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.
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
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
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:
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.
Evidence Source: NICE
The 2021 NICE evidence review1 compared intensive with standard blood pressure therapy in patients with CKD:
- 11 randomised controlled trials including over 7600 patients
- no meaningful difference in outcomes between these two groups
- the trials were mixed regarding patient characteristics and blood pressure targets
However, the committee noted that ‘lower blood pressure targets were part of standard practice’ and that some older trials had shown benefits of tight blood pressure control on some outcomes.
For example, a study with 1094 African-American patients with non-diabetic hypertensive CKD2 showed benefit for a high proteinuria sub-group (average ACR of 53 mg/mmol):
- mean BP achieved was 128/78 in intensive v 140/86 in standard group
- proportion developing ESRD, doubling of serum creatinine or death in each group respectively was 52% v 61%
References
1)National Institute for Health and Care Excellence. Chronic kidney disease: assessment and management 2021 [Internet]. [London]: NICE; 2021. (Clinical guideline [CG182])
2)Appel LJ, Wright JT, Greene T et al. Intensive Blood-Pressure Control in Hypertensive Chronic Kidney Disease. N Engl J Med 2010; 363: 918-929
Evidence Quality: VERY LOW
| This research does not provide a reliable indication of the treatment effect.
There is a very high possibility that the true effect is greater, smaller or absent. |
The NICE evidence review1 rated the trial evidence quality from low to high depending on individual studies and outcomes.
No meaningful difference in outcomes was shown overall.
- The recommendation is based on expert opinion from limited evidence.
References
1)National Institute for Health and Care Excellence. Chronic kidney disease: assessment and management 2021 [Internet]. [London]: NICE; 2021. (Clinical guideline [CG182])
Study Population
The population characteristics in the 11 trials reviewed by NICE1 were highly varied across age, ethnicity and geography. They addressed different BP targets and outcomes.
This variety may partly explain why no overall benefit for lower blood pressure targets has been firmly established.
References
1)National Institute for Health and Care Excellence. Chronic kidney disease: assessment and management 2021 [Internet]. [London]: NICE; 2021. (Clinical guideline [CG182])
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 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).
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
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
Evidence Source: NICE
Figures derived from the 2021 NICE guideline review1.
This included:
- 2 randomised controlled trials which involved 3228 patients
- ARBs v placebo
- 3 randomised controlled trials which involved 761 patients
- ACE inhibitors v placebo
References
1)National Institute for Health and Care Excellence. Chronic kidney disease: assessment and management 2021 [Internet]. [London]: NICE; 2021. (Clinical guideline [CG182])
Evidence Quality: Low
| This research provides some indication of the treatment effect.
There is a high possibility that the true effect is smaller or greater. |
NICE rated this body of evidence as LOW quality1 because:
- most of the RCTs had some risk of bias
- 3 out of 5 trials did not reach statistical significance for key outcomes
- however, the pooled analyses were statistically significant
References
1)National Institute for Health and Care Excellence. Chronic kidney disease: assessment and management 2021 [Internet]. [London]: NICE; 2021. (Clinical guideline [CG182])
Study Population
The population characteristics in the trials in the NICE review1 were:
ACE inhibitor v placebo studies
- mixed nephropathies, 1 trial with type 1 diabetes, no type 2 diabetes.
- range of mean creatinine 114-212umol/L
- ACR >70mg/mmol
- age range 18-60, mean age 41 approx
- 1/3 women
- ethnicity was only reported in 1 trial: 90% White, 7% Black
ARBs v placebo studies
- all type 2 diabetes with nephropathy
- mean creatinine >150umol/L
- ACR 30-70mg/mmol
- age range 30-70, mean age 60
- 1/3 women
- ethnicity was only reported in 1 trial: 73% White, 12% Black, 5% Hispanic, 5% Asian, 5% other
References
1)National Institute for Health and Care Excellence. Chronic kidney disease: assessment and management 2021 [Internet]. [London]: NICE; 2021. (Clinical guideline [CG182])
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)tematic 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) Association between antihypertensive treatment and adverse events: systematic review and meta-analysis.
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)
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
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
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
Evidence Source: NICE
Figures derived from the 2021 NICE guideline1.
This evidence review included data from:
- 3 randomised controlled trials including over 8000 patients
- compared an SGLT2 inhibitor with usual care (including an ACE inhibitor or ARB)
- in patients with CKD, type 2 diabetes and significant proteinuria
Reference
1)National Institute for Health and Care Excellence. Chronic kidney disease: assessment and management 2021 [Internet]. [London]: NICE; 2021. (Clinical guideline [CG182])
Evidence Quality - HIGH
| This research provides a very good indication of the treatment effect.
However, it is possible that the true effect is slightly smaller or greater. |
NICE rated this evidence as HIGH quality1:
- large randomised controlled trials
- low risk of bias
- relevant to the target population
- consistent effects demonstrated with reasonable confidence intervals
Reference
1)National Institute for Health and Care Excellence. Chronic kidney disease: assessment and management 2021 [Internet]. [London]: NICE; 2021. (Clinical guideline [CG182])
Study Population
The population characteristics in the two key trials1,2 were:
- mean age 62
- 2/3 male 1/3 female
- ethnicity was reported as: White 59%, Black 5%, Asian 28%, other 8%
- 5/6 of patients had type 2 diabetes
- 1/2 of patients has pre-existing cardiovascular disease
- mean eGFR 50 ml/min/1.73m2
- mean urine ACR 107 mg/mmol
References
1)Heerspink HJL, Stefánsson BV, Correa-Rotter R et al. Dapagliflozin in Patients with Chronic Kidney Disease. New England Journal of Medicine 2020 Oct; 383(15): 1436-1446
2)Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. New England Journal of Medicine 2019; 380(24): 2295-306
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), , 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
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
Key
People who have an adverse event
People whose adverse event is prevented by treatment
People who were never going to have an adverse event anyway
Graphics and NNTs are rounded to the nearest integer
Stats explained
These three statistical terms offer three different ways of looking at the results of trial data.
ARR
Absolute Risk Reduction
This tells you how many people out of 100 who take a treatment have an adverse event prevented.
MoreThe value of the ARR changes with the baseline risk of the person (or population) taking the treatment. The higher the starting risk, the greater the absolute chance of benefit.
You need to think about over what time the trial data show this benefit, as it is usually assumed that more absolute risk reduction is gained over time.
Your patient might be taking the treatment for much longer than the length of a clinical trial (or, if life expectancy is limited, perhaps for less time).
NNT
Number Needed to Treat
This tells you how many people need to take the treatment in order for one person to avoid an adverse event.
The lower the number, the more effective the treatment.
MoreThe value of the NNT changes with the baseline risk of the person (or population) taking the treatment. The higher the starting risk, the smaller the NNT.
You need to think about over what time the trial data show benefit, as it is usually assumed that more benefit is gained over time and therefore the NNT will drop over time.
Your patient might be taking the treatment for much longer than the length of a clinical trial (or, if life expectancy is limited, perhaps for less time).
RRR
Relative Risk Reduction
This tells you the proportion of adverse events that are avoided if the entire population at risk is treated.
MoreThe value of the RRR is usually constant in people (or populations) at varying degrees of risk.
It is also usually assumed to stay constant over time.
This can be helpful, especially when thinking about population outcomes, but can be misleading for an individual person:
For example, a RRR of 25% in someone with a baseline risk of 40% would give them an ARR of 10% and an NNT of 10.
A RRR of 25% in someone with a baseline risk of 4% would give them an ARR or 1% and an NNT of 100.