“Different types of diuretic drugs are widely used to help treat high blood pressure, fluid management, and electrolyte abnormalities in patients with CKD, but there is limited data on the effectiveness of these therapies when it comes to reduction in CKD progression,” explains Alan S. Go, MD. “Therefore, we recognized a need to provide insights that might better support clinical decision-making.”

According to Dr. Go, it is unknown if chronic diuretic use among patients with CKD is linked with durable declines in eGFR (ie, CKD progression) or heightened risk for end-stage renal disease (ESRD). No randomized clinical trials (RCTs) have assessed the impact of long-term diuretic use and type on CKD progression, he notes, and prior studies have been restricted by small sample sizes and confounding by treatment selection biases, such as physicians being more likely to prescribe diuretics to patients with more severe renal impairment.

For a study published in BMJ Open, Dr. Go and colleagues sought to address the lack of data on the impact of diuretic use on CKD progression. They conducted a retrospective cohort study at a large, integrated healthcare delivery system in northern California. Participants (>47,000) included adults with an eGFR of 15-59 mL/min/1.73 m2 with no prior diuretic use. “Our goal was to evaluate whether use of loop or thiazide diuretics was linked to a different risk for kidney disease progression in a large, real-world population with CKD by using advanced statistical methods, which allowed us to attempt to replicate an RCT,” Dr. Go says.

Diuretics Not Independently Linked With Higher ESRD Risk

The researchers found that compared with not receiving diuretics, receiving either loop or thiazide diuretics was not independently linked to a higher risk for either ESRD requiring dialysis or kidney transplant, or significant loss of kidney function, as measured by the renal composition outcome—an eGFR below 15 mL/min/1.73 m2 or experiencing a 50% reduction in pre-treatment estimated glomerular filtration.

They observed that the rate per 100 person-years was 1.35 for the renal composite outcome and 0.42 for ESRD. Crude rates per 100 person-years of the composite renal outcome were higher in patients receiving loop diuretics and thiazide diuretics compared with those who were not. Crude rates per 100-person years of ESRD were higher in patients who started loop diuretics, but not in those who received thiazide diuretics. However, neither initiation of diuretics or type of diuretic were significantly associated with CKD progression or ESRD after accounting for use of other medications and time-dependent confounders using causal inference methods.

Diuretics Increase Risk for Adverse Outcomes

“The main finding from the crude rates of adverse kidney outcomes is that, in clinical practice, patients who are treated with diuretic therapies are generally sicker and at higher risk for these outcomes,” Dr. Go says (Table). “Our study found that the type of diuretic therapy used to treat adults with CKD did not seem to directly influence the risk for progression of kidney disease. This may provide some reassurance to physicians who are considering which drug to use to manage these patients. However, we recognize that despite our advanced statistical methods to account for differences between patients who received different diuretic treatment strategies, our study was not a RCT.”

To the best of their knowledge, Dr. Go and colleagues believe their study to be the biggest and most thorough analysis of the potential impact of incident loop and thiazide diuretic exposure on CKD progression among a real-world population of patients with stage III or IV CKD. “However, given the inherent limitations of observational studies, and because of the different available diuretic therapy options, our team agrees that a definitive RCT would be beneficial to help personalize treatment of CKD to lower the risk for advancing to kidney failure.”