbA1c targets is hypoglycaemia; the benefits of strict control need to be balanced against the risk of harm for each patient.

Plus – lifestyle and risk factor modifications

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Plus –

lifestyle and risk factor modifications

Treatment recommended for ALL patients in selected patient group

Smoking cessation: smoking cessation is strongly recommended, as studies document a relation between smoking and loss of GFR. The mechanisms underlying the adverse renal effects of smoking are still incompletely understood. Beyond its effect on progression of renal failure, smoking is also an important cardiovascular (CV) risk factor in patients with chronic kidney disease (CKD).[185] American Diabetes Association (ADA) guidelines do not support e-cigarettes as an alternative to smoking nor to facilitate smoking cessation.[1] See Smoking cessation.

Nutrition: medical nutrition therapy by a registered dietitian is recommended for people with type 1 or type 2 diabetes.[29][179] An initial series of 3 to 4 encounters results in positive outcomes, including reductions in HbA1c, lipids, and weight, a positive adjustment in medications, and a decrease in comorbidities. Patients should have a follow-up visit annually.[179] High-protein diets should be avoided.[1][4][27] Every patient should be assessed individually to weigh the benefits of a moderate-protein diet (and associated avoidance of aminoaciduria and hyperfiltration). Low-protein diets (0.6 g/kg) should be avoided due to the risks of malnutrition and lack of evidence for a benefit on CKD progression.[28][29][180] For people with non-dialysis-dependent CKD, dietary protein intake should be approximately 0.8 g/kg body weight per day (the recommended daily allowance).[1][47] Limited intake of saturated fat and cholesterol is beneficial.[1] Restriction of dietary sodium (to <2300 mg/day) may be useful to control blood pressure and reduce CV risk, and individualisation of dietary potassium may be necessary to control serum potassium concentrations.[1][188] [ ] Although a multivitamin is recommended, high doses of B vitamins resulted in increased vascular events.[187]

Patients with comorbid overweight/obesity: Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend weight loss in patients with obesity, diabetes, and CKD, particularly those with estimated glomerular filtration rate (eGFR) ≥30 mL/minute per 1.73 m².[47] Additionally, weight loss will be required for those who exceed body mass index (BMI) limits for kidney transplant listing.[47][48]

Plus – lipid management

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Plus –

lipid management

Treatment recommended for ALL patients in selected patient group

People with DKD have a high risk of cardiovascular (CV) events. Management of CV risk should therefore be a strong consideration in order to reduce mortality from atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) is the most extensively studied modifiable risk factor associated with ASCVD. There is strong evidence that it is a causal factor in the pathophysiology of ASCVD, and that ASCVD risk reduction is proportional to the absolute and relative LDL-C reduction achieved.[175]

American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) consensus guidelines recommend a statin for all patients with type 1 diabetes and chronic kidney disease (CKD); moderate-intensity statin therapy for primary prevention of ASCVD; and high-intensity statin therapy for patients with known ASCVD and some patients with multiple ASCVD risk factors.[48] The Endocrine Society recommends that all adults with diabetes with CKD stages 1-4 and post renal transplant should receive statin therapy, irrespective of their CV risk score.[176] Guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) recommend that lipid treatment should be guided by CVD risk.[177] UK National Institute for Health and Care Excellence (NICE) guidelines advise offering high-intensity statin therapy (i.e., atorvastatin at the low end of the high-intensity dose range) to people with CKD for both primary and secondary prevention of CVD, with the dose being increased if lipid targets are not met.[178] It should be noted that NICE differs from the ADA and ACC/AHA regarding the dosage threshold at which it classifies certain statins as being high-intensity or moderate-intensity; local guidelines should be consulted.

For primary prevention in adults with diabetes without established ASCVD, ADA guidelines recommend: moderate-intensity statin therapy in all people aged 40-75 years; consideration of moderate-intensity statin therapy in patients aged 20-39 years with additional ASCVD risk factors; high-intensity statin therapy in people aged 40-75 years at higher CV risk, including those with one or more ASCVD risk factors, to reduce LDL-C by ≥50% of baseline and to target an LDL-C goal of <1.81 mmol/L (<70 mg/dL); the addition of ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monoclonal antibody (e.g., alirocumab, evolocumab) to maximum tolerated statin therapy should be considered in people aged 40-75 years at higher CV risk, especially those with multiple CVD risk factors and LDL-C ≥1.81 mmol/L (≥70 mg/dL); for adults aged >75 years already established on statin therapy, it is reasonable to continue statin treatment and may be reasonable to initiate moderate-intensity statin therapy following discussion of the potential benefits and risks; in people intolerant of statin therapy, treatment with bempedoic acid is recommended as an alternative cholesterol-lowering therapy.[1]

Given that CKD and albuminuria are classed as ASCVD risk factors, the majority of patients with DKD over 20 years of age should be treated with a statin based on this guidance.[1] Guidelines for lipid management differ for patients with diabetes who have established CV disease (i.e., secondary prevention). For further information, see Diabetic cardiovascular disease.

Statins are likely to be beneficial because of their anti-inflammatory properties and the correlation of inflammation in CKD with associated CV morbidity. They may decrease the rate of reduction in GFR and moderately decrease progressive increase in proteinuria in CKD.[26] Consideration should be given to the renal clearance of the statin. Pitavastatin, pravastatin, and rosuvastatin all have at least partial clearance through the kidney, whereas atorvastatin, fluvastatin, lovastatin, and simvastatin are cleared via the liver. All statins require dose adjustments in CKD, except for atorvastatin and fluvastatin.[176]

Icosapent ethyl can be considered in patients with additional CV risk factors who are on a statin and have controlled LDL-C but elevated triglycerides (1.53 to 5.64 mmol/L [135-499 mg/dL]).[1] It has been shown to modestly reduce CV events.[182][183]

Primary options

atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily

fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily; or 80 mg orally (extended-release) once daily

Secondary options

atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily

fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily; or 80 mg orally (extended-release) once daily

-- AND --

ezetimibe: 10 mg orally once daily

atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily

fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily; or 80 mg orally (extended-release) once daily

-- AND --

evolocumab: 140 mg subcutaneously every 2 weeks; or 420 mg subcutaneously once monthly

alirocumab: 75-150 mg subcutaneously every 2 weeks; or 300 mg subcutaneously every 4 weeks

atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily

fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily, or 80 mg orally (extended-release) once daily

-- AND --

icosapent ethyl: 2 g orally twice daily

Tertiary options

bempedoic acid: 180 mg orally once daily

with albuminuria (albumin to creatinine ratio [ACR] ≥3 mg/mmol [≥30 mg/g])

Consider – ACE inhibitor or angiotensin-II receptor antagonist

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Consider –

ACE inhibitor or angiotensin-II receptor antagonist

Additional treatment recommended for SOME patients in selected patient group

American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend an ACE inhibitor or angiotensin-II receptor antagonist in all patients with albuminuria and co-existing hypertension (blood pressure [BP] ≥130/80 mmHg).[48] However, KDIGO also recommends considering pharmacological therapy with one of these agents in patients with albuminuria and normal BP.[47] UK National Institute for Health and Care Excellence (NICE) guidelines also recommend treatment for all patients with albuminuria regardless of BP.[26][136]

The ADA recommends that all individuals with type 1 diabetes and BP ≥130/80 mmHg should qualify for pharmacological therapy to lower BP to <130/80 mmHg (providing this target can be safely attained).[1] It recommends an individualised approach to BP targets, however, advising that patients and clinicians should engage in a shared decision-making process to determine individual BP targets, and acknowledging that the benefits and risks of intensive BP targets are uncertain.[1] Lower BP targets may be suitable in some cases, especially in patients with severely elevated albuminuria (ACR ≥30 mg/mmol [≥300 mg/g]), provided the patient's individual benefits and risks have been taken into account.[1] KDIGO guidelines recommend a lower systolic BP goal of <120 mmHg (when tolerated) in adults with hypertension and chronic kidney disease (CKD), noting that evidence for the benefits of intensive BP control is less certain in patients with diabetes than those without.[138][139][140]

First-line treatment of patients with diabetes, hypertension, and albuminuria should be with an ACE inhibitor, or an angiotensin-II receptor antagonist if an ACE inhibitor is not tolerated, titrated to the highest tolerated approved dose (a dose reduction may be required in patients with renal impairment).[1][48][133][136][141] Treatment with these drugs has been shown to reduce proteinuria and slow the progression of DKD in patients with type 1 and type 2 diabetes with moderately increased albuminuria.[142][143][144] [ ] The ONTARGET study demonstrated that angiotensin-II receptor antagonists and ACE inhibitors are equal in prevention of cardiovascular morbidity and mortality, myocardial infarction, and stroke.[145][146]

UK NICE guidelines recommend that all patients (including those with normal BP) with type 1 or type 2 diabetes and CKD with albumin to creatinine ratio (ACR) ≥3 mg/mmol (≥30 mg/g) should be offered an ACE inhibitor or angiotensin-II receptor antagonist, titrated to the highest licensed dose that the person can tolerate (provided that they meet the criteria in the marketing authorisation, including relevant estimated glomerular filtration rate [eGFR] thresholds).[83][136]

While ADA and KDIGO guidelines specify that ACE inhibitors and angiotensin-II receptor antagonists should be used in those patients with albuminuria who have co-existing hypertension, the KDIGO guidelines note that for patients with diabetes, albuminuria, and normal BP, treatment with an ACE inhibitor or angiotensin-II receptor antagonist may be considered.[1][47] Available data suggest that ACE inhibitors and angiotensin-II receptor antagonists are not beneficial for patients with neither albuminuria nor elevated BP.[47] The ADA comments that while ACE inhibitors or angiotensin-II receptor antagonists are often prescribed for moderately increased albuminuria (ACR 3-29 mg/mmol [30-299 mg/g]) without hypertension, trials have not been performed in this setting to determine whether they improve renal outcomes.[1] Moreover, two long-term, double-blind studies demonstrated no renoprotective effect of either ACE inhibitors or angiotensin-II receptor antagonists among people with type 1 and type 2 diabetes who were normotensive, with or without moderately increased albuminuria.[147][148]

ACE inhibitors and angiotensin-II receptor antagonists are generally well tolerated. However, dry cough is a known adverse effect of ACE inhibitor treatment, affecting about 10% of patients.[47] Angio-oedema has also been associated with the use of ACE inhibitors.[47] It has been postulated that these adverse effects are due to the inhibition of ACE-dependent degradation of bradykinin, and consideration can be given to switching affected patients to an angiotensin-II receptor antagonist.[47] The incidence of angio-oedema with angiotensin-II receptor antagonists is not significantly different from that of placebo.[153] ACE inhibitors and angiotensin-II receptor antagonists can also cause hypotension, hyperkalaemia, and a rise in serum creatinine. Consequently, BP, serum potassium, and serum creatinine should be monitored in patients who are started on these medications or whenever there is a change in the dose of the drug. The changes in BP, potassium, and kidney function are usually reversible if medication is stopped or doses are reduced.[47]

Primary options

captopril: 25-50 mg orally two to three times daily; dose should be adjusted according to level of renal impairment

enalapril: 2.5 to 40 mg orally once daily; dose should be adjusted according to level of renal impairment

lisinopril: 2.5 to 40 mg orally once daily; dose should be adjusted according to level of renal impairment

ramipril: 1.25 to 20 mg orally once daily; dose should be adjusted according to level of renal impairment

trandolapril: 0.5 to 4 mg orally once daily; dose should be adjusted according to level of renal impairment

Secondary options

losartan: 25-100 mg/day orally given in 1-2 divided doses

valsartan: 80-320 mg orally once daily

candesartan: 8-32 mg orally once daily

Consider – additional antihypertensive therapy

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Consider –

additional antihypertensive therapy

Additional treatment recommended for SOME patients in selected patient group

Additional antihypertensive therapy is required in most patients to reach blood pressure (BP) targets.[154][155]

Dihydropyridine calcium-channel blockers, thiazide-like diuretics, or beta-blockers are commonly used as add-on agents to ACE inhibitors or angiotensin-II receptor antagonists and may be used in combination as triple-therapy (i.e., with an ACE inhibitor or angiotensin-II receptor antagonist) if required.[155][156]

Beta-blockers may mask symptoms of hypoglycaemia, but may be used as add-on treatment in patients who require multiple agents to reach BP targets or in those with another indication for the use of beta-blockers (e.g., ischaemic heart disease).[155]

Diuretics are almost always required to control BP in advanced DKD. Although loop diuretics have long been the cornerstone of therapy in such patients, the CLICK trial demonstrated that chlortalidone (a thiazide-like diuretic), with or without a loop diuretic, is also effective.[157]

Joint American Diabetes Association (ADA)/Kidney Disease: Improving Global Outcomes (KDIGO) consensus guidelines recommend that aldosterone antagonists (e.g., spironolactone, eplerenone) can be used in patients with resistant hypertension (BP above target despite ACE inhibitors/angiotensin-II receptor antagonists, calcium-channel blockers, and diuretics) but only if estimated glomerular filtration rate (eGFR) is ≥45 mL/minute/1.73 m².[48]

The choice of additional antihypertensive therapy depends on various patient and clinical factors.

without albuminuria (albumin to creatinine ratio [ACR] <3 mg/mmol [<30 mg/g]) and BP ≥130/80 mmHg

Plus – ACE inhibitor or angiotensin-II receptor antagonist or calcium-channel blocker or thiazide-like diuretic

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Plus –

ACE inhibitor or angiotensin-II receptor antagonist or calcium-channel blocker or thiazide-like diuretic

Treatment recommended for ALL patients in selected patient group

The American Diabetes Association (ADA) recommends that all individuals with type 1 diabetes and blood pressure (BP) ≥130/80 mmHg should qualify for pharmacological therapy to lower BP to <130/80 mmHg (providing this target can be safely attained).[1] It recommends an individualised approach to BP targets, however, advising that patients and clinicians should engage in a shared decision-making process to determine individual BP targets, and acknowledging that the benefits and risks of intensive BP targets are uncertain.[1] Lower BP targets may be suitable in some cases, especially in patients with severely elevated albuminuria (ACR ≥30 mg/mmol [≥300 mg/g]), provided the patient's individual benefits and risks have been taken into account.[1] Of note, Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend a lower systolic BP goal of <120 mmHg (when tolerated) in adults with hypertension and chronic kidney disease (CKD), noting that evidence for the benefits of intensive BP control is less certain in patients with diabetes than those without.[138][139][140]

Patients with diabetes and hypertension are at lower risk of CKD progression when urine albumin excretion is normal (ACR <3 mg/mmol [<30 mg/g]), and existing evidence does not demonstrate clear clinical benefit of renin-angiotensin system inhibition for CKD progression in this population.[47] Cardiovascular risk reduction is the most important goal of BP management with normal urine albumin excretion, and multiple classes of antihypertensive agents (including ACE inhibitors or angiotensin-II receptor antagonists, thiazide-like diuretics, and dihydropyridine calcium-channel blockers) are appropriate first-line options in this setting.[47]

Examples of suitable ACE inhibitors (e.g., captopril, enalapril, lisinopril, ramipril, trandolapril), angiotensin-II receptor antagonists (e.g., losartan, valsartan, candesartan), dihydropyridine calcium-channel blockers (e.g., amlodipine, felodipine, nifedipine), and thiazide-like diuretics (e.g., hydrochlorothiazide, chlortalidone) are included here. However, this list is not exhaustive, and you should consult your local drug information source for more options.

Primary options

captopril: 25-50 mg orally two to three times daily; dose should be adjusted according to level of renal impairment

enalapril: 2.5 to 40 mg orally once daily; dose should be adjusted according to level of renal impairment

lisinopril: 2.5 to 40 mg orally once daily; dose should be adjusted according to level of renal impairment

ramipril: 1.25 to 20 mg orally once daily; dose should be adjusted according to level of renal impairment

trandolapril: 0.5 to 4 mg orally once daily; dose should be adjusted according to level of renal impairment

losartan: 25-100 mg/day orally given in 1-2 divided doses

valsartan: 80-320 mg orally once daily

candesartan: 8-32 mg orally once daily

amlodipine: 2.5 to 10 mg orally once daily

felodipine: 2.5 to 10 mg orally once daily

nifedipine: 30-120 mg orally (extended-release) once daily

hydrochlorothiazide: 12.5 to 50 mg orally once daily

chlortalidone: 12.5 to 25 mg orally once daily

Consider – additional antihypertensive therapy

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Consider –

additional antihypertensive therapy

Additional treatment recommended for SOME patients in selected patient group

Additional antihypertensive therapy is required in most patients to reach blood pressure (BP) targets.[154][155]

If a patient is already taking an ACE inhibitor or angiotensin-II receptor antagonist, a dihydropyridine calcium-channel blocker and/or thiazide-like diuretic and/or beta-blocker can be used as add-on agents and may be used in combination as triple-therapy (i.e., agents from two of these three classes are used with an ACE inhibitor or angiotensin-II receptor antagonist) if required.[155][156]

If a patient is already on a dihydropyridine calcium-channel blocker as their first-line treatment, an ACE inhibitor or angiotensin-II receptor antagonist and/or thiazide-like diuretic and/or beta-blocker can be used as add-on agents and may be used in combination as triple-therapy.

If a patient is already on a thiazide-like diuretic as their first-line treatment, an ACE inhibitor or angiotensin-II receptor antagonist and/or dihydropyridine calcium-channel blocker and/or beta-blocker can be used as add-on agents and may be used in combination as triple-therapy.

Diuretics are almost always required to control BP in advanced DKD. While loop diuretics have long been the cornerstone of therapy in such patients, the CLICK trial demonstrated that chlortalidone (a thiazide-like diuretic) with or without a loop diuretic is also effective.[157]

Joint American Diabetes Association (ADA)/Kidney Disease: Improving Global Outcomes (KDIGO) consensus guidelines recommend that aldosterone antagonists (e.g., spironolactone, eplerenone) can be used in patients with resistant hypertension (BP above target despite ACE inhibitors/angiotensin-II receptor antagonists, calcium-channel blockers, and thiazide-like diuretics) but only if estimated glomerular filtration rate (eGFR) is ≥45 mL/minute/1.73 m².[48]

The choice of additional antihypertensive therapy depends on various patient and clinical factors.

type 2 diabetes with nephropathy: not on dialysis

1st line – glycaemic control

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1st line –

glycaemic control

American Diabetes Association guidelines recommend keeping HbA1c at <53 mmol/mol (<7%) for adults with diabetes, noting that setting a glycaemic goal during consultations is likely to improve patient outcomes.[1] Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that individualised HbA1c targets should range from <48 mmol/mol to <64 mmol/mol (<6.5% to <8.0%) for patients with diabetes and chronic kidney disease (CKD) not treated with dialysis.[47] Targets in this range have been associated with improvements in survival, cardiovascular (CV) outcomes, and microvascular endpoints, as well as lower risk of CKD progression.[47] Safe achievement of targets at the lower end of this range (e.g., <48 mmol/mol or <53 mmol/mol [<6.5% or <7.0%]) may be facilitated by continuous glucose monitoring or self-monitoring of blood glucose and by selection of glucose-lowering agents that are not associated with hypoglycaemia.[47]

Treatments and the combinations of drugs that are used need to be individualised for each patient. For further information, see Type 2 diabetes in adults. Special consideration should be given to the use of agents that reduce the risk of both CKD progression and CV events.[1]

Patients may begin with metformin if eGFR is ≥30 mL/minute/1.73 m². A sodium-glucose co-transporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) receptor agonist is a reasonable second-line option (with some caveats).[1][66][67][68] [ ]

Metformin: cleared by renal filtration, and very high circulating levels (e.g., as a result of overdose or acute renal failure) have been associated with lactic acidosis. However, the occurrence of this complication is now known to be very rare, and metformin may be safely used in people with eGFR ≥30 mL/minute/1.73 m².[1] Metformin is contraindicated if eGFR is <30 mL/minute/1.73 m².[48][81] Dose reduction should be considered when eGFR is <45 mL/minute/1.73 m² in patients continuing on existing therapy. However, metformin should not be initiated in patients with an eGFR of 30-45 mL/minute/1.73 m².[48][66] Dose reduction may also be considered in some patients with eGFR 45-59 mL/minute/1.73 m² who are at high risk of lactic acidosis.[48] One Cochrane review did not find enough evidence to show that metformin had any effect on kidney function, with the authors concluding that further evidence in the form of large, well‐designed randomised trials is needed to more robustly assess whether metformin can be a long‐term protective treatment in those with CKD.[82]

SGLT2 inhibitors: in addition to reducing hyperglycaemia, these drugs have renal benefits through independent effects on renal tubular glucose reabsorption, weight, blood pressure (BP), intraglomerular pressures, albuminuria, and slowed eGFR loss.[1][84] They are moderately to highly effective at glycaemic control and very effective at reducing proteinuria and slowing the progression of DKD.[67][85][86] They reduce the risk of serious hyperkalaemia in people with type 2 diabetes and CKD without increasing the risk of hypokalaemia.[93][94] Compared with usual care or placebo, they also reduce the risk for all-cause mortality by 12%, major adverse cardiac events (MACE; non-fatal myocardial infarction, non-fatal stroke, and CV mortality) by 10%, and hospitalisation due to congestive heart failure by 36%.[95] They have been found to reduce the risk of renal and heart failure outcomes for all eGFR categories, although the greatest benefits in terms of kidney protection may be achieved by their early initiation in people with preserved eGFR.[96][97]

Initiation of an SGLT2 inhibitor is generally not recommended (or should be done with caution) in patients with eGFR <20 mL/minute/1.73 m².[1] However, once an SGLT2 inhibitor is initiated, it is reasonable to continue it even if the eGFR falls below 20 mL/minute/1.73 m², unless it is not tolerated or kidney replacement therapy is initiated.[47][48] Patients should be monitored, however, and a dose reduction may sometimes be required. Concerns that these agents can cause acute kidney injury have been refuted by clinical outcome trials of advanced CKD.[98] Indications for SGLT2 inhibitors are expanding rapidly and are no longer limited to diabetes mellitus or albuminuria; some SGLT2 inhibitors are now indicated to help preserve kidney function and protect against end-stage renal disease (ESRD), even in the absence of diabetes mellitus and albuminuria, as well as to protect against cardiovascular death and hospitalisation for heart failure.[103] However, manufacturer recommendations for use of these drugs in patients with renal impairment may vary depending on the drug, the indication, and the country of approval; therefore, it is important to consult local guidance. Use of SGLT2 inhibitors is not indicated in patients with ESRD who are on dialysis.

GLP-1 receptor agonists: these drugs selectively bind to and activate the GLP-1 receptor, the target for native GLP-1, and are highly effective anti-diabetic medications that have been shown to reduce the risk for all-cause mortality and major adverse CV events.[95][107] Notably, they retain glycaemic efficacy and safety even in advanced CKD stages.[48] They may also improve renal outcomes independent of glucose-lowering effect and may have additional benefits of weight loss.[108][109][110] Their beneficial effect on renal outcomes appears to be inferior to that of SGLT2 inhibitors, although the landmark FLOW trial found that treatment with once-weekly subcutaneous semaglutide resulted in a 24% risk reduction in major kidney outcomes compared with placebo.[111][114] GLP-1 receptor agonists have the additional benefit of mild to moderate weight loss.[68][109] [ ]

Acute kidney injury has been reported with semaglutide.[115] Liraglutide, albiglutide, dulaglutide, and semaglutide are not renally excreted and are the preferred agents in this class. Exenatide is eliminated by renal excretion and should not be used in patients with severe renal impairment; the immediate-release formulation should not be used in patients with an eGFR <30 mL/minute/1.73 m², while the extended-release formulation should not be used in patients with an eGFR <45 mL/minute/1.73 m².

Dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist: tirzepatide is the first and only drug in this class to receive approval. It has been approved as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes. It is suitable for patients with overweight or obesity without gastroparesis who desire weight loss, are willing to take injections, and can tolerate the common adverse effect of initial nausea. It has been shown to have a greater effect on glucose levels and weight control than selective GLP-1 receptor agonists, without increased risk of hypoglycaemia.[118][119][120] CV safety trials are under way. May be used in patients with renal impairment of any degree and no dose adjustment is required.

Dipeptidyl peptidase-4 (DPP-4) inhibitors: these drugs can also be used in patients with DKD, but the dose may need to be adjusted depending on the degree of renal dysfunction.[124] Studies report that DPP-4 inhibitors may be renoprotective, although evidence for renoprotection is weak in comparison to that for SGLT2 inhibitors.[124] They show pleiotropic effects in in vitro models, reducing inflammation, fibrosis, and oxidative damage, suggesting potential kidney-protective effects.[125] Although existing trials suggest a possible benefit in the progression of DKD, further studies are needed to demonstrate kidney-specific benefits of DPP-4 inhibitors.[125] The ADA and European Association for the Study of Diabetes (EASD) report that at a class level, DPP-4 inhibitors have a neutral effect on progression of DKD.[66]

Sitagliptin, saxagliptin, and alogliptin can be used in patients with DKD, but the doses must be adjusted depending on the degree of renal dysfunction. Linagliptin can also be used in patients with DKD, including end-stage renal disease, though there is limited experience with its use. Linagliptin is not renally cleared and thus a dose adjustment is not necessary.

Sulfonylureas and meglitinides: if other agents are required for glycaemic control, glipizide is the sulfonylurea of choice due to its metabolite having little or no hypoglycaemic activity.[65] Glimepiride is also acceptable, but glyburide should not be used, due to accumulation of active metabolites and increased risk of hypoglycaemia. Nateglinide is a meglitinide that is not renally cleared and is considered within its drug class to be safest for CKD.[127]

Thiazolidenediones: although there is evidence showing that thiazolidinediones (e.g., pioglitazone) reduce hyperglycaemia, albuminuria, and proteinuria in people with diabetes, the clinical significance of this finding is unclear.[128] The ADA/EASD report that they have a neutral effect on progression of DKD.[1][66] Thiazolidinediones are associated with fluid retention and should be avoided in patients with advanced CKD and in patients on dialysis.

Insulin: treatment with insulin is required if there is evidence of ongoing catabolism (weight loss, hypertriglyceridaemia, and ketosis), symptoms of hyperglycaemia (polyuria and polydipsia), or when HbA1c or blood glucose levels are very high (i.e., HbA1c >10% and/or blood glucose ≥16.7 mmol/L [≥300 mg/dL]), regardless of background glucose-lowering therapy or disease stage.[1] Intensification to insulin is also an option for individuals who are not meeting their glycaemic targets on other antihyperglycaemic agents; it is necessary in at least 20% to 30% of those with type 2 diabetes in order to achieve recommended treatment goals. Of note, the ADA recommends that a GLP-1 receptor agonist or dual GIP/GLP-1 receptor agonist should be considered prior to insulin if injectable therapy is needed and the patient is not already being treated with one of these drugs.[1] If insulin is used, combination therapy with a GLP-1 receptor agonist or dual GIP/GLP-1 receptor agonist is recommended for greater glycaemic efficacy, as well as the beneficial effects of these drugs on reducing weight and hypoglycaemia risk (as lower insulin doses can be used), reducing CV events (GLP-1 receptor agonists), and slowing CKD progression (semaglutide).[1]

In patients with CKD, there is a risk for hypoglycaemia because of impaired kidney clearance of medications such as insulin (two-thirds of insulin is degraded by the kidney) or sulfonylureas, and because of impaired kidney gluconeogenesis. Caution should be taken when using these medications and patients counselled about the risk of hypoglycaemia.[48]

Patients with comorbid overweight/obesity: when selecting an antihyperglycaemic agent in those with type 2 diabetes mellitus, CKD, and overweight/obesity, a GLP-1 receptor agonist or tirzepatide may be preferred to promote intentional weight loss.[1][47]

Plus – lifestyle and risk factor modifications

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Plus –

lifestyle and risk factor modifications

Treatment recommended for ALL patients in selected patient group

Smoking cessation: smoking cessation is strongly recommended, as studies document a relation between smoking and loss of glomerular filtration rate (GFR). The mechanisms underlying the adverse renal effects of smoking are still incompletely understood. Beyond its effect on progression of renal failure, smoking is also an important cardiovascular (CV) risk factor in patients with chronic kidney disease (CKD).[185] American Diabetes Association (ADA) guidelines do not support e-cigarettes as an alternative to smoking nor to facilitate smoking cessation.[1] See Smoking cessation.

Nutrition: medical nutrition therapy by a registered dietitian is recommended for people with type 1 or type 2 diabetes.[29][179] An initial series of 3 to 4 encounters results in positive outcomes, including reductions in HbA1c, lipids, and weight, a positive adjustment in medications, and a decrease in comorbidities. Patients should also have a follow-up visit annually.[179] High-protein diets should be avoided.[1][4][27] Every patient should be assessed individually to weigh the benefits of a moderate-protein diet (and associated avoidance of aminoaciduria and hyperfiltration); low-protein diets (0.6 g/kg) should be avoided due to the risks of malnutrition.[29][180] For people with non-dialysis-dependent CKD, dietary protein intake should be approximately 0.8 g/kg body weight per day (the recommended daily allowance).[1][47] One systematic review was unable to show a benefit of protein restriction on renal failure.[28] Limited intake of saturated fat and cholesterol is beneficial.[1] Restriction of dietary sodium (to <2300 mg/day) may be useful to control blood pressure and reduce CV risk, and individualisation of dietary potassium may be necessary to control serum potassium concentrations.[1][188] [ ] Although a multivitamin is recommended, high doses of B vitamins resulted in increased vascular events.[187]

Patients with comorbid overweight/obesity: weight management is a primary goal of treatment in patients with type 2 diabetes and overweight or obesity.[1] Weight loss strategies may include behavioural and lifestyle counselling, pharmacotherapy, and metabolic surgery. The ADA advises that any amount of weight loss will be beneficial, but that losing 3% to 7% of baseline weight improves glycaemia and other cardiovascular risk factors. A sustained loss of >10% of body weight may result in disease-modifying effects and remission of type 2 diabetes.[1] Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend weight loss in patients with obesity, diabetes, and CKD, particularly those with estimated glomerular filtration rate (eGFR) ≥30 mL/minute per 1.73 m².[47] Additionally, weight loss will be required for those who exceed body mass index (BMI) limits for kidney transplant listing.[47][48]

Plus – lipid management

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Plus –

lipid management

Treatment recommended for ALL patients in selected patient group

American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) consensus guidelines recommend a statin for all patients with type 2 diabetes and chronic kidney disease (CKD); moderate-intensity statin therapy for primary prevention of ASCVD; and high-intensity statin therapy for patients with known ASCVD and some patients with multiple ASCVD risk factors.[48] The Endocrine Society recommends that all adults with diabetes with CKD stages 1-4 and post renal transplant should receive statin therapy, irrespective of their CV risk score.[176] Guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) recommend that lipid treatment should be guided by CVD risk.[177] UK National Institute for Health and Care Excellence (NICE) guidelines advise offering high-intensity statin therapy (i.e., atorvastatin at the low end of the high-intensity dose range) to people with CKD for both primary and secondary prevention of CVD, with the dose being increased if lipid targets are not met.[178] It should be noted that NICE differs from the ADA and ACC/AHA regarding the dosage threshold at which it classifies certain statins as being high-intensity or moderate-intensity; local guidelines should be consulted.

Statins are likely to be beneficial because of their anti-inflammatory properties and the correlation of inflammation in CKD with associated CV morbidity. They may decrease the rate of reduction in glomerular filtration rate (GFR) and moderately decrease progressive increase in proteinuria in CKD.[26] Consideration should be given to the renal clearance of the statin. Pitavastatin, pravastatin, and rosuvastatin all have at least partial clearance through the kidney, whereas atorvastatin, fluvastatin, lovastatin, and simvastatin are cleared via the liver. All statins require dose adjustments in CKD, except for atorvastatin and fluvastatin.[176]

Primary options

atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily

fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily; or 80 mg orally (extended-release) once daily

Secondary options

atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily

fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily; or 80 mg orally (extended-release) once daily

-- AND --

ezetimibe: 10 mg orally once daily

atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily

fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily; or 80 mg orally (extended-release) once daily

-- AND --

evolocumab: 140 mg subcutaneously every 2 weeks; or 420 mg subcutaneously once monthly

alirocumab: 75-150 mg subcutaneously every 2 weeks; or 300 mg subcutaneously every 4 weeks

atorvastatin: moderate intensity: 10-20 mg orally once daily; high intensity: 40-80 mg orally once daily

fluvastatin: moderate intensity: 40 mg orally (immediate-release) twice daily, or 80 mg orally (extended-release) once daily

-- AND --

icosapent ethyl: 2 g orally twice daily

Tertiary options

bempedoic acid: 180 mg orally once daily

Consider – sodium-glucose co-transporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor and/or glucagon-like peptide-1 (GLP-1) receptor agonist

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Consider –

sodium-glucose co-transporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor and/or glucagon-like peptide-1 (GLP-1) receptor agonist

Additional treatment recommended for SOME patients in selected patient group

If a patient is not already taking an SGLT2 inhibitor or a GLP-1 receptor agonist as part of their antihyperglycaemic regime, one of these medications should be initiated. The American Diabetes Association recommends that people with type 2 diabetes and established chronic kidney disease (CKD) should use an SGLT2 inhibitor and/or a GLP-1 receptor agonist with demonstrated cardiovascular disease (CVD) benefit as part of their comprehensive cardiovascular (CV) risk reduction regimen, independent of HbA1c or individualised HbA1c goal.[1] The selection of the specific agent depends on comorbidities and CKD stage. SGLT2 inhibitors should generally be favoured to reduce CKD progression and risk of CV events, although patients may be offered a GLP-1 receptor agonist if an SGLT2 inhibitor is not tolerated or contraindicated. SGLT2 inhibitors can be used in people with estimated glomerular filtration rate (eGFR) as low as 20 mL/minute/1.73 m².[1][66]

If a patient is taking an SGLT2 inhibitor or GLP-1 receptor agonist and requires additional pharmacotherapy for glucose-lowering, combined therapy with an SGLT2 inhibitor plus a GLP-1 receptor agonist may be considered, since this may provide additive reduction in the risk of adverse CV and kidney events.[1][48][116][117]

UK National Institute for Health and Care Excellence (NICE) guidelines differ and only recommend an SGLT2 inhibitor for patients with type 2 diabetes and CKD with albumin to creatinine ratio (ACR) >30 mg/mmol (>300 mg/g; severely increased albuminuria) who are already taking an ACE inhibitor or angiotensin-II receptor antagonist titrated to the highest licensed dose they can tolerate (provided they meet the criteria in the marketing authorisation, including relevant eGFR thresholds). SGLT2 inhibitor therapy can be considered for those with lower ACR (3-30 mg/mmol [30-300 mg/g]; moderately increased albuminura); however, the guidelines comment that there is more uncertainty around the clinical and cost effectiveness in this group than in people with baseline ACR >30 mg/mmol (>300 mg/g).[83]

SGLT2 inhibitors with a demonstrated CVD benefit include empagliflozin, canagliflozin, and dapagliflozin. Sotagliflozin is the first and only dual SGLT1/SGLT2 inhibitor.[104] It is approved by the US Food and Drug Administration (FDA) to reduce the risk of CV death, hospitalisation for heart failure, and urgent heart failure visit in adults with heart failure, or with type 2 diabetes mellitus, CKD, and other CV risk factors. Sotagliflozin has not been studied in patients with eGFR <25 mL/minute/1.73 m².

Reported adverse effects of SGLT2 inhibitors include a higher rate of genitourinary infections (reported to be typically mild and treatable), diabetic ketoacidosis (DKA), acute kidney injury, fracture, and/or amputation.[194][195][196][197][198] The FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA) warn of cases of necrotising fasciitis of the perineum (also known as Fournier's gangrene) observed in post-marketing surveillance.[199][200] SGLT2 inhibitors should be avoided in patients with conditions that increase the risk for limb amputations, and in patients prone to urinary tract or genital infections.

GLP-1 receptor agonists with a demonstrated CVD benefit include liraglutide, semaglutide, and dulaglutide.

The most common adverse effects of GLP-1 receptor agonists are gastrointestinal, particularly nausea, vomiting, and diarrhoea; these are frequent but tend to reduce over time.[201] An association with pancreatitis and pancreatic cancer has been reported in clinical trials; these drugs should be used with caution in patients with a history of pancreatitis.[1][201] GLP-1 receptor agonists have also been associated with increased risk of gallbladder and biliary diseases including cholelithiasis and cholecystitis.[201] Patients should be counselled about potential for ileus.[1] Hypoglycaemia risk is increased with concomitant sulfonylureas and insulin use. Treatment de-intensification of these agents or of diuretics, particularly in older and frail individuals, is recommended to avoid hypoglycaemia and hypovolaemia.[201] DKA has been reported in patients on a combination of a GLP-1 receptor agonist and insulin when the insulin was either rapidly reduced or discontinued; insulin reductions should therefore be undertaken in a cautious stepwise manner, with capillary blood glucose monitoring.[201][202] In rodent studies, GLP-1 receptor agonists were associated with medullary thyroid cancer, resulting in a warning for these agents in patients with a personal or family history of multiple endocrine neoplasia type 2 or medullary thyroid cancer; however, there is conflicting evidence as to whether this risk applies in humans.[201][203][204][205][206][207] The FDA and the European Medicines Agency (EMA) are reviewing data on the risk of suicidal thoughts and thoughts of self-harm with GLP-1 receptor agonists, following reports of such occurrences in people using liraglutide and semaglutide.[208][209][210]

Primary options

empagliflozin: 10 mg orally once daily, increase according to response, maximum 25 mg/day

canagliflozin: 100 mg orally once daily initially, increase according to response, maximum 300 mg/day

dapagliflozin: 5 mg orally once daily initially, increase according to response, maximum 10 mg/day

sotagliflozin: 200 mg orally once daily initially, increase according to response, maximum 400 mg/day

-- AND / OR --

liraglutide: 0.6 mg subcutaneously once daily initially, increase by 0.6 mg/day increments at weekly intervals according to response, maximum 1.8 mg/day

dulaglutide: 0.75 mg subcutaneously once weekly initially, may increase to 1.5 mg once weekly if response is inadequate, then increase by 1.5 mg/week increments every 4 weeks according to response, maximum 4.5 mg/week

semaglutide: 0.25 mg subcutaneously once weekly for 4 weeks initially, then increase to 0.5 mg once weekly for at least 4 weeks, then may increase to 1 mg once weekly for at least 4 weeks if response is inadequate, then may increase to 2 mg once weekly if response is inadequate; 3 mg orally once daily for 30 days initially, then increase to 7 mg once daily for at least 30 days, then may increase to 14 mg once daily if response is inadequate

with albuminuria (albumin to creatinine ratio [ACR] ≥3 mg/mmol [≥30 mg/g])

Consider – ACE inhibitor or angiotensin-II receptor antagonist

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Consider –

ACE inhibitor or angiotensin-II receptor antagonist

Additional treatment recommended for SOME patients in selected patient group

The ADA recommends that all individuals with type 2 diabetes and BP ≥130/80 mmHg should qualify for pharmacologic therapy to lower BP to <130/80 mmHg (providing this target can be safely attained).[1] It recommends an individualised approach to BP targets, however, advising that patients and clinicians should engage in a shared decision-making process to determine individual BP targets, and acknowledging that the benefits and risks of intensive BP targets are uncertain.[1] Lower BP targets may be suitable in some cases, especially in patients with severely elevated albuminuria (ACR ≥30 mg/mmol [≥300 mg/g]), provided the patient's individual benefits and risks have been taken into account.[1] KDIGO guidelines recommend a lower systolic BP goal of <120 mmHg (when tolerated) in adults with hypertension and chronic kidney disease (CKD), noting that evidence for the benefits of intensive BP control is less certain in patients with diabetes than those without.[138][139][140]

Of note, UK National Institute for Health and Care Excellence (NICE) guidelines recommend that ALL patients (including those with normal BP) with type 1 or type 2 diabetes and CKD with albumin to creatinine ratio (ACR) ≥3 mg/mmol (≥30 mg/g) should be offered an ACE inhibitor or angiotensin-II receptor antagonist, titrated to the highest licensed dose that the person can tolerate (provided that they meet the criteria in the marketing authorisation, including relevant estimated glomerular filtration rate [eGFR] thresholds).[83][136]

Primary options

captopril: 25-50 mg orally two to three times daily; dose should be adjusted according to level of renal impairment

enalapril: 2.5 to 40 mg orally once daily; dose should be adjusted according to level of renal impairment

lisinopril: 2.5 to 40 mg orally once daily; dose should be adjusted according to level of renal impairment

ramipril: 1.25 to 20 mg orally once daily; dose should be adjusted according to level of renal impairment

trandolapril: 0.5 to 4 mg orally once daily; dose should be adjusted according to level of renal impairment

Secondary options

losartan: 25-100 mg/day orally given in 1-2 divided doses

valsartan: 80-320 mg orally once daily

candesartan: 8-32 mg orally once daily

Consider – additional antihypertensive therapy

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Consider –

additional antihypertensive therapy

Additional treatment recommended for SOME patients in selected patient group

Additional antihypertensive therapy is required in most patients to reach blood pressure (BP) targets.[154][155]

Joint American Diabetes Association (ADA)/Kidney Disease: Improving Global Outcomes (KDIGO) consensus guidelines recommend that aldosterone antagonists (e.g., spironolactone, eplerenone), can be used in patients with resistant hypertension (BP above target despite ACE inhibitors/angiotensin-II receptor antagonists, calcium-channel blockers, and thiazide-like diuretics) but only if estimated glomerular filtration rate (eGFR) is ≥45 mL/minute/1.73 m².[48]

The choice of additional antihypertensive therapy depends on various patient and clinical factors.

Consider – non-steroidal mineralocorticoid receptor antagonist

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Consider –

non-steroidal mineralocorticoid receptor antagonist

Additional treatment recommended for SOME patients in selected patient group

Despite guideline-directed therapies, people with type 2 diabetes and chronic kidney disease (CKD) with persistent albuminuria remain at increased risk for cardiovascular (CV) events and CKD progression.[1][47]

Finerenone, a non-steroidal mineralocorticoid receptor antagonist, is the first mineralocorticoid receptor antagonist to demonstrate positive kidney and CV outcomes in patients with CKD associated with type 2 diabetes.[173][174] It has also shown benefit in reducing all-cause mortality and new-onset hypertension.[164] By blocking mineralocorticoid receptor over-activation, a key driver of CKD progression and fibrosis, finerenone works on a pathway largely unaddressed by existing treatments for CKD in type 2 diabetes. Finerenone efficacy is not modified by baseline HbA1c, HbA1c variability, diabetes duration, baseline insulin use, or baseline atherosclerotic cardiovascular disease (ASCVD) history.[165]

Guidelines recommend that for people with type 2 diabetes and CKD with persistent albuminuria (≥3 mg/mmol [≥30 mg/g]) despite maximum tolerated doses of an ACE inhibitor or angiotensin-II receptor antagonist, finerenone should be added.[1][47][166] It can be used simultaneously with an SGLT2 inhibitor.

The main risk is hyperkalaemia, although finerenone has a lower risk of hyperkalemia and/or acute kidney injury compared with spironolactone. People with low estimated glomerular filtration rate (eGFR), higher serum potassium levels, or previous episodes of hyperkalaemia are at increased risk for developing hyperkalaemia. Accordingly, finerenone should be used with caution and with more frequent monitoring in people with these characteristics.[170] Finerenone should not be initiated if eGFR is <25 mL/minute/1.73m² and should be discontinued in people who have progressed to end-stage renal disease (eGFR <15 mL/minute/1.73m²). It should not be initiated if serum potassium level is >5.0 mmol/L. The risk of hyperkalaemia increases with concomitant medications that can raise serum potassium, and finerenone should not be administered with potassium-sparing diuretics or other mineralocorticoid antagonists.[170]

Other common (≥1/100 to <1/10) adverse effects include hypotension, decreased eGFR, and pruritus.[170]

Primary options

finerenone: 10-20 mg orally once daily; dose should be adjusted according to level of renal impairment

without albuminuria (albumin to creatinine ratio [ACR] <3 mg/mmol [<30 mg/g]) and BP ≥130/80 mmHg

Plus – ACE inhibitor or angiotensin-II receptor antagonist or calcium-channel blocker or thiazide-like diuretic

Back

Plus –

ACE inhibitor or angiotensin-II receptor antagonist or calcium-channel blocker or thiazide-like diuretic

Treatment recommended for ALL patients in selected patient group

The American Diabetes Association (ADA) recommends that all individuals with type 2 diabetes and blood pressure (BP) ≥130/80 mmHg should qualify for pharmacological therapy to lower BP to <130/80 mmHg (providing this target can be safely attained).[1] It recommends an individualised approach to BP targets, however, advising that patients and clinicians should engage in a shared decision-making process to determine individual BP targets, and acknowledging that the benefits and risks of intensive BP targets are uncertain.[1] Lower BP targets may be suitable in some cases, especially in patients with severely elevated albuminuria (ACR ≥30 mg/mmol [≥300 mg/g]), provided the patient's individual benefits and risks have been taken into account.[1] Of note, Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend a lower systolic BP goal of <120 mmHg (when tolerated) in adults with hypertension and chronic kidney disease (CKD), noting that evidence for the benefits of intensive BP control is less certain in patients with diabetes than those without.[138][139][140]

Primary options

captopril: 25-50 mg orally two to three times daily; dose should be adjusted according to level of renal impairment

enalapril: 2.5 to 40 mg orally once daily; dose should be adjusted according to level of renal impairment

lisinopril: 2.5 to 40 mg orally once daily; dose should be adjusted according to level of renal impairment

ramipril: 1.25 to 20 mg orally once daily; dose should be adjusted according to level of renal impairment

trandolapril: 0.5 to 4 mg orally once daily; dose should be adjusted according to level of renal impairment

losartan: 25-100 mg/day orally given in 1-2 divided doses

valsartan: 80-320 mg orally once daily

candesartan: 8-32 mg orally once daily

amlodipine: 2.5 to 10 mg orally once daily

felodipine: 2.5 to 10 mg orally once daily

nifedipine: 30-120 mg orally (extended-release) once daily

hydrochlorothiazide: 12.5 to 50 mg orally once daily

chlortalidone: 12.5 to 25 mg orally once daily

Consider – additional antihypertensive therapy

Back

Consider –

additional antihypertensive therapy

Additional treatment recommended for SOME patients in selected patient group

Additional antihypertensive therapy is required in most patients to reach blood pressure (BP) targets.[154][155]

Joint American Diabetes Association (ADA)/Kidney Disease: Improving Global Outcomes (KDIGO) consensus guidelines recommend that aldosterone antagonists (e.g., spironolactone, eplerenone) can be used in patients with resistant hypertension (BP above target despite ACE inhibitors/angiotensin-II receptor antagonists, calcium-channel blockers, and thiazide-like diuretics) but only if estimated glomerular filtration rate (eGFR) is ≥45 mL/minute/1.73 m².[48]

The choice of additional antihypertensive therapy depends on various patient and clinical factors.

on peritoneal dialysis or haemodialysis

1st line – glycaemic control

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1st line –

glycaemic control

In all patients with type 1 diabetes, regardless of whether they are on dialysis or not, treatment with insulin is needed. Doses are titrated to achieve individualised glycaemic goals but may need to be decreased in comparison with earlier stages of chronic kidney disease (CKD) due to reduced insulin clearance and other changes in metabolism with advanced CKD.[48] For further information, see Type 1 diabetes.

Patients with type 2 diabetes who are on dialysis (e.g., due to end-stage renal disease [ESRD]) are also preferentially treated with insulin. Insulin is usually given subcutaneously. Selected oral antihyperglycaemic agents (below) can also be considered in patients with type 2 diabetes. When possible, drugs that control glycaemia without increasing risk of hypoglycaemia are preferred. For further information, see Type 2 diabetes in adults.

Glucagon-like peptide-1 (GLP-1) receptor agonists: have been studied with estimated glomerular filtration rate (eGFR) as low as 15 mL/minute/1.73 m² and retain glucose-lowering potency across the range of eGFRs and among dialysis patients.[48] They have been shown to reduce atherosclerotic cardiovascular disease (ASCVD) events and albuminuria in large randomised controlled trials; they are thus theoretically appealing for people with type 2 diabetes and advanced CKD on dialysis, but have not been prospectively tested for cardiovascular (CV) efficacy or safety in this population.[48] However, findings of a meta-analysis of the CV outcome trials showed that ASCVD risk was reduced at least as much among individuals with eGFR <60 mL/minute/1.73 m² compared with those with higher eGFR.[129] GLP-1 receptor agonists induce weight loss and can cause nausea and vomiting, so caution is warranted among patients with or at risk for malnutrition. Notably, in people who have obesity exceeding body mass index (BMI) limits required for kidney transplant listing, GLP-1 receptor agonists can be used to aid with weight loss that may facilitate qualification for transplant.[48]

Dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonists: tirzepatide can be used in patients with advanced DKD. No adjustment in dose is required. In subjects with renal impairment including ESRD, no change in tirzepatide pharmacokinetics was observed.[130]

Dipeptidyl peptidase-4 (DPP-4) inhibitors: DPP-4 inhibitors can be used with eGFR <30 mL/minute/1.73 m² and with dialysis and provide a safe and effective option for treatment of patients who are not treated with GLP-1 receptor agonists.[48] Saxagliptin, sitagliptin, and alogliptin require a dose adjustment, whereas linagliptin is not renally cleared and thus a dose adjustment is not necessary.

Thiazolidinediones (e.g., pioglitazone): improve insulin sensitivity, a common abnormality in advanced CKD, and retain antihyperglycaemic effects in this population. Fluid retention and heart failure are concerns with low eGFR and require careful monitoring.[48]

Sulfonylureas and meglitinides: there is evidence to suggest that low-dose glipizide can be used in dialysis patients with type 2 diabetes (either instead of insulin or added to insulin). There is no evidence to support the use of repaglinide in dialysis patients.

Metformin: contraindicated with estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m² and with dialysis treatment.[48]

Sodium-glucose co-transporter-2 (SGLT2) inhibitors: very few data are available evaluating use of SGLT2 inhibitors for patients receiving dialysis, and the glycosuric actions of SGLT2 inhibitors are likely to be insignificant with this degree of kidney failure. For this reason, Kidney Disease: Improving Global Outcomes (KDIGO) guidelines advise that they should be discontinued prior to initiation of dialysis treatment.[47]

KDIGO guidelines state that the optimal HbA1c target range in the dialysis population is unknown.[47] American Diabetes Association (ADA) guidelines recommend a general HbA1c target of <53 mmol/mol (<7%) for adults with diabetes, noting that setting a glycaemic goal during consultations is likely to improve patient outcomes.[1] They note that less stringent goals may be appropriate for very young children, older adults, people with frailty, people with a history of severe hypoglycaemia, and those with limited life expectancies, advanced microvascular or macrovascular complications, or comorbid conditions.[1] Treatment goals need to be individualised, taking into account age, disease progression, and macrovascular risk, as well as the patient's lifestyle and disease management capabilities.[80] UK guidelines recommend setting individualised HbA1c targets in discussion with the patient. A goal of 48 mmol/mol (6.5%) is appropriate for most adults. A goal of 53 mmol/mol (7.0%) may be used for adults on drugs associated with hypoglycaemia.[83]

HbA1c measurements should be used with caution in people with diabetes on dialysis as they may not provide a true reflection of glucose control; direct glucose estimations via self-monitoring of blood glucose should be offered, and continuous glucose monitoring should be considered.[131]

Plus – lifestyle and risk factor modifications

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Plus –

lifestyle and risk factor modifications

Treatment recommended for ALL patients in selected patient group

Nutrition: medical nutrition therapy by a registered dietitian is recommended for people with type 1 or type 2 diabetes.[29][179] High-protein diets should be avoided.[1][4][27] Every patient should be assessed individually to weigh the benefits of a moderate-protein diet (and associated avoidance of aminoaciduria and hyperfiltration); low-protein diets (0.6 g/kg) should be avoided due to the risks of malnutrition.[29][30] One systematic review was unable to show a benefit of protein restriction on renal failure.[28] For people with non-dialysis-dependent CKD, dietary protein intake should be approximately 0.8 g/kg body weight per day (the recommended daily allowance).[1][47] However, for patients on dialysis, higher levels of dietary protein intake (1.0 to 1.2 g/kg/day) should be considered as protein energy wasting malnutrition is a major problem in this group.[1][187] Limited intake of saturated fat and cholesterol is beneficial.[1][30] Restriction of dietary sodium (to <2300 mg/day) may be useful to control blood pressure and reduce CV risk, and individualisation of dietary potassium may be necessary to control serum potassium concentrations.[1][188] [ ] Although a multivitamin is recommended, high doses of B vitamins resulted in increased vascular events.[187]

Physical activity: guidelines recommend that people with DKD undertake moderate-intensity physical activity for a cumulative duration of at least 150 minutes per week, or to a level compatible with their CV and physical tolerance.[47] Although dedicated trials among dialysis patients with diabetes are lacking, simple home-based exercise programmes have been shown to be feasible and offer health benefits in those on dialysis.[47]

Consider – individualised antihypertensive therapy

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Consider –

individualised antihypertensive therapy

Additional treatment recommended for SOME patients in selected patient group

Management of hypertension is challenging in this population and requires specialist review.[159] There is insufficient evidence from data in the published literature to decide how best to manage blood pressure (BP) in people with diabetes who are on dialysis.[160] Many factors affect BP in this population, including fluid status, salt intake, sympathetic nervous system activity, and the renin-angiotensin-aldosterone system.[160] People with diabetes who are undergoing haemodialysis often have autonomic dysfunction, which increases the risk of cardiovascular (CV) instabilities during dialysis; it causes severe orthostatic reduction in cerebral blood flow velocity and may subsequently increase the risk of cerebrovascular injury post haemodialysis. This makes management of hypertension in people with diabetes who are on dialysis even more challenging.[160]

Kidney Disease: Improving Global Outcomes (KDIGO) guidance does not make a recommendation for BP targets in patients on dialysis.[138] UK guidelines suggest a target BP of <140/90 mmHg between dialysis sessions for patients on haemodialysis. The same target is suggested for patients on peritoneal dialysis.[160] Individualisation of the BP target may be indicated in patients with multiple comorbidities in order to reduce potential adverse events of BP lowering. Hypotension between dialysis sessions should be avoided in patients on haemodialysis.[160]

UK guidelines suggest using ACE inhibitors or angiotensin-II receptor antagonists (but not in combination) and/or dihydropyridine calcium-channel blockers and/or beta-blockers to reduce CV complications in people with diabetes and hypertension who are on dialysis.[160] Combination therapy is required in most patients to reach BP targets.[154][155] There are few data on the effectiveness of renin-angiotensin system blockade in patients with diabetes and end-stage renal disease; however, use of these agents may improve CV outcomes and lower mortality.[161]

Beta-blockers may mask symptoms of hypoglycaemia but may be used as add-on treatment in patients who require multiple agents to reach BP targets or in those with another indication for the use of beta-blockers (e.g., ischaemic heart disease).[155]

Diuretics are also recommended in people with diabetes who are on dialysis and have residual renal function.[160] They are almost always required to control BP in advanced DKD. While loop diuretics have long been the cornerstone of therapy in such patients, the CLICK trial demonstrated that chlortalidone (a thiazide-like diuretic) with or without a loop diuretic is also effective in patients with advanced chronic kidney disease (CKD).[157] Although diuretics are generally ineffective for BP management in dialysis patients due to markedly impaired renal function, in selected patients with residual renal function, loop diuretics may still be efficacious in preventing fluid overload and hypertension as adjunctive therapy to ultrafiltration during dialysis.[138]

The choice of specific antihypertensive therapy in these patients depends on various patient and clinical factors.

Consider – statin

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Consider –

statin

Additional treatment recommended for SOME patients in selected patient group

People with DKD have a high risk of cardiovascular (CV) events. Management of CV risk should therefore be a strong consideration in people with DKD in order to reduce mortality from atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) is the most extensively studied modifiable risk factor associated with ASCVD. There is strong evidence that it is a causal factor in the pathophysiology of ASCVD, and that ASCVD risk reduction is proportional to the absolute and relative LDL-C reduction achieved.[175]

Statins are likely to be beneficial because of their anti-inflammatory properties and the correlation of inflammation in chronic kidney disease (CKD) with associated CV morbidity.

In patients on dialysis who are already taking a statin, continuation of therapy is recommended. However, statin therapy should not be initiated for primary prevention of ASCVD due to lack of evidence of benefit in patients with end-stage renal disease (ESRD).[177][211]

Guidelines for lipid management differ for patients with diabetes who have established CV disease (i.e., secondary prevention). For further information, see Diabetic cardiovascular disease.

Consider – consideration for pancreas-kidney transplantation

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Consider –

consideration for pancreas-kidney transplantation

Additional treatment recommended for SOME patients in selected patient group

Diabetes is the most common cause of end-stage renal disease (ESRD) requiring renal replacement therapy (RRT). RRT is not only time consuming and fraught with uncomfortable adverse effects such as cramps, fatigue, and central venous stenosis, but it is also associated with significant morbidity and mortality. Pancreas-kidney transplantation should be considered in those with type 1 and selected type 2 diabetes. Pancreas-kidney transplantation not only frees patients from the need for RRT, but it also has a significant survival benefit. With modern surgical and immunosuppressive protocols, 5-year patient survival is 95%, kidney survival is 90%, and pancreas survival is greater than 80%.[193]

Simultaneous pancreas kidney (SPK) recipients are generally younger (≤60 years) than kidney transplant recipients (≤70 years). They are usually patients with type 1 diabetes who have hypoglycaemia unawareness or markedly uncontrolled diabetes; generally they are on insulin therapy (typically <1 unit/kg/day) and their C-peptide is <2 nanograms/mL. Patients with type 2 diabetes may be considered if they do not have significant insulin resistance (C-peptide >2 and body mass index <30). In addition, recipients must have an estimated glomerular filtration rate (eGFR) <20 mL/minute/1.73 m² or be dialysis-dependent. They must go through strict cardiovascular, psychosocial, and anatomical (computed tomography angiogram) clearance.[193] Weight loss will be required for those who exceed body mass index (BMI) limits for kidney transplant listing.[47][48]

Other management strategies should be continued as necessary.

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Diabetic kidney disease

Treatment algorithm

type 1 diabetes with nephropathy: not on dialysis

glycaemic control

lifestyle and risk factor modifications

lipid management

Primary options

Secondary options

Tertiary options

ACE inhibitor or angiotensin-II receptor antagonist

Primary options

Secondary options

additional antihypertensive therapy

ACE inhibitor or angiotensin-II receptor antagonist or calcium-channel blocker or thiazide-like diuretic

Primary options

additional antihypertensive therapy

type 2 diabetes with nephropathy: not on dialysis

glycaemic control

lifestyle and risk factor modifications

lipid management

Primary options

Secondary options

Tertiary options

sodium-glucose co-transporter-2 (SGLT2) inhibitor or dual SGLT1/SGLT2 inhibitor and/or glucagon-like peptide-1 (GLP-1) receptor agonist

Primary options

ACE inhibitor or angiotensin-II receptor antagonist

Primary options

Secondary options

additional antihypertensive therapy

non-steroidal mineralocorticoid receptor antagonist

Primary options

ACE inhibitor or angiotensin-II receptor antagonist or calcium-channel blocker or thiazide-like diuretic

Primary options

additional antihypertensive therapy

on peritoneal dialysis or haemodialysis

glycaemic control

lifestyle and risk factor modifications

individualised antihypertensive therapy

statin

consideration for pancreas-kidney transplantation