Patients with autosomal dominant polycystic kidney disease (ADPKD) who have lower serum bicarbonate levels within the normal range may be more likely to experience worsening kidney outcomes, according to study findings published online in Nephrology Dialysis Transplantation.

In a study that included 296 patients with ADPKD, those in the lowest tertile of baseline serum bicarbonate (mean 23.1 mmol/L) had a nearly 3-fold increased risk for worsening kidney function, defined as a 30% decrease in estimated glomerular filtration rate (eGFR) or kidney failure (eGFR less than 15 mL/min/1.73 m2), compared with those in the highest tertile (mean 29.0 mmol/L).

In addition, each 1 mmol/L decrease in serum bicarbonate was significantly associated with a 21% increased risk for worsening kidney function and increased the annual decline in eGFR by 0.12 mL/min/1.73 m2 per year in fully adjusted models.


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“Serum bicarbonate may add to prognostic models and should be explored as a treatment target in ADPKD,” the investigators concluded.

The investigators said that as far as they are aware, their study is the first to specifically analyze the association between serum bicarbonate and kidney outcomes in patients with ADPKD.

“Of interest, the association between serum bicarbonate and kidney outcomes was independent of variables that are included in two established prognostic models for ADPKD, the Mayo image class and PROPKD score,” they noted.

For the study, the investigators used data from the DIPAK (Developing Interventions to half Progression of ADPKD) randomized controlled trial. The study population had a mean age of 48 years and mean serum bicarbonate level of 26.1 mmol/L. Only 7.4% of the study patients had serum bicarbonate levels that would classify them as having metabolic acidosis (less than 22 mmol/L), the investigators reported.

“Two findings surprised us,” said corresponding study author Ewout J. Hoorn MD, of the Erasmus Medical Center in Rotterdam, The Netherlands. “First, the association between serum bicarbonate and kidney outcomes was present, despite the fact that serum bicarbonate was largely in the normal range.”

He said this raises the question of what may be the optimal target of serum bicarbonate. Currently, most physicians treat metabolic acidosis when serum bicarbonate drops below 21 mEq/L, but the “sweet spot” may be as high as 24 mEq/L, Dr Hoorn said. The current study appears to support this notion.

Second, the team specifically examined urinary ammonium, which is a measure of the kidney’s response to metabolic acidosis. “Previous studies in patients with CKD showed that urinary ammonium predicted kidney outcomes better than serum bicarbonate, but we did not find this in ADPKD. This suggests that acid-base handling in ADPKD may differ from CKD,” Dr Hoorn said.

Samuel Saltzberg, MD, a nephrologist at Rush University Medical Center in Chicago, Illinois said this study is important because ADPKD now accounts for approximately 5% of new dialysis patients in the US. “As there are limited therapeutic interventions available for this disease, any insight into factors that play a role in the progression of this this disease is welcomed,” Dr Saltzberg said.

The current study demonstrates that a lower serum bicarbonate is associated with significant progression of renal insufficiency over a 2.5 year period, so Dr Saltzberg said this raises the possibility that intervention with inexpensive sodium bicarbonate may be helpful in slowing the progression of disease in ADPKD patients. “Of particular interest is that this correlation of lower serum bicarbonate with progression was seen at a baseline serum bicarbonate level of 23, a level at which most nephrologists probably would not have considered treating,” Dr Saltzberg said.

However, he noted the study is limited due to its relatively short follow-up in a typically slowly progressing disease. In addition, association does not prove causality as the authors point out. “It is possible that the factors that led to the lower serum bicarbonate were responsible for the more rapid progression of disease as opposed to the metabolic acidosis itself. The proof of the pudding would be a randomized therapeutic trial of sodium bicarbonate in ADPKD patients,” Dr Saltzberg said.

Nephrologist Christopher Passero, MD, clinical assistant professor of medicine in the Renal-Electrolyte Division at the University of Pittsburgh in Pittsburgh, Pennsylvania, said several studies have described an association between serum bicarbonate as a marker of acidemia and progression of chronic kidney disease and a few investigations indicate that correction of the acidemia can improve the life of the kidneys.  “This article further expands on that idea, but shows the surprising finding that the relationship of serum bicarbonate and kidney failure in patients with autosomal dominant polycystic kidney disease continues to hold even within the normal bicarbonate range. Also, this finding was independent of other markers of progression in autosomal dominant polycystic kidney disease, like total kidney volume,” Dr Passero said.

Reference

Blijdorp CJ, Severs D, Musterd-Bhaggoe UM, et al. Serum bicarbonate is associated with kidney outcomes in autosomal dominant polycystic kidney disease. Published online December 30, 2020. Nephrol Dial Transplant. doi:10.1093/ndt/gfaa283