The UK eCKD Guide

Definition

Chronic kidney disease (CKD) can be defined as a sustained reduction in the glomerular filtration rate (GFR) and/or urinary abnormalities or structural abnormalities of the renal tract.

The impact of CKD

Chronic kidney disease has a global prevalence of 9.1% and is more common in females but men are more likely to progress to kidney failure. Kidney failure is defined as GFR <15 mL/min/1.73 m² or treatment by dialysis therapy. CKD increases in prevalence with age and high-income countries report more kidney disease than low income countries, probably as a consequence of both demography and under-reporting.

Where studied, social deprivation is associated with a higher prevalence of CKD. The scale of CKD and the consequences for health care delivery are profound; CKD is now the 4th most common global cause of non-communicable disease death.

Outcomes for those with CKD

The large majority of those affected by CKD never progress to kidney failure, the major clinical outcome burden of CKD relates to the major increased risk of cardiovascular disease events in those with CKD compared to those without CKD. This increased risk is directly related to the severity of kidney disease, as measured both by excretory kidney function (eGFR), so the lower the eGFR the higher the risk, and albuminuria quantified in clinical practice by albumin-to-creatinine ratio.

CKD is often referred to as 'silent'. This is incorrect. Whilst CKD does not have a clear symptom complex in the same way as other long-term conditions, persons with CKD have a major symptom burden including severe fatigue, pain, breathlessness, and a high prevalence of psychological health problems. These symptoms increase with the severity of CKD.

Glomerular Filtration Rate (GFR)

Glomerular Filtration Rate (GFR) is the standard measure of kidney function. Measurement of true GFR is not practical in routine clinical practice as it is time consuming and expensive. Therefore, standardised formulae have been developed to calculate estimated GFR (eGFR). These formulae incorporate serum or plasma creatinine, age and sex. eGFR is routinely calculated by all laboratories in the United Kingdom and reported alongside creatinine values.

There are important practical considerations in interpreting eGFR. Whilst 'normal' eGFR is defined as 90 ml/min/1.73 m² or more, caution should be applied as follows:

• an eGFR of 60 to 89 ml/min/1.73 m² should be classified as normal in the absence of any other evidence of CKD.
• a single eGFR of 51-59 ml/min/1.73 m² in an individual who has had a previous eGFR of 60 ml/min/1.73 m² or has not previously had an eGFR reported should not trigger a diagnosis of CKD without a confirmatory eGFR.
• There is biological variation in creatinine generation and clearance and laboratory variation in the performance of the creatinine assay such that a change in eGFR of up to 10% may represent variation that is not significant. Care should be taken in communicating a change in eGFR (e.g. do make statements about kidney function declining without confirmatory blood tests)
• eGFR calculations assume that the level of creatinine in the blood is stable, within biological variance, over days or longer - i.e. steady-state; the calculations are not valid if creatinine is rapidly changing, such as in acute kidney injury (AKI) or in patients receiving dialysis.
• Use change in eGFR with time (delta or slope eGFR) to confirm decline in kidney function.
• Always interpret the risk of progression of CKD by considering both the eGFR and the ACR (see below)

If a more accurate GFR is needed, for example, for chemotherapy drug dosing or in the evaluation of kidney function in potential living kidney donors, measured GFR can be undertaken using a reference standard (e.g. 51Cr-EDTA, 125I-iothalamate or iohexol).

Creatinine Clearance

In product literature for therapeutic drugs, the effects of kidney impairment on drug elimination is usually stated in terms of creatinine clearance (CrCl) as a surrogate for GFR. Although eGFR and CrCl are not interchangeable, for most drugs and for most adult patients of average build and height, eGFR (rather than CrCl) can be used to determine dosage adjustments. Exceptions to the use of eGFR include toxic drugs, older individuals, and in those with extremes of muscle mass. In addition, the Medicines Healthcare products Regulatory Agency (MHRA) advises that CrCl should be used as an estimate of renal function for direct-acting oral anticoagulants (DOACs), and drugs with a narrow therapeutic index that are mainly kidney excreted.

eGFR and ethnicity adjustment:

There is increasing concern worldwide that the previous practice of applying a fixed ethnicity adjustment when calculating eGFR for individuals of Black ethnicity is inaccurate and may lead to inequity in care. These adjustments do not reflect the wide diversity present amongst individuals from this ethnic group and were based on outdated and unfounded biological assumptions for differences, at the expense of better understanding of social and ancestral determinants of health. For this reason, in the 2021 NICE CKD guideline update, the recommendation to adjust for ethnicity (which was present in the 2014 version) was removed. The UKKA supports NICE recommendations that adjustments in eGFR for black ethnicity may not be valid or accurate and should be removed from UK practice.

Interpretation of eGFR:

eGFR is used to classify severity of kidney disease in conjunction with proteinuria/albuminuria. It is important to bear in mind the following when applying eGFR values in clinical practice:

• The equations used for eGFR tend to underestimate normal or near-normal kidney function, although the CKD-epi (2009) equation is more reliable at higher eGFR than the previous widely used 'Modification of Diet in Renal Disease' (MDRD) formula. It is advisable that slightly lower values (i.e. around or just below the 60 ml/min/1.73m CKD "cut-off" level) should not be over-interpreted. In this situation repeat testing, looking for a progressive decline in eGFR over time is useful.
• Differences in the assays used by laboratories to measure serum creatinine (NICE recommend use of the more specific enzymatic assays in preference to Jaffe colorimetric assays)*.
• Blood samples should ideally be received and processed by the laboratory within 12 hours of venepuncture, as unnecessary delays can interfere with assay results.
• Adults should be advised not to eat any meat in the 12 hours before having a blood test for eGFR, as this can affect serum creatinine concentration.
• If a sudden significant decline in kidney function is noted, this should be repeated within 2 weeks to exclude an acute kidney injury (AKI).
• The CKD-EPI equation is not validated for patients under 18 years of age or in pregnancy. There is also limited evidence regarding its accuracy in patients from different ethnic groups living in the UK.
• eGFR is only an "estimation" of true kidney function: It is important to remember that eGFR is only an estimate of true kidney function and significant error is possible, especially in people at extremes of body habitus e.g. patients with limb amputations, those who are severely malnourished, bodybuilders, oedematous or morbidly obese. For any individual patient, identifying trends in eGFR can be more informative than one-off readings.

Patient information

eGFR is an equation that uses your creatinine, age, and gender to see how well your kidneys are working. Creatinine is the level of muscle waste in your bloodstream, which your kidneys are supposed to filter out into urine.

If there is a high level of creatinine in your bloodstream, it could mean that your kidneys are not working well at filtering.

Your healthy creatinine level depends on how much muscle you have in your body and the "good" number may be different for people who have lower or higher muscle mass than average. Because the "good" creatinine number is different in everyone, eGFR is used as a more reliable measure of kidney function in stable patients than creatinine alone.

"Normal" eGFR is approximately 100 but you will often see it reported as >90 ("greater than 90") or >60 ("greater than 60"). It is for this reason that patients (and some doctors) sometimes quote the eGFR as a percentage of normal kidney function. Whilst not factually correct, it does help to make the numbers easier to understand.

Haematuria

Visible (also known as macroscopic or frank) haematuria

Management:

• Usually, fast track Urology referral for imaging and cystoscopy unless strong pointers to acute renal disease.

Non-visible (also known as microscopic) haematuria

Detection:

• Use reagent strips rather than urine microscopy for detection. (There is no need to perform microscopy to confirm a positive result.)
• Evaluate further if there is a result of 1+ or more.
• Non-visible haematuria should be confirmed on at least 2 out of 3 consecutive urine tests (taken on separate occasions).
• Measure renal function and assess for proteinuria in all cases.

Management:

Age >60:

• Usually refer to urology (see local guidance for referral pathways). If renal impairment and/or proteinuria also present, consider simultaneous referral to nephrology.

Age <60 or >60 with negative urological investigations

• If no proteinuria AND eGFR > 60 ml/min/1.73m² manage as CKD stage G1/G2 otherwise refer to nephrology.

For further information please review the NICE guidelines.

Information for patients

Haematuria means blood in the urine. Sometimes this is visible to the naked eye or it may only detected by a urine dipstick test or when urine is examined using a microscope. Lots of different conditions can result in blood urine in the urine. The most likely cause varies depending on your age, if you are leaking protein (as well as blood) in the urine, and whether your kidney function is impaired. Further investigations may be required to find the cause.

CKD Classification

A patient is said to have chronic kidney disease (CKD) if they have abnormalities of kidney function or structure present for more than 3 months.

The definition of CKD includes all individuals with markers of kidney damage (see below*) or those with an eGFR of less than 60 ml/min/1.73m² on at least 2 occasions 90 days apart (with or without markers of kidney damage).

• *Markers of kidney disease may include: albuminuria (ACR > 3 mg/mmol), haematuria (of presumed or confirmed renal origin), electrolyte abnormalities due to tubular disorders, renal histological abnormalities, structural abnormalities detected by imaging (e.g. polycystic kidneys, reflux nephropathy) or a history of kidney transplantation.

CKD Classification

CKD is classified based on the eGFR and the level of proteinuria and helps to risk stratify patients.

Patients are classified as G1-G5, based on the eGFR, and A1-A3 based on the ACR (albumin:creatinine ratio) as detailed below:

For Example

• A person with an eGFR of 25 ml/min/1.73 m² and an ACR of 15 mg/mmol has CKD G4A2.
• A person with an eGFR of 50 ml/min/1.73 m² and an ACR of 35 mg/mmol has CKD G3aA3.

It is important to note that patients with an eGFR of >60 ml/min/1.73m² should not be classified as having CKD unless they have other markers of kidney disease (see above*).

Patient information

Patients with CKD can be classified depending on their level of kidney function, or eGFR, and the amount of protein present in the urine. This information forms the basis of CKD staging which is useful for planning follow up and management. The higher the stage (G1->G5) and the greater the amount of protein present in the urine (A1->A3) the more "severe" the CKD and the higher the risk that a patient may develop renal failure requiring dialysis in the future.

CKD Stages G1 and G2

Identifying patients with CKD stages G1 & G2

An eGFR of >90 ml/min/1.73m² is considered normal kidney function. If these patients have evidence of kidney disease* however (see below) they should be classified as CKD stage G1.

Patients with an eGFR of 60-90 ml/min/1.73m² have mildly reduced kidney function which may be appropriate for their age. If these patients have any other evidence of kidney disease* (see below) they have CKD stage G2.

*Evidence of kidney disease, required to diagnose CKD in patients with an eGFR >60 ml/min/1.7m², may include:

• Proteinuria
• Haematuria (of presumed or proven renal origin)
• Structural abnormalities (e.g. reflux nephropathy, renal dysgenesis, medullary sponge kidney)
• A known diagnosis of a genetic kidney disease (e.g. polycystic kidney disease)
• Abnormalities detected by examination of renal histology
• Electrolyte abnormalities due to renal tubular disorders
• History of kidney transplantation

Initial assessment of CKD stages G1 and G2

The initial assessment for most of these patients will be undertaken in primary care settings.

The aim of the initial assessment is to determine which patients are at risk of progressive renal disease.

• All patients should have a urine specimen sent for measurement of the albumin:creatinine ratio (ACR).
• Urine reagent stick should be used to check for haematuria.
• If assessment is precipitated by a first discovery of an elevated serum creatinine level it is important to ensure that the renal function is stable. Previous blood tests, if available, will give you the answer. If no previous blood tests are available and the patient is well with no other worrying features (e.g. high potassium, symptoms of bladder outflow tract obstruction, severe hypertension), repeat the test within 14 days. Patients with deteriorating renal function require rapid assessment.
• Measure blood pressure. CKD can be a consequence of hypertension and CKD of any aetiology can be associated with hypertension. An elevated serum creatinine level may be the first clue that a patient is hypertensive.

Management of CKD stages G1 and G2

This applies to patients with stable stages G1 and G2 CKD. To diagnose CKD, two or more blood tests are required at least 90 days apart. The CKD staging and management outlined below is predicated on stable renal function.

Almost all patients with stages G1 and G2 CKD can be appropriately managed in primary care. The principal aim is to identify individuals at risk of progressive renal disease.

Some patients need further investigation where there are indications that progression to end stage renal failure (Stage G5) may be a possibility. These patients should usually be referred to the local nephrology service. Pointers to progression of renal disease include:

• Proteinuria - the risk is graded but a common cut-off for further investigation in patients without diabetes is ACR>70 mg/mmol or PCR>100 mg/mmol
• Haematuria of renal origin
• Rapidly deteriorating renal function
• Young age - the referral threshold should be much lower for younger patients in whom the lifetime risk of developing progressive kidney disease is higher.
• Family history of renal failure
• Hypertension which is difficult to control

Risk of cardiovascular events and death is substantially increased by the presence of CKD and or proteinuria and the risks of these two are additive. Patients with stages G1 and G2 CKD are much more likely to suffer a cardiovascular event than they are to require renal replacement therapy (dialysis or a transplant) in their lifetime. Patients should be offered lifestyle advice including recommendations for regular exercise, smoking cessation and attainment and maintenance of a healthy weight.

Long term monitoring of renal function, proteinuria and blood pressure should be performed for all patients. The principal aim of long term monitoring is to identify the minority of patients with stage G1 and G2 CKD who will go on to develop progressive renal disease.

• Renal function and proteinuria - patients with a urine ACR >3 mg/mmol (i.e. A2 and A3) should undergo annual monitoring of renal function and proteinuria. Patients with ACR<3 mg/mmol may be monitored less frequently (See more on stages of CKD). Patients with evidence of rapidly progressive renal impairment or who have worrying features (e.g. difficult to control hypertension, anaemia, hyperkalaemia, features of a systemic disease) should be considered for referral to renal services.
• Worsening proteinuria is an adverse prognostic sign. In patients with worsening proteinuria which exceeds ACR>70mg/mmol consider referral / discussion with nephrology unless it is known to be caused by diabetes and is appropriately treated. (See the management of patients with CKD section on Referral Guidelines).
• Blood pressure - Aim to keep the BP <140/90. In patients with CKD and diabetes or an ACR>70 mg/mmol aim to keep BP<130/80. (See the management of patients with CKD section on blood pressure (hypertension) management.)
• Cardiovascular disease - Offer advice on smoking cessation, exercise and lifestyle. (See the management of patients with CKD section on cardiovascular risk reduction.)

Patient information - CKD G1 and G2

CKD stage G1 is kidney disease with normal renal function. Patients with CKD stage G2 have mild impairment of kidney function. Most patients with CKD stages G1 and G2 just need occasional testing to ensure things are stable. A small minority of patients need further investigations to see if they have a disease which may benefit from treatment or could lead to more serious kidney damage.

CKD Stages G4 and G5

Identifying patients with CKD stage G4 and G5

Patients with an eGFR of 15-29 ml/min/1.73m² have CKD stage G4 which represents significant impairment of kidney function.

Patients with an eGFR of <15 ml/min/1.73m², or who require some form of dialysis, have CKD stage G5 which is often referred to as End-Stage Renal Failure (ESRF). This CKD stage represents patients with the lowest level of kidney function.

Creatinine and eGFR in an individual are usually quite stable. Deteriorating renal function needs rapid assessment. Note that CKD staging and management outlined below are only applicable to stable renal function.

Initial assessment of CKD stage G4

Initial assessment is identical to CKD Stage G3 but, in contrast to Stage G3, referral to or discussion with a specialist service will be usual. Exceptions to 'always refer or discuss' may include patients in whom:

• Severe renal impairment is part of another terminal illness.
• All appropriate investigations have been performed and there is an agreed and understood care pathway.
• Further investigation and management is clearly inappropriate.

If assessment is precipitated by a first discovery of an elevated serum creatinine level it is important to ensure that the renal function is stable. Previous blood tests, if available, will give you the answer. If no previous blood tests are available, and the patient is well with no other worrying features (e.g. high potassium, symptoms of bladder outflow tract obstruction, severe hypertension), repeat the test within 14 days. Patients with deteriorating renal function require rapid assessment.

In addition to referring these patients for specialist assessment in the majority of cases, patients should be evaluated with particular reference to the following points:

• Clinical assessment - If the patient is clinically unwell, consider telephoning for advice and to discuss expediting specialist assessment. Undertake an assessment of volume status (i.e. hypovolaemia - and hypervolaemia) and for symptoms or signs suggestive of renal tract obstruction (e.g. a palpable bladder).
• Medication review - any potentially nephrotoxic drugs, or drugs that need dose alterations when GFR reduced? Remember non-prescribed and over the counter medications, e.g. NSAIDs.
• Urine tests: dipstick for blood and quantitation of proteinuria by ACR/PCR. Presence of haematuria or proteinuria may suggest intrinsic renal disease (in contrast to pre- or post- renal disease).
• Blood tests: K⁺, Ca²⁺, Phosphate, Hb.
• Imaging - It is recommended to have a low threshold for performing an ultrasound scan in these patients to rule out a structural explanation and to provide additional clues about the aetiology and chronicity (i.e. renal size, cortical thickness, cortico-medullary differentiation). Consider requesting a scan urgently if there is a strong clinical suspicion of obstructive uropathy or prominent lower urinary tract symptoms. Consider requesting imaging at the same time as referring the patient for specialist assessment. (i.e. ordinarily referral to renal services should not be delayed pending the results of imaging studies).

Management of CKD stage G4 and G5

These patients should have a management plan that has been advised by a kidney specialist, either with an agreed management plan and a defined threshold for re-referral or under follow-up in a kidney clinic. The aims of management for patients with CKD stages G4 and G5 are to try and slow the progression of CKD, identify and treat the complications of CKD, reduce the incidence of cardiovascular disease, and to allow timely and informed decision making regarding the management of kidney failure.

Typically patients will be assessed, often through a combination of patient-clinician encounters and / or blood test, on a 3-4 monthly basis. The frequency of review will be determined by factors such as the rate of progression of CKD, KFRE, the patient's comorbidities, and the associated complications of CKD.

Factors which should be monitored and addressed in these patients include:

• Potassium levels - hyperkalaemia that is severe or not responsive to changes in therapy should lead to discussion or referral. Medications are often contributory in this setting.
• Bicarbonate level - bicarbonate levels fall as renal function declines. Sodium bicarbonate is often used in these patients.
• Haemoglobin – if low, exclude non-renal causes. Management of "renal" anaemia can include the provision of iron and the use of erythropoiesis stimulating agents. (see more on anaemia in the complications of advanced CKD section)
• Calcium and phosphate - Secondary hyperparathyroidism (SHPT) is frequently encountered in these patients. Management is multifaceted and can include dietary phosphate restriction and oral phosphate binders. Nutritional vitamin D (cholecalciferol) supplementation should be used where indicated, activated vitamin D (calcitriol or alfacalcidol) should be reserved for patients with SHPT that is severe or progressing towards severe.
• Urinary protein - monitor with ACR or PCR.
• KFRE
• Blood pressure - Aim to keep the BP <140/90. In patients with CKD and diabetes or an ACR>70 mg/mmol aim to keep BP<130/80. (see more on hypertension in the management of patients with CKD section)
• Cardiovascular risk - offer advice on smoking, exercise and lifestyle. Consider offering Atorvastatin 20 mg nocte for the primary and secondary prevention of cardiovascular disease. (see more on cardiovascular risk reduction in the management of patients with CKD section).
• Fluid Status- Salt and water retention is common in patients with impaired kidney function. Worsening of fluid retention may require initiation or up titration of diuretics and can precipitate the need to commence renal replacement therapy.
• Immunisation - influenza and pneumococcal vaccinations should be given. Patients who are likely to require renal replacement therapy should be vaccinated against hepatitis B. Seasonal COVID booster vaccinations are being offered to patients in this cohort.
• Medication review - regular review of medication to minimise nephrotoxic drugs (particularly NSAIDs) and ensure doses of others are appropriate to renal function. Metformin should be avoided in patients with CKD stage G4 and G5.

Patient information - CKD stages G4 and G5

Patients with CKD stages G4 and G5 have the most severe impairment of kidney function. Treatment of these patients involves trying to preserve kidney function and managing the complications that arise in patients with poor kidney function. These patients are also at very high risk of diseases which affect the heart and blood vessels, such as heart attacks and strokes. End-stage renal failure refers to patients who have insufficient kidney function to keep them feeling well and who may benefit from treatments which take on some of the functions of the kidney, such as dialysis or a transplant.

Aetiology

Some of the leading causes of CKD in the UK include:

• Diabetes
• Hypertension
• Renovascular disease
• Inherited renal diseases
• Glomerulonephritis
• Reflux nephropathy
• Heart Failure (cardio-renal syndrome)

History taking, examination and investigations may help identify the likely aetiology of CKD in individual cases but where the diagnosis remains uncertain, especially in those patients with a progressive decline in renal impairment consider referral to your local nephrology unit (see referral criteria in the management of patients with CKD section).

Examination

When trying to determine the aetiology of CKD, the examination may provide a number of clues:

• Diabetes - Presence of other systemic microvascular complications will increase suspicion of diabetic kidney disease (diabetic nephropathy). Ophthalmoscopy is helpful to identify features of proliferative retinopathy or previous laser treatment. Neurological examination of the foot (typically with a monofilament) can help identify peripheral neuropathy as can evidence of neuropathic foot ulcers, previous lower limb amputation or Charcot foot.
• Hypertension - Blood pressure examination is essential in all patients with kidney disease, it is not only important to help identify the aetiology but is a critical component of patient management. Good blood pressure control can reduce the risk of CKD progression and cardiovascular complications. In patients with advanced CKD volume overload can lead to oedema and hypertension. Ophthalmoscopy can be used to identify evidence of hypertensive changes in the retina, such as silver wiring, arteriovenous nipping and retinal haemorrhages which can be indicative of suboptimal control, at least historically, and increase the likelihood of hypertensive nephropathy.
• Fluid balance - Patients with advanced CKD or underlying nephrotic syndrome may develop significant peripheral oedema. Those with decompensated heart failure at risk of cardio-renal syndrome may also present with significant fluid overload.
• Renovascular disease - Renal bruits may be heard. The presence of femoral bruits and weak or absent peripheral pulses indicates significant peripheral vascular disease, which increases the likelihood of associated renovascular disease.
• Inherited kidney diseases - Polycystic kidneys are often palpable and some patients may also have hepatomegaly due to liver cysts. Patients with Alport's syndrome may require hearing aids for sensorineural hearing loss caused by abnormal collagen IV in the basement membrane of the inner ear.
• Glomerulonephritis - rash, fever, murmur, red eye and joint swelling may point to an underlying multi-system disorder. Significant peripheral oedema may be noted in patients with nephrotic syndrome. Pleural effusions and ascites may also be present.
• Obstructive uropathy - A palpable enlarged bladder is suggestive of outflow tract obstruction. This may be painless if it has developed insidiously over a prolonged period of time. Patients with a hydronephrotic kidney may occasionally complain of loin pain.

Blood Pressure (Hypertension) Management

Multiple trials have shown the benefits of blood pressure control in patients with renal disease. These benefits include slowing the progression of CKD and reducing cardiovascular outcomes and mortality.

Patients with diabetic kidney disease or significant proteinuria (ACR>30 mg/mmol) particularly benefit from pharmacological blockade of the renin-angiotensin system with ACE (angiotensin converting enzyme) inhibitors or ARBs (angiotensin receptor blockers) to control their blood pressure (see the RAS inhibitor section).

Targets

These apply to all stages of CKD.

• ACR<70 mg/mmol or PCR<100 mg/mmol: Target blood pressure <140/90
• ACR>70 mg/mmol or PCR>100 mg/mmol OR CKD and diabetes: Target blood pressure <130/80

Referral criteria

Patients with poorly controlled BP despite the use of 4 agents should be referred to a specialist for further evaluation (see the referral to specialists section)

Dietary advice

All patients with CKD should be advised to minimise dietary salt. This will improve blood pressure control, fluid retention and can also slow down progression of their CKD.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors were initially developed to treat hyperglycaemia in people with type 2 diabetes mellitus (DM). Results from large placebo-controlled clinical outcome trials have shifted the focus to SGLT-2 inhibition's potential to manage cardio-renal risk rather than hyperglycaemia. In people with type 2 DM at high risk of atherosclerotic cardiovascular disease, SGLT-2 inhibition reduces cardiovascular risk, particularly from heart failure.

In people with chronic kidney disease (CKD), the CREDENCE, DAPA-CKD and EMPA-KIDNEY trials have demonstrated SGLT-2 inhibition's particular efficacy at also reducing risk of kidney disease progression in people with type 2 DM as well as in patients with albuminuric CKD due to other causes. In patients with CKD SGLT-2 inhibitors have additionally been shown to reduce risk of serious adverse cardiovascular events, hospitalisations with heart failure and all-cause mortality.

The effectiveness of SGLT-2 inhibitors at glucose lowering diminishes as the kidney function falls; however, the relative effects of SGLT-2 inhibition on kidney disease progression and cardiovascular risk appear preserved in people with type 2 DM and CKD, at least within the range of kidney function represented in the reported trials (down to eGFR 15 mLs/min).

Recommendations for starting SGLT2 inhibitors

The UK Kidney Association Clinical Practice Guideline: Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease includes the following recommendations and suggestions for when to start SGLT2 inhibitors in people with CKD:^♦

For more information, click here for the UKKA clinical practice guidelines on SGLT2 inhibitors.

Cardiovascular risk reduction

CKD significantly increases the risks of both fatal and non-fatal cardiovascular events. At the population level these increased risks can be observed even in patients with low levels of proteinuria and preserved renal function. The risks increase with declining renal function and worsening proteinuria. Standard cardiovascular risk prediction tools, such as Framingham tables and Qrisk scores, significantly underestimate the risks of cardiovascular disease in patients with CKD.

These observations reinforce the importance of trying to control the modifiable cardiovascular risk factors in patients with CKD. Such approaches may include:

General measures

• Smoking cessation
• Weight loss
• Regular aerobic exercise
• Limiting salt intake

Control of hypertension

• To a maximum of 140/90 or 130/80 according to absence/presence of proteinuria or diabetes (see the blood pressure (hypertension) management section)

Lipid lowering therapies

• Offer Atorvastatin 20 mg for the primary prevention of cardiovascular disease in all patients with CKD, irrespective of their serum lipid levels.
• Increase the dose if there is <40% reduction in non-HDL cholesterol and eGFR is > 30 ml/min/1.73m², particularly for secondary prevention of cardiovascular disease.

Prescription of anti-proteinuric drugs

Both RAS inhibitors and SGLT2 inhibitors in eligible patients have been shown to reduce patient risk of serious adverse cardiovascular events.

Information for patients

Patients with CKD are more likely to develop heart disease or other diseases of the blood vessels such as strokes than they are kidney failure. A number of things can be done to minimise these risks including lifestyle changes and medications.

Referral to a specialist

Referral to a specialist should be considered and discussed with patients, taking into account their frailty and wishes for the following group of patients:

• a 5-year risk of needing renal replacement therapy of greater than 5% (measured using the 4-variable Kidney Failure Risk Equation) (see KFRE)
• an ACR of 70 mg/mmol or more, unless known to be caused by diabetes and already appropriately treated
• an ACR of more than 30 mg/mmol (ACR category A3), together with haematuria
• a sustained decrease in eGFR of 25% or more and a change in eGFR category within 12 months
• a sustained decrease in eGFR of 15 ml/min/1.73 m² or more per year
• hypertension that remains poorly controlled (above the person's individual target) despite the use of at least 4 antihypertensive medicines at therapeutic doses
• known or suspected rare or genetic causes of CKD
• suspected renal artery stenosis

Anaemia

Anaemia becomes more prevalent as renal function declines. Severe anaemia (e.g. Hb < 100 g/L) due to CKD is uncommon before at least CKD stage G3b. Other causes of a low haemoglobin should always be considered. The management of "renal anaemia" usually consists of erythropoiesis stimulating agents (ESAs - usually based on erythropoietin) and / or iron supplementation. Treating anaemia in patients with CKD has been shown to improve quality of life.

Investigation and management of anaemia in CKD

• Exclude other causes of anaemia.
• When Hb falls below 100-110g/L treatment with intravenous iron ± erythropoiesis stimulating agents may be considered.
• The aim of treatment is to maintain Hb levels in the range 100-120 g/L. (i.e. not to 'normalise' the haemoglobin level).

Useful tips

• Haemoglobin levels both above and below the recommended target range of 100-120 g/L have been associated with adverse patient outcomes in CKD patients receiving ESAs.
• Although iron supplementation is used in the management of "renal anaemia", absolute iron deficiency is NOT a complication of CKD and should be investigated appropriately. (CKD is associated with relative iron deficiency as a result of impaired iron utilisation.)
• The tempo of change in the renal function and haemoglobin level in an individual patient can give useful pointers as to whether the anaemia is likely to be due to the CKD. i.e. stable mild CKD for several years is unlikely to be the cause of a new, progressive anaemia.
• Anaemia due to renal impairment is normally an isolated normocytic anaemia. In patients with anaemia and a macro- or micro-cytosis and / or abnormal levels of white cells or platelets consider other causes.
• Following commencement on an ESA it typically takes 2-3 months to achieve a "steady state" haemoglobin concentration therefore frequent ESA dose adjustments should be avoided.
• Failure to respond to ESA/iron therapy or increased ESA/iron requirements in a patient with stable CKD should prompt re-assessment. Common explanations for this scenario include occult bleeding (especially from the GI tract), ESA non-administration (often withheld on the basis of high blood pressure) or inter-current inflammatory illness (usually infection which blunts the erythropoietic response to ESA-administration).

There are likely to be local algorithms and protocols for management of renal anaemia.

Information for patients

Anaemia (low haemoglobin concentration), is frequently encountered in patients with CKD. It becomes more common with lower kidney function declines. Treatment of the anaemia, once the cause has been established, usually consists of giving patients iron (either in tablet or liquid form to swallow or as an infusion through a drip) and or injections treatment (given weekly to monthly) of a medication known as an ESA or a tablet, usually given three times a week called a HIF inhibitor. With both of these treatments ongoing monitoring is required, and dose adjustments are common.

Click here to download our Clinical Practice Guideline:
Anaemia of Chronic Kidney Disease.

Click here to download our quick reference guide on anaemia of CKD.

Key clinical points for patient review

Focus on patient symptoms. For patients requiring AKC the commonest symptoms are fatigue (70%), pain, particularly bone and joint pain (60%), poor sleep, itching, cramps, sexual dysfunction (50%), psychological health symptoms are very common. Malnutrition affects 30-50% of patients.

eGFR is not a good surrogate for patients with advanced CKD. Support patients to understand this and not to over-focus on eGFR but on how they feel.

Don't express eGFR as a percentage (%).

Continue to focus on CVD risk; statin for primary prevention; RASi to continue; SGLT2i to continue; BP target to <140/80 (individualise).

Advise on reduction in salt and processed foods; this supports blood pressure control, heart disease, phosphate management and oedema management. For more information, see 'A healthy diet and lifestyle for your kidneys' (Kidney Care UK).

Manage congestion (oedema); support patients to self-manage, enable them to adjust diuretic dose using daily weights and assessment of oedema. Diuretics are not directly nephrotoxic.

Hb target is 105-125 g/L. There is a SOP for anaemia and the renal anaemia team manage this through the AKC MDT.

Bone chemistry evidence is not strong, avoid activated vitamin D (alfacalcidol or calcitriol) unless severe and progressive SHPT, nutritional vitamin D can be used. Avoid calcium containing binders unless hypocalcaemic. Vitamin D levels should be checked yearly and nutritionally supplemented if deficient. Advise on limiting processed foods and avoid calcium containing binders unless hypocalcaemic or conservative management. Hyperphosphataemia may indicate that RRT is imminent.

Bicarbonate, the evidence is conflicting; BICARB (UK RCT) showed no benefit and increased adverse events; Cochrane review was low certainty evidence; animal evidence suggests delayed progression; have an informed discussion and don't be didactic, remember pill burden.