Conditions

Treatment options for

Chronic Kidney Disease

The definition of Chronic Kidney Disease (CKD) is wide and ranges from mild age-related changes in kidney function to severe progressive kidney disease.

It is helpful to think about an individual’s risk of developing different problems related to their CKD – the first two sections provide a guide to this.

Then you can think about how individual treatment options might help them.

For many people, the most important thing may be their cardiovascular risk.

For others, it may be their chance of progression to end stage renal disease (ESRD), or both.

Understanding how CKD affects cardiovascular risk

CKD is associated with an increase in cardiovascular risk.

QRISK cardiovascular risk calculations multiply cardiovascular risk by roughly 1.5 for a CKD diagnosis.

  • QRISK 2 includes CKD stages 4+5
  • QRISK 3 includes CKD stages 3-5

These calculations are approximate as they lump together a range of renal impairment.

The amount of albuminuria also affects cardiovascular risk.

Figure: Cardiovascular risk increases with reducing eGFR and rising albuminuria1

Made with Flourish

Reference

1)Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010; 375(9731): 2073-2081

Estimating the risk of end-stage renal disease

Most people with CKD will never develop end-stage renal disease, but those at high risk are most likely to benefit from some of the interventions below.

NICE recommend calculating an individual’s  5-year risk of developing end-stage renal disease using the “4 variable kidney risk failure equation”.

  • this uses age, sex, eGFR and ACR1,2

An online calculator can be found here

Note: this tool is validated in a US population so should be used as a guide only

 

References

1)National Institute for Health and Care Excellence. Chronic kidney disease: assessment and management 2021 [Internet]. [London]: NICE; 2021. (Clinical guideline [CG182])

2)Major RW, Shepherd D, Medcalf JF et al. The Kidney Failure Risk Equation for prediction of end stage renal disease in UK primary care: An external validation and clinical impact projection cohort study. PLOS Medicine 2019; 16(11): e1002955

Treatment options:

Tighter BP control to below 130mmHg

NICE recommends that:

  • most patients with CKD and hypertension should be treated to a standard target blood pressure of below 140/90mmHg
  • those with an ACR of 70 mg/mmol or more should be treated to a lower target blood pressure of  130/80mmHg

The recommendation for a lower target is based on committee opinion in the absence of clear evidence.

The trials of tighter blood pressure control in CKD do not provide good information about harms of more intensive treatment.

Information on harms of lower blood pressure targets when treating hypertension in a wider population may provide a guide to the risk of harms in a population with CKD. A 2020 Cochrane review1 found:

Standard treatment

mean SBP 135mmHg

Intensive treatment

mean SBP 123mmHg

Absolute Risk Increase Number Needed to Harm Relative Risk Increase
Serious adverse events 6.8% 9.8% 3% 33 1.44
  • Adverse events included hypotension, syncope, bradycardia or arrhythmia, hyperkalaemia, angioedema, acute kidney injury and renal failure.
  • These occurred over an average trial duration of 3.7 years.
  • This data is based on 6 studies including 19,000 people with  isolated hypertension or with co-morbidities (diabetes, previous stroke, CKD or AF).
  • This evidence quality was appraised as LOW due to:
    • missing data from some trials
    • wide confidence intervals

 

References

1)Arguedas JA, Leiva V, Wright JM. Blood pressure targets in adults with hypertension. Cochrane Database of Systematic Reviews 2020, Issue 12. Art. No.: CD004349. DOI: 10.1002/14651858.CD004349.pub3

ACE inhibitors and ARBs for albuminuria

ACE inhibitors and ARBs reduce progression to end-stage renal disease in patients with albuminuria.

There is no evidence for this benefit in patients with CKD without albuminuria.

NICE recommends offering them to these groups at higher risk of end-stage renal disease:

  • CKD with urine ACR 70 mg/mmol
  • CKD with hypertension and urine ACR >30mg/mmol
  • CKD with diabetes and urine ACR >3mg/mmol

They have not been shown to reduce cardiovascular events or overall mortality (outside of their role treating any co-morbidities such as hypertension or heart failure).

No treatment
With treatment
ARR -- Absolute Risk Reduction
NNT -- Number Needed to Treat
RRR -- Relative Risk Reduction
No treatment
20.7 people develop end-stage renal disease after 3 years
With treatment
12 people develop end-stage renal disease after 3 years
ARR 8.7% Absolute Risk Reduction
NNT 11 Number Needed to Treat
RRR 41% Relative Risk Reduction

If 100 people with CKD and significant albuminuria take an ACE inhibitor for 3 years, 8.7 people will avoid end-stage renal disease compared with if they hadn't taken an ACE inhibitor

No treatment
21 people develop end-stage renal disease after 3 years
With treatment
16.5 people develop end-stage renal disease after 3 years
ARR 4.5% Absolute Risk Reduction
NNT 22 Number Needed to Treat
RRR 21% Relative Risk Reduction

If 100 people with CKD, type 2 diabetes and significant albuminuria take an ARB for 3 years, 4.5 will avoid end-stage renal disease compared to those who don't take an ARB

There is little data available on the rates of harms from ACE inhibitors or ARBs in patients with CKD.

These numbers from various trial populations might serve as a guide:

Outcome Placebo ACE inhibitor Absolute Risk Increase Number Needed to Harm
Cough1 1.3% 4.4% 3.1% 32
Cough2 12.5% 18.2% 5.7% 18
Withdrawal due to adverse event2 6.7% 14.2% 7.5% 13
ACEi ARB
Withdrawal due to adverse event3* 11.3% 9.4% 2.1% 48
Placebo ACEi and ARB
Hyperkalaemia4 3.0% 4.8% 1.9% 54
Acute kidney injury4 1.1% 1.5% 0.4% 250

1. Population with diabetes and CKD

2. Population with Ischaemic heart disease

3,4. Population with hypertension

Evidence quality is rated as VERY LOW – LOW (except 3* which is HIGH) due to:

  • poor reporting in trials
  • possible publication bias
  • small numbers of harm events in trials

 

References

1)Strippoli GFM, Bonifati C, Craig ME et al. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD006257

2)Baker WL, Coleman CI, Kluger J, et al. Systematic Review: Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II–Receptor Blockers for Ischemic Heart Disease. Ann Intern Med 2009; 151: 861-871

3)Li ECK, Heran BS, Wright JM. Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No.: CD009096

4)Albasri A, Hattle M, Koshiaris C et al. Association between antihypertensive treatment and adverse events: systematic review and meta-analysis.

SGLT2 inhibitors

NICE recommends offering an SGLT2 inhibitor to patients with CKD with

  • type 2 diabetes or
  • urine ACR >22.6mg/mmol and
  • who meet the criteria in the marketing authorisation (including relevant eGFR thresholds – see BNF)
No treatment
With treatment
ARR -- Absolute Risk Reduction
NNT -- Number Needed to Treat
RRR -- Relative Risk Reduction
No treatment
7.5 people develop end-stage renal disease after 2.5 years
With treatment
5.2 people develop end-stage renal disease after 2.5 years
ARR 2.3% Absolute Risk Reduction
NNT 43 Number Needed to Treat
RRR 31% Relative Risk Reduction

If 100 people with CKD, T2DM and urine ACR >30mg/mmol take an SGLT2 inhibitor for 2.5 years, 2.3 will avoid end stage renal disease compared with if they hadn't taken an SGLT2 inhibitor

No treatment
5.1 cardiovascular deaths after 2.5 years
With treatment
4 cardiovascular deaths after 2.5 years
ARR 1.1% Absolute Risk Reduction
NNT 91 Number Needed to Treat
RRR 21% Relative Risk Reduction

If 100 people with CKD, T2DM and urine ACR>30mg/mmol take an SGLT2 inhibitor for 2.5 years, 1.1 will avoid a cardiovascular death compared with if they hadn't taken an SGLT2 inhibitor

No treatment
7.7 deaths over 2.5 years
With treatment
6 deaths over 2.5 years
ARR 1.7% Absolute Risk Reduction
NNT 59 Number Needed to Treat
RRR 22% Relative Risk Reduction

If 100 people with CKD, T2DM and urine ACR >30mg/mmol take an SGLT2 inhibitor for 2.5 years, 1.7 will avoid death compared with if they hadn't taken an SGLT2 inhibitor

Polyuria, thirst, lightheadedness

Between 1 in 10 – 100 people.

SGLT2 inhibitors work by increasing glucose excretion in the urine.

More

Absolute risk data is not available, but the BNF lists these as “common or very common” (defined as 1 in 10 – 100)

Genital infections (mainly candidiasis)

3 in 100 people will develop this due to treatment.

More

Diabetes is a risk factor for this in itself.

In a Cochrane review1, 4.6% of people with diabetes taking an SGLT2i developed this compared with 1.6% of people  taking placebo.

  • MODERATE quality evidence

Urinary tract infections

No increase in UTIs was seen due to treatment with SGLT2 inhibitors in the RCTs1.

Hypoglycaemia

No increase in hypoglycaemia seen in RCTs comparing SGLT2i  with placebo1,2.

  • MODERATE quality evidence

Hypoglycaemia may occur in combination with insulin or sulfonylurea.

  • The BNF lists this as “common or very common” (defined as 1 in 10 – 100).

Diabetic ketoacidosis

The BNF lists this as “rare or very rare” (defined as 1 in 1000 – 10,000).

It occurs usually within the first 2 months of treatment3.

May present with only mildly elevated blood glucose.

More

A suggestion of an increased risk of DKA is seen in the meta-analysis of RCTs1,2, but not to a level of statistical significance.

The estimate of frequency comes from post-marketing surveillance data.

The causal mechanism is unknown.

The MHRA recommend caution and vigilance in the context of:

  • acute severe illness
  • sudden changes to insulin dosing
  • restricted food intake or dehydration
  • alcohol abuse

and to

  • test for ketones if there are systemic symptoms suggestive of DKA even with near-normal blood glucose.

Lower limb amputations (mainly toes)

One clinical trial (of canafliglozin) found an excess of 2 – 4 cases per 1000 (depending on dose).

Though there is no evidence of this risk being associated with other drugs in the class, the MHRA issued a warning for “the potential increased risk of lower-limb amputation, mostly affecting the toes” for all SGLT2i4.

Fournier’s gangrene

It is uncertain if this severe condition is caused by SGLT2i, but case reports triggered a safety warning.

  • 6 case reports in the UK by January 2019 in the context of 548,565 patient-years of treatment5.

More

Fournier’s gangrene is a bacterial infection of the perineum which can be rapidly progressive and cause abscesses and necrotising fasciitis.

Diabetes is a risk factor in itself.

The MHRA advise patients to seek urgent medical attention if they experience severe pain, tenderness, erythema, or swelling in the genital or perineal area, accompanied by fever or malaise.

If suspected, it requires immediate referral to secondary care.

 

References

1)Lo C, Toyama T, Wang Y et al. Insulin and glucose‐lowering agents for treating people with diabetes and chronic kidney disease. Cochrane Database of Systematic Reviews 2018, Issue 9. Art. No.: CD011798

2)Toyama T, Neuen BL, Jun M et al. Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta-analysis. Diabetes Obes Metab 2019; 21: 1237-1250

3)MHRA. SGLT2 inhibitors: updated advice on the risk of diabetic ketoacidosis. Drug Safety Update, 18 April 2016. Accessed online July 2021

4)MHRA. SGLT2 inhibitors: updated advice on increased risk of lower-limb amputation (mainly toes). Drug Safety Update, 22 March 2017. Accessed online July 2021

5)MHRA. SGLT2 inhibitors: reports of Fournier’s gangrene (necrotising fasciitis of the genitalia or perineum). Drug Safety Update, 18 Feb 2019. Accessed online July 2021

Statins for the primary prevention of cardiovascular disease in CKD

NICE recommends offering atorvastatin 20mg to all patients with CKD, because most will have a 10-year cardiovascular risk of 10% or much higher1.

The committee opinion was that using cardiovascular risk scores to select patients with CKD for statin treatment is not ideal because they may mis-estimate risk.

However, if you or your patient wished to better understand their potential benefits, you could:

Get a rough idea of someone’s baseline risk by either:

  • using QRISK2 bearing in mind that this only accounts for CKD 4+5, so will underestimate risk in CKD3
  • using QRISK3 – this accounts for CKD3-5

Note: QRISK does not account for albuminuria which raises CV risk greatly.

Or

  • see the graph in the “Understanding how CKD affects cardiovascular risk” section above to get an idea of how baseline CV risk increases according to eGFR and albuminuria

then

  • with an estimated baseline QRISK score, see the effect of atorvastatin 20mg in the section linked below.

Patients on dialysis

2 major systematic reviews showed no benefit from statins amongst patients on renal dialysis2,3.

  • Cochrane rated the evidence as MODERATE – HIGH  quality

Pros and cons of statin therapy in this group may vary, so could be discussed on an individual basis with a renal physician.

 

References

1)National Institute for Health and Care Excellence. Cardiovascular disease: Risk Assessment and reduction, including lipid modification 2014 [Internet]. [London]: NICE; 2014 [updated 2016 Sep]. (Clinical guideline [CG181])

2)Palmer SC, Navaneethan SD, Craig JC et al. HMG CoA reductase inhibitors (statins) for dialysis patients. Cochrane Database of Systematic Reviews 2013, Issue 9. Art. No.: CD004289

3)Cholesterol Treatment Trialists (CTT) Collaboration. Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials. Lancet Diabetes & Endocrinology 2016; 4(10): 829-839