NaHCO3 loading causes increased arterial pressure and kidney damage in rats with chronic kidney disease.

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.

Assessment of clinical continuity strategies offered by dual-degree training programs in the USA.

Background: Integration of clinical skills during graduate training in dual-degree programs remains a challenge. The present study investigated the availability and self-perceived efficacy of clinical continuity strategies for dual-degree trainees preparing for clinical training. Methods: Survey participants were MD/DO-PhD students enrolled in dual-degree-granting institutions in the USA. The response rate was 95% of 73 unique institutions surveyed, representing 56% of the 124 MD-PhD and 7 DO-PhD recognized training programs. Respondents were asked to indicate the availability and self-perceived efficacy of each strategy. Results: Reported available clinical continuity strategies included clinical volunteering (95.6%), medical grand rounds (86.9%), mentored clinical experiences (84.2%), standardized patients/ practice Objective Structured Clinical Examinations (OSCEs) (70.3%), clinical case reviews (45.9%), clinical journal clubs (38.3%), and preclinical courses/review sessions (37.2%). Trainees rated standardized patients (µ = 6.98 ± 0.356), mentored clinical experiences (µ = 6.94 ± 0.301), clinical skills review sessions (µ = 6.89 ± 0.384), preclinical courses/review sessions (µ = 6.74 ± 0.482), and clinical volunteering (µ = 6.60 ± 0.369), significantly (p < 0.050) higher than clinical case review (µ = 5.34 ± 0.412), clinical journal club (µ = 4.75 ± 0.498), and medicine grand rounds (µ = 4.45 ± 0.377). Further, 84.4% of respondents stated they would be willing to devote at least 0.5-1 hour per week to clinical continuity opportunities during graduate training. Conclusion: Less than half of the institutions surveyed offered strategies perceived as the most efficacious in preparing trainees for clinical reentry, such as clinical skills review sessions. Broader implementation of these strategies could help better prepare dual-degree students for their return to clinical training.

New mechanisms for the kidney-protective effect of alkali in chronic kidney disease.

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.

Renal mass reduction increases the response to exogenous insulin independent of acid-base status or plasma insulin levels in rats.

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 0.1 M sodium bicarbonate solution in drinking water had no effect on insulin sensitivity. Acid loading with 0.1 M 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.NEW & NOTEWORTHY Impairments in insulin sensitivity can occur in patients with chronic kidney disease, and previous work has suggested that metabolic acidosis may be the underlying cause. Our study investigated the effect of acid or alkali loading on insulin sensitivity in a rodent model of chronic kidney disease. We found that renal mass reduction increases the blood glucose response to insulin and that this is not acutely reversed by the development of acidosis.

Alkali supplementation as a therapeutic in chronic kidney disease: what mediates protection?

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.

Redefining the Influence of Ethnicity on Simultaneous Kidney and Pancreas Transplantation Outcomes: A 15-year Single-center Experience.

OBJECTIVE: To examine the largest single-center experience of simultaneous kidney/pancreas transplantation (SPK) transplantation among African-Americans (AAs). BACKGROUND: Current dogma suggests that AAs have worse survival following SPK than white recipients. We hypothesize that this national trend may not be ubiquitous. METHODS: From August 30, 1999, through October 1, 2014, 188 SPK transplants were performed at the University of Alabama at Birmingham (UAB) and 5523 were performed at other US centers. Using Kaplan-Meier survival estimates and Cox proportional hazards regression, we examined the influence of recipient ethnicity on survival. RESULTS: AAs comprised 36.2% of the UAB cohort compared with only 19.1% nationally (P < 0.01); yet, overall, 3-year graft survival was statistically higher among UAB than US cohort (kidney: 91.5% vs 87.9%, P = 0.11; pancreas: 87.4% vs 81.3%; P = 0.04, respectively) and persisted on adjusted analyses [kidney adjusted hazard ratio (aHR): 0.58, 95% confidence interval (95% CI) 0.35-0.97, P = 0.04; pancreas aHR: 0.54, 95% CI 0.34-0.85, P = 0.01]. Among the UAB cohort, graft survival did not differ between AA and white recipients; in contrast, the US cohort experienced significantly lower graft survival rates among AA than white recipients (kidney 5 years: 76.5% vs 82.3%, P < 0.01; pancreas 5 years: 72.2% vs 76.3%, P = 0.01; respectively). CONCLUSION: Among a single-center cohort of SPK transplants overrepresented by AAs, we demonstrated similar outcomes among AA and white recipients and better outcomes than the US experience. These data suggest that current dogma may be incorrect. Identifying best practices for SPK transplantation is imperative to mitigate racial disparities in outcomes observed at the national level.

A basic solution to activate the cholinergic anti-inflammatory pathway via the mesothelium?

Much research now indicates that vagal nerve stimulation results in a systemic reduction in inflammatory cytokine production and an increase in anti-inflammatory cell populations that originates from the spleen. Termed the 'cholinergic anti-inflammatory pathway', therapeutic activation of this innate physiological response holds enormous promise for the treatment of inflammatory disease. Much controversy remains however, regarding the underlying physiological pathways mediating this response. This controversy is anchored in the fact that the vagal nerve itself does not innervate the spleen. Recent research from our own laboratory indicating that oral intake of sodium bicarbonate stimulates splenic anti-inflammatory pathways, and that this effect may require transmission of signals to the spleen through the mesothelium, provide new insight into the physiological pathways mediating the cholinergic anti-inflammatory pathway. In this review, we examine proposed models of the cholinergic anti-inflammatory pathway and attempt to frame our recent results in relation to these hypotheses. Following this discussion, we then provide an alternative model of the cholinergic anti-inflammatory pathway which is consistent both with our recent findings and the published literature. We then discuss experimental approaches that may be useful to delineate these hypotheses. We believe the outcome of these experiments will be critical in identifying the most appropriate methods to harness the therapeutic potential of the cholinergic anti-inflammatory pathway for the treatment of disease and may also shed light on the etiology of other pathologies, such as idiopathic fibrosis.

Oral NaHCO3 Activates a Splenic Anti-Inflammatory Pathway: Evidence That Cholinergic Signals Are Transmitted via Mesothelial Cells.

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.

Identification of strategies to facilitate organ donation among African Americans using the nominal group technique.

BACKGROUND AND OBJECTIVES: African Americans are disproportionately affected by ESRD, but few receive a living donor kidney transplant. Surveys assessing attitudes toward donation have shown that African Americans are less likely to express a willingness to donate their own organs. Studies aimed at understanding factors that may facilitate the willingness of African Americans to become organ donors are needed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A novel formative research method was used (the nominal group technique) to identify and prioritize strategies for facilitating increases in organ donation among church-attending African Americans. Four nominal group technique panel interviews were convened (three community and one clergy). Each community panel represented a distinct local church; the clergy panel represented five distinct faith-based denominations. Before nominal group technique interviews, participants completed a questionnaire that assessed willingness to become a donor; 28 African-American adults (≥19 years old) participated in the study. RESULTS: In total, 66.7% of participants identified knowledge- or education-related strategies as most important strategies in facilitating willingness to become an organ donor, a view that was even more pronounced among clergy. Three of four nominal group technique panels rated a knowledge-based strategy as the most important and included strategies, such as information on donor involvement and donation-related risks; 29.6% of participants indicated that they disagreed with deceased donation, and 37% of participants disagreed with living donation. Community participants' reservations about becoming an organ donor were similar for living (38.1%) and deceased (33.4%) donation; in contrast, clergy participants were more likely to express reservations about living donation (33.3% versus 16.7%). CONCLUSIONS: These data indicate a greater opposition to living donation compared with donation after one's death among African Americans and suggest that improving knowledge about organ donation, particularly with regard to donor involvement and donation-related risks, may facilitate increases in organ donation. Existing educational campaigns may fall short of meeting information needs of African Americans.