rational use of antihypertensives in CKD

hypertension and ckd 1/8/2024

1. PANEL DISCUSSION Rational use of anti-hypertensives in CKD Moderator- Lalit Agarwal Panelists: Tapas Behera , Biswaranjan Mohanty , Jamshed Anwar and Nikhil Shinde

2. Introduction Hypertension is both a cause and more often a complication of CKD. As kidney function declines , the incidence and severity of hypertension increases. H ypertension is a risk factor for progression of kidney disease and both are independent risk factor for CVD which is the most important cause of morbidity and mortality in patients with CKD The goals of antihypertensive therapy in CKD are to lower blood pressure, reduce the risk of CVD, and slow progression of CKD Although trials failed to demonstrate that intensive BP lowering results in lower rate of kidney function decline but effective in reducing CV events and thus all cause mortality in CKD population

3. Definition of hypertension in CKD The US/Europe/KDIGO 2021 and rest of world don’t agree about “what is normal BP” GUIDELINES CLINIC HBPM DAYTIME ABPM NIGHTTIMEABPM 24H ABPM ACC/AHA 2017 ≥130/80 ≥130/80 ≥130/80 ≥110/65 ≥125/75 ESC/ESH 2018 ≥140/90 ≥135/85 ≥135/85 ≥120/70 ≥130/80

4. Accurate/Standardized measurement of BP is important In practice treatment of Hypertension is often based on routine Clinic or Office BP recordings 24-Hour ambulatory BP monitoring (ABPM) provides a more accurate depiction of BP. It also allows assessment of the diurnal variation in BP. However frequent ABPM is not practical Home BP monitoring (HBPM) is an alternative strategy that is less resource intensive and much more practical. In our daily practice adopt a standardized BP/AOBP measurement methodology. In SPRINT trial research grade office SBP was 12.7 mmHg lower.

5. Non-pharmacological treatment of hypertension in CKD (lifestyle changes) Weight control if one is overweight or obese Diet- salt restriction and DASH diet Exercise Reduce consumption of coffee and caffeine rich products Reduce intake of alcohol in those who consume more Stop Smoking Updated Cochrane meta analysis (2021) – mean dietary Na intake 73.51mmol/day associated with av. reduction of 6.91/3.91 mmHg in office BP and 36% reduction in albuminuria)

6. Choice of drugs in CKD Maladaptive changes in surviving nephrons in CKD (intra-glomerular hypertension) mainly by activation of RAAS system Drugs that reduce BP as well as glomerular hypertension in CKD Antihypertensive agents of FIRST CHOICE - ACEi and ARB (watch creatinine and potassium) 1 mechanism of action ( theoretically ) 2 Multiple robust clinical trial ( RENAAL -Losartan reduce risk of ckd progression in T2D by25% & ESRD 28%, IDNT - Irbesartan decreased progression of renal disease independent of BP lowering effect of Irbesartan) 3 KDIGO 2021 GUIDELINES (1B) as well as all major hypertension guidelines provide a strong recommendations.

7. Choice of drugs in CKD SECOND LINE THERAPY Long acting dihydropyridine inhibitors or a diuretic ( more appropriate if fluid overloaded) THIRD LINE THERAPY Combination of RAS blocker, a dihydropyridine CCB and a diuretic.

8. Resistant hypertension BP remains uncontrolled despite maximally tolerated doses of RAS blocker, a CCB and a diuretic fulfil the diagnostic criteria of resistant hypertension. SPIRONOLACTONE is recommended by guidelines as fourth line agent in drug resistant hypertension ( avoid if eGFR < 45ml and K >4.5MMOL/L) AMBER TRIAL CKD (eGFR 25 to < 45 ml/min) resistant hypertension treated with spironolactone with PATIROMER.

9. OTHER ANTIHYPERTENSIVES Beta blockers Alfa blockers Centrally acting alfa agonist /sympatholytic Direct vasodilators

10. GOAL BP in CKD Recommendation 3.1.1: KDIGO suggest that adults with high BP and CKD be treated with a target systolic blood pressure (SBP) of <120 mm Hg, using standardized office BP measurement (2B). This recommendation is weak according to GRADE because there is less certainty that the benefits outweigh the harms in the following scenarios: • CKD G4 and G5 • Diabetes • Individuals with SBP 120-129 mm Hg • Patients with very low baseline diastolic BP, particularly in the presence of coronary artery disease • Specific etiology of CKD • Severely increased proteinuria • Older age • Younger age • Very frail • “White coat” hypertension • Severe hypertension INDIVIDUALIZATION IS KEY

11. RATIONALE FOR TARGET SBP <120 MM HG IN CKD • For most patients with CKD, a cardiovascular event is a more likely outcome than ESKD (1 in 1000). • SPRINT confirmed cardiovascular and survival benefits in non-diabetic CKD.(25% RRR in primary outcome with < 120mmHg BP) • ACCORD showed marked reduction in stroke in diabetes, but only included 401 patients with eGFR <60 ml/min/1.73m2 ; nonetheless, benefits of SBP <120 mm Hg in the standard glycemia arm similar to those seen in SPRINT. • Meta-analyses demonstrate reduction of CV risk proportional to BP lowering, though some show lower proportional risk reduction in the presence of CKD and of DM

12. Controversies of KDIGO BP targets in all patients – calls for debate Most people don’t use standardized BP measurements Most measure attended BP and not unattended BP measurement KDIGO defines high BP as systolic above 120 (no diastolic targets) Difficult to reach targets of 120mmHg, faster progression of CKD Fear of higher incidence of strokes with SBP below 120 c/w 140mmHg Fear of higher incidence of falls in older, frail with target of 120 mmHg KDIGO concluded largely from SPRINT trial

13. Sodium Glucose co-transporter type 2 inhibitors (SGLT2i) Initially introduced as hypoglycemic drugs but later discovered that cardiorenal protection is the main therapeutic effect of these agents irrespective of presence or absence of T2D Canvas trial 2019 Empa reg trial 2020 Dapa CKD 2020

14. FINRENONE: Highly selective Non- steroidal MRA Effective in improving cardio renal outcomes in patients with diabetic kidney disease The FIDELITY POOLED ANALYSIS : combined FIDELIO-DKD and FIGARO –DKD TRIALS – pooled analysis of data from 13026 patients with T2D and a broad spectrum of CKD, as c/w placebo, Finrenone retarded the progression of DKD reduced the risk of hospitalization for heart failure, CV death and Myocardial infarction. Although risk of hyperkalemia is more common with Finrenone . A post hoc analysis indicate that combined therapy (SGLT2i) is superior by reducing risk of hyperkalemia in patients who are receiving std. of care treatment.

15. SGLT2i and Finrenone has modest BP lowering effect SGLT2i - meta-analysis of 7 trials of 2381 patients a reduction of 3.61 mmHg in ABPM (osmotic diuresis/natriuresis) Finrenone - (ARTS-DN trial) relative with placebo at day 90 reduction in ABPM 8.3 mmHg for 10 mg/day and 9.9 mmHg for 20 mg per day BP lowering effect ? as a mediator of the improvement in cardiorenal outcome.

16. Newer antihypertensives Non steroidal MRA – OCEDURENONE Aldosterone synthase inhibitor – BAXDROSTAT ( BrigHTN trial) Dual Endothelin receptor antagonist –APROCITENTAN (PRECISION TRIAL)

17. Renal Denervation Interest dampened after the neutral results of the renal denervation in patients with uncontrolled/resistant hypertension trial by Bhatt et al in 2014 (SYMPLICITY HTN-3) More recent studies support the antihypertensive efficacy tolerability, and safety of catheter based renal denervation in CKD patients with eGFR >45 ml/min. RADIANCE-HTN-SOLO 2018,RADIANCE-HTN-TRIO 2021, SPYRAL-HTN-ON MED 2022 More studies needed in patients with eGFR < 45ml/min

18. Stopping or continuing RASi in advanced CKD This remains an area of controversy. OBSERVATIONAL STUDY – discontinuation has better preservation of kidney function (NDT-2010) Another observational study stopping RASi is associated with lower absolute risk of initiating dialysis but higher absolute risk of adverse CV events and all cause mortality (JASN -2021) MORE CONCLUSIVE ANSWER PROVIDED BY – multicenter RCT : STOP- ACEi (NDT-2016) discontinuation of RAS blockers did not lead to stabilization of long term decline in kidney function and does not delay the initiation of dialysis . In fact , a trend toward earlier dialysis was noted. (NEJM 2022)