Chapter 6 Slowing CKD progression

6.1 Lifestyle measures

Kelly et al. (2021): - in observational studies including over 2 million adults, factors associated with prevention of incident CKD were: high-K, plant-rich, low-NaCl diet; exercise, not smoking, moderate EtOH consumption.

6.2 Does blood pressure reduction delay progression of kidney disease?

AASK (2002): - with 3x2 factorial design - higher (acheiving c. 140/85) vs. lower (achieving c. 130/80) MAP target and metoprolol vs. ramipril vs. amlodipine in African Americans with hypertensive CKDIII–IV. Rate of decline in GFR over 4 yrs did not differ between MAP target groups. Ramipril was superior to the other agents for preventing composite of 50% reduction in GFR, ESRD, death. See also APOL1 nephropathy.

Combined re-analysis of MDRD & AASK (2020): - strict ABP control delayed ESKD in patients with high (> 0.44 g/day) but not low (< 0.44 g/day) baseline proteinuria.

Ettehad et al. (2016): - META-ANALYSIS of trials of anti-hypertensive therapy (total >600,000 patients). There was no significant effect of blood-pressure lowering on renal failure (whereas blood pressure lowering did reduce risks of MACE, coronary disease, stroke and heart failure).

6.3 RASi & progression in non-diabetic disease

6.3.1 Starting RASi

Jafar et al (2001): - ACEi are more effective than alternative anti-hypertensives in preventing ESRF (and doubling of SCr) in non-diabetic CKD. Benefits were greater if proteinuria; unclear if benefits at PER < 0.5 g/day.

Hou et al (2006): - benazepril vs. placebo in non-diabetic CKD (eGFR 20–70) and proteinuria (PER > 0.3 g/day). Benazepril reduced primary end-point (composite of doubling SCr, ESRD, death) over 3.4 yr follow-up. Effects on primary outcome and on proteinuria independent of ABP.

Xie et al (2016): - Bayesian network meta-analysis of RCTs of RASi in CKD. ACEi and ARB (vs. placebo or active controls) reduced risk of ESRF and CVS events. ACEi (vs. ARB) were associated with higher probability of preventing these outcomes.

O’Hare et al. (2014): - simlation to predict real-world benefits of RASi from their RCT-proven efficacy at preventing ESKD. Anticiapted NNTs over 3 yrs ranged from 16 (CKD IV with heavy proteinuria) to 2500 (CKD III with negligible proteinuria).

See also RASi in DKD.

See also trials of RASi in heart failure.

6.3.2 Stopping RASi

STOP-ACEi (2022): - open-label RCT of ACEi withdrawal in progressive CKD4 (n = 420). ESKD in 60%; CVS events in 50%; deaths in 10%. No difference in these outcomes between two groups.

Fu et al. (2021): - observational study in Swedish registry of CKD patients referred to nephrology (median eGFR 22). Over 5 years, stopping RASi associated with higher rates of mortality and MACE but lower rates of rates of RRT.

6.4 SGLT2i

See also SGLT2i in DKD.

The first large trial to confirm efficacy in non-diabetic CKD was DAPA-CKD.

DAPA-CKD (2020): - dapagliflozin 10 mg od vs. placebo in CKD (eGFR 25–75) and uACR >30. Primary composite outcome (ESKD, doubling of SCr, death from renal or CVS cause). T2DM in 67%. Terminated early (median follow-up 2.4 yrs) for efficacy. RR of primary outcome 40% lower in flozin group; NNT = 19.

This was confirmed in EMPA-KIDNEY, in a trial population that included patients with lower levels of eGFR and albuminuria.

EMPA-KIDNEY (2022): - empagliflozin 10 mg od vs. placebo in CKD (either eGFR 20 – 45 or eGFR 45 – 90 and uACR > 20 mg/mmol). Stopped early for efficacy. Empagliflozin reduced composite outcome (CKD progression, renal mortality, cardiovascular mortality) by 30%. Effect similar in diabetic and non-diabetic participants. Great safety profile (higher rate of discontinuation in the placebo arm).

Absolute benefit lower in patients with lower levels of albuminuria. Improvements in GFR slope were observed at all levels of albuminuria (even uACR < 3 mg/mmol) - although the magnitude of this effect is greater at higher levels (and of course absolute benefit will also increase in this group as cardiovascular event rate is higher). There was no significant benefit in the primary outcome or in the kidney disease progression outcome when uACR < 30 mg/mmol - but there were low event rates in these groups.

Chertow et al. (2021): - pre-specified analysis of patients with CKD4 in DAPA-CKD. Benefits in this group were similar to those in overall study group.

Johansen & Argyropoulos (2020): - a systematic review showed consistent cardiorenal benefits of SGLT2i in cardiovascular disease, CKD and HFrEF: a likely class effect.

Cardio-renal consortium meta-analysis (2022): - meta-analysis of 13 RCTs in 90,000 participants. SGLT2i RRRs for progressive CKD = 40%, for AKI = 20%, for cardiovascular death or heart failure hospitalisation = 20%, for cardiovascular death = 10%. Effect sizes similar in diabetic and non-diabetic individuals.

The sensitivity analysis on p16 of the supplemental material is worth looking at. This shows that beneficial effect (i.e. RRR) with respect to kidney outcomes (ESKD or AKI) does not vary according between trials in association with mean uACR. However, the absolute event rate (and hence the absolute benefit of SGLT2i) does, as expected. In trials with mean uACR <3 , 3 – 30 or >30 mg/mmol, rates of ESKD were respectively ~5, 15 and 50 events per 1000 patient years in the placebo groups. There are very limited data on patients without diabetes and uACR <30 mg/mmol (so for these trial populations, estimate of effect size crosses the null).