A 62-year-old man with a history of coronary artery disease, hypertension, and stage IV chronic kidney disease from presumed long-standing hypertension is seen for routine follow up. He feels well and denies any chest pain, urinary symptoms, or lower extremity edema.
On physical examination, the patient's blood pressure is 120/72 mm Hg, heart rate 64/min. His cardiac examination is normal, lungs are clear and he has no peripheral edema. Laboratories are notable for a serum creatinine of 2.4 mg/dL (eGFR 27 mL/min/1.73m2), potassium 5.2 mEq/L, blood urea nitrogen 41 mg/dL. Urinalysis shows 1+ proteinuria and quantification reveals 250mg/g of albuminuria on a spot urine albumin to creatinine ratio. Medications include lisinopril 40mg daily, amlodipine 10mg daily, aspirin 81mg daily and metoprolol 25mg BID. He has no history of diabetes, heart failure, urinary retention or recurrent urinary tract infections.
What is the next best step in management to reduce his risk of progression to end stage kidney disease?
The correct answer is: B. Dapagliflozin
Sodium/glucose cotransporter-2 inhibitors (SGLT2is) have emerged as promising therapy to lower morbidity and mortality in patients with cardiovascular and chronic kidney disease (CKD). Initially developed as oral hypoglycemic agents and studied in patients with diabetes, their utility was expanded to non-diabetics after the overwhelming success of DAPA-HF and EMPEROR-REDUCED, which demonstrated reduction in cardiovascular mortality and heart failure hospitalizations. DAPA-CKD1 was the first trial to establish a reduction in adverse renal and cardiovascular events in patients with CKD with or without diabetes. DAPA-CKD enrolled patients with albuminuria between 30 and 5000mg and an eGFR as low as 25 mL/min/1.73m2. Treatment with dapagliflozin was associated with lower progression of CKD (decline of ≥50% in eGFR or new end stage renal disease [ESRD]), renal mortality and cardiovascular disease (CVD) mortality compared to placebo. The trial was halted early due to overwhelming efficacy. The study demonstrated a beneficial safety profile of dapagliflozin. Of particular interest was the lack of hypoglycemic episodes in non-diabetic participants. Ongoing trials will continue to challenge the GFR threshold for this class of agents.
Combination angiotensin converting enzyme inhibitor and angiotensin receptor blocker therapy (Choice A) reduces proteinuria to a greater extent than either agent alone, however studies have failed to show long-term benefit and in fact the ONTARGET trial noted an increased incidence of ESRD with combination therapy.
Intensive blood pressure control (Choice C) to <120/80 appears to have a favorable effect on mortality in patients with chronic kidney disease,2 however reduction in risk of progression to ESRD is limited to patients with proteinuric but not nonproteinuric CKD. This patient's blood pressure is within goal and the addition of hydralazine is unlikely to provide benefit. Dapagliflozin may reduce blood pressure,3 however the decrease in risk of progression to ESRD appears to be independent of any antihypertensive effect.
Selective mineralocorticoid antagonists, such as spironolactone, (Choice D) have been shown to reduce proteinuria, particularly in combination with angiotensin converting enzyme inhibitor and angiotensin receptor blocker therapy. This therapy may slow eGFR decline based on small trials, however long-term kidney benefits have not been definitively established. Furthermore, his serum potassium is 5.2 mEq/L and he would be unlikely to tolerate the addition of spironolactone without developing significant hyperkalemia.
Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-46.
Cheung AK, Rahman M, Reboussin DM, et al. Effects of intensive blood pressure control in CKD. J Am Soc Nephrol 2017;28:2812-23.
Sternlicht H, Bakris GL. Blood pressure lowering and sodium-glucose co-transporter 2 inhibitors (SGLT2is): more than osmotic diuresis. Curr Hypertens Rep 2019;21:12.