CKD disrupts the normal pressure-natriuresis relationship: the kidney normally excretes excess sodium in response to rising blood pressure, thereby correcting BP. As nephron mass is lost, the surviving nephrons must compensate by increasing their individual filtration and excretory burden. This adaptation initially preserves sodium balance but at the cost of resetting the pressure-natriuresis curve to a higher operating point, meaning the kidney now defends a higher BP.²

Sodium and water retention occurs because reduced functioning nephron mass decreases total natriuretic capacity, while surviving nephrons have increased tubular sodium reabsorption. The result is volume expansion, increased cardiac preload, and elevated cardiac output, with volume-dependent hypertension predominating in advanced CKD. RAAS activation occurs as ischemic nephrons activate juxtaglomerular cells to release renin; in some forms of CKD, inappropriate renin secretion sustains angiotensin II levels even in the face of volume expansion, a failure of the normal suppression mechanism. Angiotensin II causes systemic vasoconstriction, aldosterone release, and further sodium retention, while aldosterone independently promotes inflammation, fibrosis, and further nephron loss through the aldosterone-escape phenomenon.

CKD also activates afferent renal nerves from ischemic and damaged kidney tissue, increasing efferent sympathetic outflow and raising cardiac output and peripheral vascular resistance, with sympathetic activation further stimulating renin release. Uremic toxins impair endothelial nitric oxide (NO) production, oxidative stress quenches NO increasing vasoconstriction, and endothelin-1 upregulation contributes to sustained vasoconstriction. CKD-related anemia from reduced erythropoietin production causes compensatory increased cardiac output, contributing to systolic hypertension, and elevated parathyroid hormone levels increase intracellular calcium in vascular smooth muscle, contributing to vasoconstriction.

Intraglomerular hypertension, representing elevated pressure within the glomerular capillaries, is a critical mediator of progressive nephron loss. Even when systemic BP is controlled, intraglomerular pressure may remain elevated due to preferential dilation of the afferent arteriole relative to the efferent arteriole, hyperfiltration in surviving nephrons due to compensatory glomerular hypertrophy, and in early diabetic nephropathy, diabetes-related glomerular vasodilation.

Elevated intraglomerular pressure drives proteinuria, which is itself nephrotoxic through multiple mechanisms: filtered proteins activate tubular cells promoting inflammation and fibrosis; albumin carries fatty acids that are toxic to proximal tubular cells; protein casts obstruct tubular lumina; and complement activation within tubular fluid drives interstitial injury. This creates a self-amplifying cycle in which systemic hypertension leads to intraglomerular hypertension, which causes proteinuria, which drives tubular injury and interstitial fibrosis, leading to further nephron loss, which worsens systemic hypertension. Pharmacological intervention that specifically reduces intraglomerular pressure through RAAS inhibition interrupts this cycle more effectively than equivalent systemic BP reduction achieved by non-RAAS agents.

At this stage, renal function is preserved or mildly reduced. The approach mirrors that for the general hypertensive population, with the addition of RAAS inhibition when proteinuria is present. When albuminuria is above 30 mg/g, the first-line agent is an ACEi or ARB for renoprotection and antiproteinuric effect, with a CCB (amlodipine) or thiazide-like diuretic added for additional BP control. The target is below 130/80 mmHg per KDIGO 2021.¹ Without albuminuria, the standard four-class framework applies and RAAS inhibitors are acceptable but not mandated, with CCBs and thiazide-like diuretics being particularly effective.

This is the most clinically important stage for pharmacological decision-making. Thiazide and thiazide-like diuretics retain partial but progressively reduced efficacy as eGFR falls through this range. RAAS inhibitors remain first-line with albuminuria and should be continued if already initiated, with close monitoring of creatinine and potassium with dose changes. CCBs, particularly amlodipine, are highly effective with no dose adjustment required and no adverse renal effects. The CLICK trial (2021) demonstrated that chlorthalidone 12.5–25 mg reduced 24-hour ambulatory systolic BP by 11 mmHg versus placebo in patients with Stage 4 CKD on optimal background therapy including RAAS inhibitors, confirming efficacy at this advanced stage.⁸ Indapamide retains efficacy at lower eGFR than hydrochlorothiazide (HCTZ) and has a favorable metabolic profile.

Regarding diuretic transition, at eGFR 30–45 mL/min/1.73m² (Stage 3b), thiazide efficacy is substantially reduced and adding or transitioning to a loop diuretic should be considered if volume control is inadequate. Renal function and potassium should be monitored every 3 months in stable Stage 3 CKD on RAAS inhibition, with more frequent monitoring after dose changes, intercurrent illness, or addition of any nephrotoxin.

This stage requires the most careful pharmacological selection. RAAS inhibitors can be continued with careful monitoring if potassium is controlled below 5.0 mEq/L and creatinine is stable or acceptably elevated. The benefit-risk calculation favors continuation for renoprotection and cardiovascular protection even at eGFR 15–29. Fosinopril, which has dual renal and hepatic elimination, is the preferred ACEi, and telmisartan, which has biliary elimination, is the preferred ARB. Loop diuretics become the first-line diuretic class at this stage, as thiazides are largely ineffective below eGFR 30 mL/min/1.73m². Torsemide is preferred over furosemide for superior oral bioavailability and more predictable response. CCBs require no dose adjustment and remain highly effective and safe across all CKD stages, with amlodipine as the preferred dihydropyridine CCB. Non-DHP CCBs can be used but add a constipation burden to a population often already affected by uremic constipation.

Regarding potassium-sparing diuretics and MRAs: spironolactone and eplerenone should be used with extreme caution in Stage 4 CKD due to high hyperkalemia risk with concurrent RAAS inhibition. Finerenone, the non-steroidal MRA, was studied in the FIDELIO-diabetic kidney disease (DKD) trial to eGFR as low as 25 mL/min/1.73m² and demonstrated cardiovascular and renal benefit in diabetic CKD with acceptable hyperkalemia rates, making it the preferred MRA in Stage 4 diabetic CKD on background RAAS inhibition.¹²

Among beta-blockers, bisoprolol is preferred in advanced CKD due to dual elimination (approximately 50% hepatic, 50% renal), providing more predictable drug levels than purely renally eliminated agents such as atenolol, which accumulates in advanced CKD and requires dose adjustment. Carvedilol and metoprolol are hepatically metabolized and are reasonable options.

Gadolinium-based contrast carries a risk of nephrogenic systemic fibrosis in severe CKD; group II and III agents are safer at lower eGFR but should still be avoided when eGFR is below 30 unless essential.

Before dialysis at eGFR below 15, loop diuretics at high doses (furosemide 80–200 mg twice daily or torsemide 40–100 mg once daily) are used to maintain any residual urine output and sodium excretion. RAAS inhibitors should be continued for residual renal function and cardiovascular protection if potassium is manageable, stopping only if causing dangerous hyperkalemia (potassium above 6.0 mEq/L unresponsive to other measures). CCBs remain effective and safe. Volume control is the dominant mechanism of BP management at this stage.

On hemodialysis, BP is primarily controlled by ultrafiltration and sodium removal during dialysis sessions, and interdialytic weight gain is a key driver of hypertension. ACEi and ARBs may provide cardiovascular outcome benefit in dialysis patients; some are removed by dialysis (lisinopril, enalapril may require supplemental dosing post-dialysis), while telmisartan and candesartan are not significantly dialyzed and are preferred. Long-acting agents are preferred for between-dialysis hypertension management. On peritoneal dialysis (PD), hypertension is very common, and ACEi and ARBs may preserve residual renal function in PD patients, where residual function is better preserved than in hemodialysis. All standard antihypertensive classes can be used in PD.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as a landmark class for CKD management, with cardiovascular and renal benefits that extend well beyond their glucose-lowering effects.^9,11 Their antihypertensive mechanisms include SGLT2 inhibition in the proximal tubule reducing glucose and sodium co-reabsorption, promoting osmotic diuresis and natriuresis with a modest but consistent systolic BP reduction of approximately 3–5 mmHg and diastolic reduction of 1–2 mmHg; modest body weight reduction of 2–3 kg with reduced visceral adiposity; and reduction of intraglomerular pressure through tubuloglomerular feedback restoration. This last mechanism involves increased distal sodium delivery to the macula densa restoring tubuloglomerular feedback and causing afferent arteriolar constriction, reducing intraglomerular pressure.

The CREDENCE trial (2019) showed that canagliflozin in type 2 diabetes with CKD (eGFR 30–90 mL/min/1.73m² and UACR 300 mg/g or above) on background RAAS inhibition produced a 40% relative risk reduction in the primary composite renal endpoint and a 30% reduction in ESRD.¹¹ The DAPA-CKD trial (2020) demonstrated that dapagliflozin in CKD (eGFR 25–75 mL/min/1.73m² and UACR 200 mg/g or above) with or without diabetes produced a 39% reduction in the primary composite endpoint, the first trial to show renal benefit independent of diabetes status.⁹ The EMPA-KIDNEY trial (2022) showed that empagliflozin in CKD at eGFR as low as 20 produced a 28% reduction in composite kidney disease progression or cardiovascular death. Current KDIGO 2022 diabetes management guidelines and ADA standards now recommend SGLT2 inhibitors for all patients with type 2 diabetes and CKD (eGFR 20 or above) as add-on to metformin and RAAS inhibition, with SGLT2 inhibitors increasingly recommended in non-diabetic CKD with significant albuminuria as well.

Finerenone, the non-steroidal MRA, has demonstrated dual cardiovascular and renal benefit in type 2 diabetic CKD. The FIDELIO-DKD trial (2020) randomized patients with type 2 diabetes and CKD (eGFR 25–75 and UACR 300 mg/g or above) on maximum tolerated RAAS inhibition to finerenone versus placebo, finding an 18% reduction in the primary composite kidney outcome (sustained eGFR decline of 40% or more, ESRD, or renal death) and a 14% reduction in the cardiovascular composite endpoint.¹² FIGARO-DKD (2021) enrolled patients with a lower albuminuria range (UACR 30–300 mg/g) and found a significant reduction in the cardiovascular composite endpoint. The FIDELITY pooled analysis of both trials confirmed that finerenone significantly reduced both cardiovascular and renal composite endpoints across the full spectrum of CKD severity and albuminuria in type 2 diabetes.

Finerenone is approved as add-on therapy to RAAS inhibition for type 2 diabetic CKD with significant albuminuria and should be considered in all eligible patients, particularly those with persistent albuminuria despite optimized RAAS inhibition and SGLT2 inhibitor use. The combination of RAAS inhibitor plus SGLT2 inhibitor plus finerenone represents the emerging triple renoprotective strategy in type 2 diabetic CKD.