#356 Low-dose thiazide/fludrocortisone use in advanced CKD can rapidly improve potassium-elevated metabolic acidosis with renal and cardiovascular safety
Authors: Kaneko Shuzo , Hoshimoto Ainori , Hisada Rina , Harano Makiko , Anno Emi , Hagiwara So , Imai Eri , Tsukamoto Yusuke 
Published: May 2024

Abstract

Background and Aims
Advanced chronic kidney disease (CKD) is often complicated by metabolic acidosis(MA) with elevated serum potassium(K). MA is a risk factor for CKD progression, and elevated serum K forces dietary K restriction, which is also undesirable in CKD, stalling the use and escalation of renin-angiotensin-aldosterone system inhibitors (RAASi). Sodium bicarbonate(SB) and K binders, which are not well tolerated due to gastrointestinal symptoms, are often used to correct MA and hyperkalemia. On the other hand, the concurrent use of thiazide and fludrocortisone to promote urinary excretion of K and hydrogen ions has been reported in the type IV renal tubular acidosis, but its efficacy and safety in advanced CKD is unclear.

Method
This single-center, retrospective, observational study included CKDG3b-G5 outpatients with MA([HCO3−]&lt;22 mM) and elevated K (serum [K]≥ 5.0 mEq/L) at our center. A total of 59 patients were selected, excluding those who had already been prepared for renal replacement therapy at the start of treatment. Patients who continued to receive trichlormethiazide (1 mg, at 1-3 day intervals) plus fludrocortisone (0.1 mg, at 1-3 day intervals) (low-T/F group, N = 10) or SB(0.5 g-5 g/day) alone (SB group, N = 49) were followed up until 2 years after the start of treatment and the two groups were compared. Background factors including age, sex, cause of CKD, estimated glomerular filtration rate (eGFR), CKD stage, urinary protein(g/gCr),serum [K]/ [HCO3−]/[Na]/[CL]/albumin/phosphate, hemoglobin levels, and the use of RAASi/K binders/diuretics were investigated. Efficacy and safety comparisons between the two groups were evaluated based on changes in serum [HCO3−]and [K] levels before and after starting of treatment (at 2, 6, 12, 18, and 24 months), percentage of patients achieving [HCO3−] ≥22 mM, change in eGFR, incidence of renal events (&gt;30% reduction in eGFR or renal replacement therapy), the incidence of cardiovascular events, and the incidence of treatment-modified events such as initiation or increase of antihypertensive, K-binding, and uric acid-lowering agents.

Results
In all 59 subjects, the mean age was 72.0±11.7 years, 81% were male, mean eGFR was 19.6 ± 7.2 mL/min/1.73 m2, CKDG4/5 account for 92% (G4 60%/G5 32%), primary disease was diabetic nephropathy 30%, nephrosclerosis 43%, RAASi use 68%, mean [K] was 5.5 ± 0.4 mEq/L and mean [HCO3−] was 18.1 ± 2.2 mM. The low-T/F group consisted of patients who switched due to prior SB intolerance or in whom SB was ineffective, and included 5 patients who received concomitant SB. Comparison of background factors showed no significant difference between the two groups. The changes in the serum [HCO3−] and [K] levels 2 months after starting the treatment were significantly larger in the low-T/F group compared with the SB group ([K]after - [K]before (mEq/L):median −1.2, IQR-1.6 to −0.48 vs −0.57, −0.80 to −0.10, p = 0.036; {[K]after -[K]before}×100/[K]before(%): median −20.3, IQR −26.4 to −9.2 vs −9.3, −14.8 to −1.85, p = 0.032; [HCO3−]after-[HCO3−]before (mM):median +5.2, IQR +3.75 to +8.23 vs +3.2, +1.7 to +5.1, p = 0.022) . The percentage of patients achieving [HCO3−] ≥22 mM at 2 months after treatment was significantly higher in the low-T/F group at 88.9% (SB group 38.8%, p = 0.007). There were no renal events in the low-T/F group, and cumulative renal survival (no renal events) tended to be higher in the low-T/F group than in the SB group in the all conditions such as unadjusted condition, presence of RAASi, CKDG4/5 and matched for age, sex, primary cause of CKD and eGFR (p = 0.06, p = 0.265, p = 0.16, p = 0.14, respectively) (Figure). In patients with no renal events, the low-T/F group had a significantly better mean eGFR change of +4.2% at 6 months (SB group: −11.0%, p = 0.019). There were also no cardiovascular events in the low-T/F group, and there were no significant differences between the two groups in either cardiovascular events or treatment-modified events (Table).

Conclusion
Even in advanced CKD, the low-dose combination of thiazide and fludrocortisone can rapidly improve K-elevating MA and continue without adverse renal or cardiovascular outcomes.