What are some research gap ideas for optimizing blood pressure management in patients with Chronic Kidney Disease (CKD), particularly those with advanced disease?

Research Gap Ideas for Blood Pressure Management in CKD Patients

Critical Evidence Gaps in Advanced CKD (Stages 4-5)

The most urgent research need is establishing optimal blood pressure targets for patients with advanced CKD stages 4-5, as these patients were systematically excluded from major trials including SPRINT. 1, 2

Key Areas Requiring Investigation:

Optimal BP Targets in Advanced Disease:

• Most major hypertension trials excluded patients with eGFR <20-30 mL/min/1.73 m², leaving stage 4-5 CKD patients without robust evidence for BP targets 1, 2
• The REIN-2 trial, one of few including stage 4 CKD patients, was stopped early for futility, highlighting the complexity of this population 2
• Research is needed comparing <130/80 mmHg versus <140/90 mmHg targets specifically in stage 4-5 CKD with hard outcomes (mortality, cardiovascular events, kidney failure) 1, 2

Risk-Benefit Analysis of Intensive BP Lowering:

• The risk of acute kidney injury with intensive BP lowering is substantially higher in advanced CKD than earlier stages, yet optimal thresholds remain undefined 2
• Studies are needed to determine whether intensive BP lowering accelerates the need for kidney replacement therapy and if this trade-off is acceptable given potential cardiovascular benefits 2
• Investigation of diastolic BP thresholds is critical, as older CKD patients often have low diastolic BP due to arterial stiffness, making aggressive systolic lowering potentially harmful 2

Medication-Specific Research Needs

RAAS Inhibitor Dosing and Monitoring:

• The acceptable threshold for creatinine rise after initiating ACE inhibitors/ARBs in stage 4-5 CKD requires clarification beyond the current 30% guideline 2
• Research comparing continuation versus withdrawal of RAAS inhibitors in progressive stage 4-5 CKD is needed, as anecdotal reports suggest withdrawal may preserve residual function, but robust data are lacking 1
• Studies examining optimal monitoring intervals for potassium and creatinine in advanced CKD patients on RAAS inhibitors 2

Novel Potassium Management Strategies:

• Clinical trials evaluating whether newer potassium binders (patiromer, sodium zirconium cyclosilicate) enable higher-dose RAAS inhibitor therapy in advanced CKD with improved kidney and cardiovascular outcomes 3
• Investigation of potassium-enriched salt substitutes in early-stage CKD (stages 1-3a), as current guidelines warn against use in advanced CKD but evidence for benefit in earlier stages exists 1
• The Chinese guideline suggests careful use of 25% potassium-substituted salt in predialysis patients may reduce BP, but this requires validation in rigorous trials 1

Population-Specific Evidence Gaps

Race and Ethnicity Considerations:

• Lisinopril demonstrated less effectiveness in Black patients compared to Caucasians, yet optimal first-line therapy for Black patients with CKD and proteinuria remains unclear 4
• Research is needed on whether initial therapy with thiazide diuretics or calcium channel blockers followed by RAAS inhibitor addition (as suggested for Black patients) provides equivalent renoprotection to RAAS inhibitor monotherapy 2

Elderly and Frail Patients:

• Guidelines encourage individualization in elderly patients but provide minimal specific guidance 1
• Studies are needed establishing BP targets that balance cardiovascular protection against fall risk, orthostatic hypotension, and acute kidney injury in patients >75 years with CKD 2

Diabetic versus Non-Diabetic CKD:

• Most guidelines provide nearly identical recommendations for diabetic and non-diabetic CKD, yet pathophysiology differs 1
• Research comparing intensive versus standard BP targets specifically in diabetic CKD patients with stage 4-5 disease is lacking 5

Measurement and Monitoring Innovations

Home and Ambulatory BP Monitoring:

• Masked hypertension affects up to 30% of CKD patients and associates with worse outcomes, yet optimal screening strategies remain undefined 2
• Research is needed on whether home BP monitoring-guided therapy improves outcomes compared to office-based management in CKD 2
• The SPRINT protocol used automated office BP measurement (5-minute rest, three readings averaged, often without observers), which yields lower values than typical office measurement—studies are needed determining if this method should become standard in CKD management 5

Implementation Science Research

Guideline Adherence and Clinical Inertia:

• Despite clear guidelines, BP control remains poor in CKD patients—implementation research is needed identifying effective strategies to improve adherence 6
• Guideline-concordant decision support systems showed significant effects (pooled OR 1.19) but require further development and validation 6
• Studies examining barriers to achieving BP targets in real-world CKD populations, particularly in primary care settings 6

Multidisciplinary Care Models:

• Shared care models showed non-significant effects (pooled OR 1.71,95% CI 0.96-3.03), requiring larger trials to determine true efficacy 6
• Pharmacist-facing interventions showed no significant benefit (pooled OR 1.04), suggesting need for redesigned approaches 6

Novel Therapeutic Targets

Emerging Antihypertensive Agents:

• Non-steroidal mineralocorticoid receptor antagonists (e.g., ocedurenone) may avoid hyperkalemia while providing BP control—phase III trials in advanced CKD are needed 3, 7
• Dual endothelin receptor antagonists (aprocitentan) and aldosterone synthase inhibitors (baxdrostat) require evaluation specifically in CKD populations with hard outcomes 7
• Chlorthalidone demonstrated efficacy in stage 4 CKD in the CLICK trial, but longer-term studies examining kidney and cardiovascular outcomes are needed 7

Combination Therapy Strategies:

• Optimal sequencing and combinations of antihypertensive agents in CKD beyond RAAS inhibitors require systematic investigation 7
• Research on whether chlorthalidone plus spironolactone combinations can safely achieve BP control in stage 4 CKD while managing hyperkalemia risk 7

Mechanistic and Biomarker Research

Early Disease Mechanisms:

• Research should focus on unraveling early CKD mechanisms before tubulointerstitial fibrosis is established, as interventions at later stages prove insufficient 3
• Studies examining epigenetic regulators as therapeutic targets are in phase II-III trials and may provide coordinated regulation of CKD progression pathways 3
• Investigation of biomarkers predicting which CKD patients will benefit most from intensive BP lowering versus those at higher risk for adverse events 3