Urine citrate excretion identifies changes in acid retention as eGFR declines in patients with chronic kidney disease

Abstract

Previous studies have shown that acid (H+) retention in patients with chronic kidney disease (CKD) but without metabolic acidosis increases as the estimated glomerular filtration rate (eGFR) decreases over time. The present study examined whether changes in urine excretion of the pH-sensitive metabolite citrate predicted changes in H+ retention over time in similar patients with CKD that were followed for 10 yr. We randomized 120 CKD2 nondiabetic, hypertension-associated nephropathy patients with plasma total CO2 of >24 mM to receive 0.5 meq·kg body wt−1·day−1 NaHCO3 ([Formula: see text]; n = 40), 0.5 meq·kg body wt−1·day−1 NaCl (NaCl; n = 40), or usual care (UC; n = 40). We assessed eGFR (CKD-EPI) and H+ retention by comparing the observed with expected plasma total CO2 increase 2 h after an oral NaHCO3 bolus (0.5 meq/kg body wt). Although 10 yr versus baseline eGFR was lower for each group, 10-yr eGFR was higher ( P < 0.01) in [Formula: see text] (59.6 ± 4.8 ml·min−1·1.73 m−2) than NaCl and UC (52.1 ± 5.9 and 52.3 ± 4.1 ml·min−1·1.73 m−2, respectively) groups. Less eGFR preservation was associated with higher 10-yr versus baseline H+ retention in the NaCl group (26.5 ± 13.1 vs. 18.2 ± 15.3 mmol, P < 0.01) and UC group (24.8 ± 11.3 vs. 17.7 ± 10.9 mmol, P < 0.01) and with lower 10-yr versus baseline 8-h urine citrate excretion (UcitrateV) for the NaCl group (162 ± 47 vs. 196 ± 52 mg, respectively, P < 0.01) and UC group (153 ± 41 vs. 186 ± 42 mg, respectively, P < 0.01). Conversely, better eGFR preservation in the [Formula: see text] group was associated with no differences in 10-yr versus baseline H+ retention (14.2 ±13.5 vs. 16.1 ± 15.1 mmol, P = 1.00) or UcitrateV (212 ± 45 vs. 203 ± 49 mg, respectively, P = 0.74). An overall generalized linear model for repeated measures showed that UcitrateV predicted H+ retention ( P < 0.01). Less eGFR preservation in patients with CKD2 without metabolic acidosis was associated with increased H+ retention that was predicted by decreased UcitrateV.

Spot urinary citrate-to-creatinine ratio is a marker for acid-base status in chronic kidney disease

“…Thus, to assess acid loading on an organism, it is much more logical to measure the defense mechanism (urinary citrate excretion) rather than the defended parameter (serum [HCO 3 -]). Urine citrate excretion has been suggested to identify changes in acid retention with progressive decline in renal function 46,47 , and post-base loading in CKD 48 .…”

Metabolic Acidosis and CKD Progression

“…At both 5 and 10 years, eGFR calculated using the serum cystatin C level and the CKD-EPI equation was higher in the NaHCO 3 group than the other groups. By 10 years, H 1 retention remained unchanged in the NaHCO 3 group but increased in the other groups, and serum [HCO 3 2 ] was unchanged in the NaHCO 3 group but decreased in the other groups, although remaining within the normal range (7,8).…”

“…These animal and human data of milder CKD frame an expanded concept of metabolic acidosis of CKD that encompasses H 1 retention occurring during eubicarbonatemia ( Figure 1B). Initial H 1 retention augments acidification per residual nephron such that achieved steady-state net H 1 excretion is similar to controls with normal GFR (sham animals or patients with CKD 1); consequently, external H 1 balance is reestablished but under conditions of H 1 retention (2,8). Subclinical H 1 retention should challenge both bicarbonate and nonbicarbonate buffers residing in extracellular and intracellular spaces.…”

“…Studies have shown that 85%-90% of patients with CKD 2-4 have serum [HCO 3 2 ] $22 meq/L. Virtually all eubicarbonatemic patients with CKD 2 tested at baseline had H 1 retention of variable severity (8). Therefore, metabolic acidosis is an early, not late, complication of CKD.…”

“…Experience with patients with CKD 2 suggests that eubicarbonatemia can last for many years (8). Putative factors affecting the duration of subclinical metabolic acidosis include the baseline serum [HCO 3 2 ]; the higher the level, the longer the duration of eubicarbonatemia, other factors being equal.…”