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Sodium bicarbonate (NaHCO3) is commonly utilized as a therapeutic to treat metabolic acidosis in people with chronic kidney disease (CKD). While increased dietary sodium chloride (NaCl) is known to promote volume retention and increase blood pressure, the effects of NaHCO3 loading on blood pressure and volume retention in CKD remain unclear. In the present study, we compared the effects of NaCl and NaHCO3 loading on volume retention, blood pressure, and kidney injury in both 2/3 and 5/6 nephrectomy remnant kidney rats, a well-established rodent model of CKD. We tested the hypothesis that NaCl loading promotes greater volume retention and increases in blood pressure than equimolar NaHCO3. Blood pressure was measured 24 h daily using radio telemetry. NaCl and NaHCO3 were administered in drinking water ad libitum or infused via indwelling catheters. Rats were housed in metabolic cages to determine volume retention. Our data indicate that both NaHCO3 and NaCl promote hypertension and volume retention in remnant kidney rats, with salt-sensitivity increasing with greater renal mass reduction. Importantly, while NaHCO3 intake was less pro-hypertensive than equimolar NaCl intake, NaHCO3 was not benign. NaHCO3 loading significantly elevated blood pressure and promoted volume retention in rats with CKD when compared with control rats receiving tap water. Our findings provide important insight into the effects of sodium loading with NaHCO3 in CKD and indicate that NaHCO3 loading in patients with CKD is unlikely to be benign. [ABSTRACT FROM AUTHOR]

Impairments in insulin sensitivity can occur in patients with chronic kidney disease (CKD). Correction of metabolic acidosis has been associated with improved insulin sensitivity in CKD, suggesting that metabolic acidosis may directly promote insulin resistance. Despite this, the effect of acid or alkali loading on insulin sensitivity in a rodent model of CKD (remnant kidney) has not been directly investigated. Such studies could better define the relationship between blood pH and insulin sensitivity. We hypothesized that in remnant kidney rats, acid or alkali loading would promote loss of pH homeostasis and consequently decrease insulin sensitivity. To test this hypothesis, we determined the impact of alkali (2 wk) or acid (5-7 days) loading on plasma electrolytes, acid-base balance, and insulin sensitivity in either sham control rats, 2/3 nephrectomized rats, or 5/6 nephrectomized rats. Rats with 5/6 nephrectomy had the greatest response to insulin followed by rats with 2/3 nephrectomy and sham control rats. We found that treatment with 0.1M sodium bicarbonate solution in drinking water had no effect on insulin sensitivity. Acid loading with 0.1M ammonium chloride resulted in significant reductions in pH and plasma bicarbonate. However, acidosis did not significantly impair insulin sensitivity. Similar effects were observed in Zucker obese rats with 5/6 nephrectomy. The effect of renal mass reduction on insulin sensitivity could not be explained by reduced insulin clearance or increased plasma insulin levels. We found that renal mass reduction alone increases sensitivity to exogenous insulin in rats and that this is not acutely reversed by the development of acidosis. [ABSTRACT FROM AUTHOR]

Sodium bicarbonate (NaHCO3) has been recognized as a possible therapy to target chronic kidney disease (CKD) progression. Several small clinical trials have demonstrated that supplementation with NaHCO3 or other alkalizing agents slows renal functional decline in patients with CKD. While the benefits of NaHCO3 treatment have been thought to result from restoring pH homeostasis, a number of studies have now indicated that NaHCO3 or other alkalis may provide benefit regardless of the presence of metabolic acidosis. These data have raised questions as to how NaHCO3 protects the kidneys. To date, the physiological mechanism(s) that mediates the reported protective effect of NaHCO3 in CKD remain unclear. In this review, we first examine the evidence from clinical trials in support of a beneficial effect of NaHCO3 and other alkali in slowing kidney disease progression and their relationship to acid-base status. Then, we discuss the physiological pathways that have been proposed to underlie these renoprotective effects and highlight strengths and weaknesses in the data supporting each pathway. Finally, we discuss how answering key questions regarding the physiological mechanism(s) mediating the beneficial actions of NaHCO3 therapy in CKD is likely to be important in the design of future clinical trials. We conclude that basic research in animal models is likely to be critical in identifying the physiological mechanisms underlying the benefits of NaHCO3 treatment in CKD. Gaining an understanding of these pathways may lead to the improved implementation of NaHCO3 as a therapy in CKD and perhaps other disease states. [ABSTRACT FROM AUTHOR]

R2365 --> 854.1 --> Sodium bicarbonate (NaHCO3) is used in patients with chronic kidney disease (CKD) to treat metabolic acidosis and slow CKD progression. One potential adverse effect of NaHCO3 use in patients with CKD is the increase in dietary sodium (Na+) intake, which may worsen both fluid retention and hypertension in this already vulnerable population. Previous data, however, indicate that anions other than Cl‐ coupled to Na+ may not lead to increases in volume retention and blood pressure. These data raise the possibility that ingestion of NaHCO3 in patients with CKD may be relatively benign. The effects of NaHCO3 loading on fluid retention and blood pressure, however, have not been directly investigated in a model of CKD. We hypothesized that NaHCO3 loading promotes similar levels of Na+ retention and hypertension as NaCl loading in a rat model of CKD. We utilized 21, 12‐week‐old male Sprague Dawley rats that underwent sham (n=6), 2/3 (n=7), or 5/6 nephrectomy (n=8, Nx). In order to limit intra‐animal variability, we utilized a crossover study design. After 4 weeks of recovery from surgery, rats were matched by renal mass reduction and assigned to one of two groups. One group was started on a 0.1M NaHCO3 (n=11) drinking water solution while the other was started on 0.1M NaCl (n=10) in the drinking water for 2 weeks before a wash‐out (tap water for 2 weeks). The first group was then started on 0.1M NaCl while the other received 0.1M NaHCO3 for 2 weeks. Rats were maintained in metabolic cages during the initiation of treatments to allow for daily measurements of urine output, fluid, and food ingestion. Urine Na+ content was measured by atomic absorption spectrometry. Mean arterial pressure was measured in separate group with telemetry over 2 weeks of treatment with NaHCO3 or NaCl. Following the initiation of treatment, there was a significantly greater increase in urinary Na+following NaCl treatment (1.18 ± 0.09 mmol vs 5.74 ± 0.39 mmol) compared to NaHCO3 treatment (1.23 ± 0.06 mmol vs 4.82 ± 0.40 mmol; Two‐Way ANOVA, PRx=0.006). However, there was no significant difference in total retained Na+ following NaCl (2.03 ± 0.73 mmol) and NaHCO3 treatment (2.19 ± 0.62 mmol; unpaired t‐test, P=0.87). There was also no significant difference in Na+ retention between the different levels of Nx after the initiation of NaCl (Two‐Way ANOVA, PLevelofNx=0.50) and NaHCO3 treatments (Two‐Way ANOVA, PLevelofNx=0.53). Despite a similar amount of Na+ retention, we found that 0.1M NaCl resulted in greater increases in mean arterial pressure over 2 weeks in 5/6 Nx rats compared to 0.1M NaHCO3 (RM Two‐Way ANOVA, PInteraction=0.02, PSubjects<0.0001; n=4/5). The change in mean arterial pressure from baseline was greater in 5/6 Nx rats treated with NaCl (40.5 ± 5.6 mmHg) compared to NaHCO3 (20.9 ± 0.82 mmHg; unpaired t‐test, P=0.03). We conclude NaHCO3 supplementation promotes Na+ and fluid retention and increases in blood pressure in rats with CKD, however, blood pressure responses are less than that observed with NaCl. Our data indicate that NaHCO3 loading in patients with CKD is unlikely to be benign. As NaHCO3 loading can promote increases in blood pressure, caution is warranted with chronic NaHCO3 use in patients with CKD. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that oral NaHCO3 intake stimulates splenic anti-inflammatory pathways. Following oral NaHCO3 loading, macrophage polarization was shifted from predominantly M1 (inflammatory) to M2 (regulatory) phenotypes, and FOXP3+CD4+ T-lymphocytes increased in the spleen, blood, and kidneys of rats. Similar anti-inflammatory changes in macrophage polarization were observed in the blood of human subjects following NaHCO3 ingestion. Surprisingly, we found that gentle manipulation to visualize the spleen at midline during surgical laparotomy (sham splenectomy) was sufficient to abolish the response in rats and resulted in hypertrophy/hyperplasia of the capsular mesothelial cells. Thin collagenous connections lined by mesothelial cells were found to connect to the capsular mesothelium. Mesothelial cells in these connections stained positive for the pan-neuronal marker PGP9.5 and acetylcholine esterase and contained many ultrastructural elements, which visually resembled neuronal structures. Both disruption of the fragile mesothelial connections or transection of the vagal nerves resulted in the loss of capsular mesothelial acetylcholine esterase staining and reduced splenic mass. Our data indicate that oral NaHCO3 activates a splenic anti-inflammatory pathway and provides evidence that the signals that mediate this response are transmitted to the spleen via a novel neuronal-like function of mesothelial cells. [ABSTRACT FROM AUTHOR]

Worldwide, more than one in ten adults are estimated to have chronic kidney disease (CKD). As CKD progresses, both the cost of treatment and associated risk of morbidity and mortality increase exponentially. As such, there is a great need for therapies that effectively slow CKD progression. Evidence from several small clinical trials indicates that alkali therapy may slow the rate of CKD progression. The biological mechanisms underlying this protective effect, however, remain unknown. In their recently published manuscript, Pastor Arroyo et al. (Clin Sci (Lond) (2022) 136(8): https://doi.org/10.1042/CS20220095) demonstrate that the alkali sodium bicarbonate protects against loss of renal function in a crystal nephropathy model in mice. Using unbiased approaches in both mice and human tissue, the authors go on to identify two novel mechanisms that may underly this protection. The first pathway is through promoting pathways of cell metabolism, which they speculate helps the remaining functional nephrons adapt to the greater metabolic needs required to maintain kidney filtration. The second pathway is by restoration of α-Klotho levels, which may limit the expression of adhesion molecules in the injured kidney. This, the authors speculate, may prevent inflammation from driving the functional decline of the kidney. Identifying these novel pathways represents an important step forward harnessing the potential benefits of alkali therapy in CKD., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

We tested the hypothesis that oral NaHCO 3 intake stimulates splenic anti-inflammatory pathways. Following oral NaHCO 3 loading, macrophage polarization was shifted from predominantly M1 (inflammatory) to M2 (regulatory) phenotypes, and FOXP3 + CD4 + T-lymphocytes increased in the spleen, blood, and kidneys of rats. Similar anti-inflammatory changes in macrophage polarization were observed in the blood of human subjects following NaHCO 3 ingestion. Surprisingly, we found that gentle manipulation to visualize the spleen at midline during surgical laparotomy (sham splenectomy) was sufficient to abolish the response in rats and resulted in hypertrophy/hyperplasia of the capsular mesothelial cells. Thin collagenous connections lined by mesothelial cells were found to connect to the capsular mesothelium. Mesothelial cells in these connections stained positive for the pan-neuronal marker PGP9.5 and acetylcholine esterase and contained many ultrastructural elements, which visually resembled neuronal structures. Both disruption of the fragile mesothelial connections or transection of the vagal nerves resulted in the loss of capsular mesothelial acetylcholine esterase staining and reduced splenic mass. Our data indicate that oral NaHCO 3 activates a splenic anti-inflammatory pathway and provides evidence that the signals that mediate this response are transmitted to the spleen via a novel neuronal-like function of mesothelial cells., (Copyright © 2018 by The American Association of Immunologists, Inc.)