SGLT2 inhibitors in the management of proteinuria

Last edited 11/2021 and last reviewed 07/2023

Proteinuria is protein in the urine.

Proteinuria is defined as:

• albumin:creatinine ratio >30mg/mmol or albumin concentration >200mg/l (1,2) or
  
  
• urine protein:creatinine ratios >45 mg/mmol (2)

The loss of up to 150 mg of protein per day is normal; this may be expressed as normal is less than 4 mg per hour per square metre of body surface area.

Proteinuria may be increased by a factor of 2-3 times by strenuous exercise or fever.

• other causes of transient include urinary tract infection, vaginal mucus, orthostatic proteinuria (occurs after patient has been upright for some time and is not found in early morning urine - this condition is uncommon in patients over 30 years old) and pregnancy

Causes of persistent proteinuria include:

• primary renal disease: this may be glomerular (e.g. glomerulonephritis) or tubular
• secondary renal disease: diabetes mellitus, hypertension, connective tissue diseases, vasculitis, amyloidosis, myeloma, congestive cardiac failure

• for adults with CKD and diabetes (type 1 or type 2) offer an ARB (angiotensin receptor blocker) or an ACE inhibitor (titrated to the highest licensed dose that the person can tolerate) if ACR (albumin-creatinine ratio) is 3 mg/mmol or more
• for children and young people with CKD and diabetes (type 1 or 2), offer an ARB or an ACE inhibitor (titrated to the highest licensed dose that they can tolerate) if ACR is 3 mg/mmol or more
• for adults with CKD but without diabetes:
  • refer for nephrology assessment and offer an ARB or an ACE inhibitor (titrated to the highest licensed dose that they can tolerate), if ACR is 70 mg/mmol or more
  • if ACR is above 30 but below 70 mg/mmol; consider discussing with a nephrologist if eGFR declines or ACR increases
• for children and young people with CKD but without diabetes:
  • offer an ARB or an ACE inhibitor if ACR (titrated to the highest licensed dose that they can tolerate) is 70 mg/mol or more
  • if ACR is above 30 but below 70 mg/mmol; consider discussing with a nephrologist if eGFR declines or ACR increase

SGLT2 inhibitors and CKD (2,5)

• for adults with CKD and type 2 diabetes, offer an SGLT2 inhibitor, in addition to an ARB or an ACE inhibitor at an optimised dose if:
  • ACR is more than 30 mg/mmol, and
  • they meet the criteria in the marketing authorisation (including relevant eGFR thresholds)
  • monitor for volume depletion and eGFR decline
  • in November 2021, not all SGLT2 inhibitors were licensed for this indication
• for adults with type 2 diabetes and chronic kidney disease who are taking an ARB or an ACE inhibitor (titrated to the highest licensed dose that they can tolerate), consider an SGLT2 inhibitor (in addition to the ARB or ACE inhibitor) if:
  • ACR is between 3 and 30 mg/mmol and
  • they meet the criteria in the marketing authorisation (including relevant eGFR thresholds)
  • in November 2021, not all SGLT2 inhibitors were licensed for this indication

Notes:

• NICE suggest that (2):
  • Do not use reagent strips to identify proteinuria in children and young people
    
    
  • Do not use reagent strips to identify proteinuria in adults unless they are capable of specifically measuring albumin at low concentrations and expressing the result as an albumin:creatinine ratio (ACR)
    
    
  • For the initial detection of proteinuria in adults, children and young people:
    • use urine ACR rather than protein:creatinine ratio (PCR) because of the greater sensitivity for low levels of proteinuria
    • check an ACR between 3 mg/mmol and 70 mg/mmol in a subsequent early morning sample to confirm the result
    • a repeat sample is not needed if the initial ACR is 70 mg/mmol or more
      
      
  • Regard a confirmed ACR of 3 mg/mmol or more as clinically important proteinuria
    
    
  • Measure proteinuria with urine ACR in the following groups:
    • adults, children and young people with diabetes (type 1 or type 2)
    • adults with an eGFR of less than 60 ml/min/1.73 m2
    • adults with an eGFR of 60 ml/min/1.73 m2 or more if there is a strong suspicion of CKD
    • children and young people without diabetes and with creatinine above the upper limit of the age-appropriate reference range
      
      When ACR is 70 mg/mmol or more, PCR can be used as an alternative to ACR

  Incidental finding of proteinuria on reagent strips

  • If unexplained proteinuria is an incidental finding on a reagent strip, offer testing for CKD using eGFRcreatinine and ACR

  • • ACR (albumin creatinine ratio) category	ACR (mg/mmol)
      A1	<3
      A2	3-30*
      A3	>30**

      * Relative to young adult level

      ** Including nephrotic syndrome (ACR usually >220 mg/mmol)

Reference:

• (1) MeReC Briefing 2004;26:1-8.
• (2) NICE (August 2021). Chronic kidney disease: assessment and management
• (3) The Renal Association (May 2006).UK CKD Guidelines
• (4) Haynes J, Haynes R. Proteinuria. BMJ 2006;332:284.
• (5) NICE (November 2021). Type 2 diabetes in adults: management