In an adolescent with chronic kidney disease stage 5 who has uncontrolled hypertension despite being on losartan (angiotensin II receptor blocker), a thiazide diuretic, and amlodipine (calcium‑channel blocker), what additional antihypertensive medication can be added?

Management of Uncontrolled Hypertension in CKD Stage 5 Adolescent on Triple Therapy

Add a loop diuretic (furosemide 20–40 mg once or twice daily) as the fourth antihypertensive agent, because thiazide diuretics lose effectiveness when eGFR falls below 30 mL/min and volume expansion is a dominant mechanism of resistant hypertension in advanced CKD. 1, 2, 3

Rationale for Loop Diuretic in CKD Stage 5

• Thiazide diuretics become ineffective when creatinine clearance drops below 30 mL/min (CKD stage 4–5), because they require adequate glomerular filtration to reach their site of action in the distal convoluted tubule. 2, 3, 4

• Loop diuretics maintain efficacy even in advanced renal failure by acting on the thick ascending limb of the loop of Henle, where they block sodium reabsorption regardless of GFR. 2, 5, 4

• Volume overload is the primary driver of resistant hypertension in CKD stage 5, and loop diuretics directly address this pathophysiology by promoting natriuresis and reducing extracellular fluid volume. 2, 3

• The KDIGO 2021 guideline explicitly recommends loop diuretics for advanced CKD patients when thiazide-type diuretics are insufficient, particularly in the context of fluid retention. 1

Specific Loop Diuretic Selection and Dosing

• Start furosemide 20–40 mg once daily in the morning, titrating upward by 20–40 mg increments every 6–8 hours (or as a twice-daily regimen) until adequate diuresis and blood pressure control are achieved. 5

• Furosemide doses up to 600 mg/day may be required in severe edematous states, though careful clinical and laboratory monitoring is mandatory at doses exceeding 80 mg/day. 5

• Alternative: torsemide 5–10 mg once daily is preferred over furosemide in some settings due to longer duration of action (12–16 hours vs. 6–8 hours) and more reliable bioavailability (80–100% vs. 12–112% for furosemide). 2, 6, 4

• Low-dose loop diuretics (e.g., torsemide 2.5–5 mg) can provide antihypertensive effects without significant diuresis, making them suitable for blood pressure control even when overt volume overload is not clinically apparent. 6

Monitoring After Loop Diuretic Initiation

• Check serum potassium, sodium, magnesium, and creatinine within 1–2 weeks of starting or intensifying loop diuretic therapy, as these agents cause significant electrolyte wasting. 2, 4

• Monitor for orthostatic hypotension, especially in adolescents who may be volume-depleted despite elevated blood pressure, by measuring standing and supine blood pressures. 2

• Reassess blood pressure within 2–4 weeks after adding the loop diuretic, with the goal of achieving <130/80 mmHg (or <140/90 mmHg minimum) within 3 months. 1

• Watch for hypokalemia and metabolic alkalosis, which are common with loop diuretics and may require potassium supplementation or addition of a potassium-sparing agent. 1, 4

Why Not Other Fourth-Line Agents?

• Spironolactone (the typical fourth-line agent for resistant hypertension) carries prohibitive hyperkalemia risk in CKD stage 5, especially when combined with losartan (an ARB), making it unsuitable in this population. 1

• Beta-blockers should not be added as a fourth agent unless there are compelling indications (heart failure, coronary disease, arrhythmia), as they are less effective than diuretics for stroke prevention and do not address the volume-dependent mechanism of hypertension in CKD. 1, 4

• Alpha-blockers (e.g., doxazosin) are inferior to diuretics for cardiovascular outcomes and should be reserved for cases where all other options have failed. 1, 4

Sequential Nephron Blockade (If Loop Diuretic Alone Is Insufficient)

• If blood pressure remains uncontrolled on a loop diuretic alone, consider adding metolazone 2.5–5 mg once daily to achieve sequential nephron blockade, which synergistically enhances natriuresis by blocking both the loop of Henle and the distal tubule. 2

• This combination (loop + thiazide-type diuretic) is extremely potent and should be reserved for refractory cases, with intensive electrolyte monitoring (potassium, magnesium, sodium) every 3–7 days initially. 2

• Never combine two loop diuretics or two thiazides, as this provides no additional benefit and dramatically increases adverse effects. 2

Addressing Volume Status Before Adding Medication

• Confirm medication adherence first (pill counts, pharmacy refills, direct questioning), as non-adherence is the most common cause of apparent treatment resistance. 1

• Assess for dietary sodium intake >2 g/day, which directly undermines the efficacy of all antihypertensive classes and is particularly problematic in CKD patients who cannot excrete sodium loads. 1

• Evaluate for interfering substances (NSAIDs, decongestants, systemic corticosteroids), which can raise blood pressure and impair diuretic responsiveness. 1

Lifestyle Modifications (Adjunctive to Pharmacotherapy)

• Sodium restriction to <2 g/day (≈5 g salt) is mandatory in CKD stage 5, as it provides 5–10 mmHg systolic reduction and enhances the efficacy of loop diuretics and ARBs. 1

• Fluid restriction may be necessary if the patient is oliguric or anuric, as excessive fluid intake will overwhelm even high-dose loop diuretics. 1

• Regular aerobic exercise (≥30 minutes most days) lowers blood pressure by ≈4/3 mmHg, though exercise tolerance may be limited in CKD stage 5 due to anemia and uremia. 1

Critical Pitfalls to Avoid

• Do not continue thiazide diuretics as monotherapy in CKD stage 5, as they are ineffective below eGFR 30 mL/min and will not provide meaningful blood pressure control or volume management. 2, 3, 4

• Do not add spironolactone or other potassium-sparing diuretics in CKD stage 5 without extreme caution, as hyperkalemia risk is prohibitive when combined with losartan. 1

• Do not delay treatment intensification—uncontrolled hypertension in CKD stage 5 accelerates progression to end-stage renal disease and increases cardiovascular mortality. 1, 3

• Do not assume treatment failure without first optimizing volume status, as inadequate diuresis is the most common reversible cause of resistant hypertension in advanced CKD. 2, 3

When to Consider Dialysis or Renal Replacement Therapy

• If blood pressure remains ≥160/100 mmHg despite optimized four-drug therapy (losartan + thiazide + amlodipine + loop diuretic) and volume management, consider referral for renal replacement therapy (hemodialysis or peritoneal dialysis), as ultrafiltration may be required to achieve adequate volume control. 1

• Ultrafiltration or hemodialysis should be considered for diuretic-resistant volume overload in CKD stage 5, particularly if the patient is oliguric or anuric. 1