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.

It is estimated that more than one in ten adults have chronic kidney disease (CKD) [1]. CKD is defined as a prolonged decrease in the filtration rate of the kidneys of greater than 3 months duration, or abnormalities in kidney structure and function. There is currently no cure for CKD [2]. As CKD progresses, cardiovascular disease risk and the cost of treatment rise exponentially [3,4]. Given this, there is a desperate need to identify new therapies that can slow the progression of CKD.

The development of metabolic acidosis is common in CKD [5]. The kidneys regulate systemic pH by excreting acid and producing new bicarbonate ions. As nephrons are lost, the ability of the kidneys to excrete acid and produce new bicarbonate ions is reduced, often leading to the development of metabolic acidosis [6]. Metabolic acidosis leads to systemic complications including bone and muscle loss and vascular calcification [6]. There is also evidence that metabolic acidosis may increase the rate at which kidney function declines in CKD [7,8].

It is now common for alkali to be given to patients with CKD to reverse metabolic acidosis and prevent bone and muscle loss. Preclinical studies and several small clinical trials now indicate that treatment of metabolic acidosis with alkali supplementation may also slow the rate of kidney function decline [7]. Studies in rodents have demonstrated a renoprotective effect of alkali to slow renal functional decline or prevent structural abnormalities in a diverse array of CKD models, including polycystic kidney disease [9,10], remnant kidney models [11–13], chronic potassium deficiency [14], and in the Dahl salt-sensitive rat [15]. The results of several small clinical trials provide additional evidence for a role of alkali therapy to slow renal function decline in humans with CKD [16–23].

Despite the promise of alkali therapy as a cost-effective approach to slow CKD progression, significant roadblocks remain. In contrast with the positive results of earlier single-center clinical trials, more recent multicenter, well-controlled clinical studies have found no significant effect of alkali therapy to slow CKD progression [8,24]. While there are several potential explanations for this, an important consideration relates to difficulties in designing clinical trials that can detect potential benefits of alkali therapy in CKD. These difficulties are highlighted by the general lack of understanding of the underlying pathological processes, driving nephron loss in various forms of CKD [7]. Based on the result of studies in rodents, several potential protective mechanisms have been suggested. These include preventing acid induced increases in intrarenal endothelin and angiotensin II levels [13] or limiting complement C3 activation by acid stimulated tubular NH4+ production [11]. Additional mechanisms that have been suggested including the metabolic effects of citrate metabolism [12], limiting the precipitation of proteins in the tubular lumen, which may hasten cast formation and nephron loss [15], or stimulation of a systemic anti-inflammatory profile by activation of the cholinergic anti-inflammatory pathway [7,25]. To date, however, none of these pathways have been found to definitively underlie the kidney protection from alkali therapy [7]. In the absence of identification of a primary mechanism of protection, when designing a clinical trial, one can only guess as the type of alkali to use, the most effective alkali dose and treatment duration, and the population that would likely receive the most benefit.

In their recent study, Pastor Arroyo et al. provide additional evidence of a protective effect of alkali treatment to limit renal function decline in a model of oxalate crystal nephropathy [26]. In addition, they tackled the question as to the underlying mechanism(s) of alkali renoprotection, using unbiased approaches in both animal and human tissues. Pastor Arroyo et al. utilized 10 days of feeding of a 0.67% oxalate, calcium-free diet to produce a crystal nephropathy in C57BL/6JRj mice. They demonstrated that treatment with 0.2 M sodium bicarbonate (NaHCO3) in the drinking water ad libitum prevented the development of metabolic acidosis and limited renal function decline (creatinine clearance, plasma urea) over 28 days of recovery [26]. This was true both when NaHCO3 was initiated along with the start of the oxalate diet, and when it was started after the 10 days of oxalate feeding, albeit to a lesser extent with the latter [26]. The authors demonstrated that this effect was mediated by bicarbonate, rather than the sodium load, as 0.2 M sodium chloride had no beneficial effect on renal function [26]. These data provide additional evidence, in a rodent CKD model of yet another pathological etiology, of a protective effect of alkali treatment to limit kidney functional decline.

Interestingly, Pastor Arroyo et al. found that alkali therapy seemed to improve kidney function independent of the degree of nephron injury. That is, when comparing mice with similar tubular injury and crystal deposition, creatinine clearance was uniformly higher in alkali treated mice when compared with controls [26]. From this, the authors postulated that the benefits of alkali treatment may not be mediated simply by preventing nephron injury, but largely through a positive effect on remaining healthy tissue. The results of their unbiased transcriptome analysis lend support to this conclusion. This analysis identified pathways involved in cell metabolism, including fatty acid metabolism, triglyceride lipase activity, and heme binding as the primary pathways down-regulated by crystal nephropathy and rescued by alkali therapy [26]. The authors go on to suggest that by restoring the activity of these pathways, alkali therapy may limit kidney functional decline by promoting improved adaptation of the remaining functional nephrons. This represents a novel concept that would explain the reported benefits of alkali therapy across a broad range of kidney disease states of varying etiology.

A strength of the study by Pastor Arroyo et al. is that these authors were able to demonstrate the cellular pathways they identified in rodents were similarly altered in human kidneys subjected to alkali therapy. RNA sequence analysis of human kidney tissue biopsies from kidney transplant recipients, both with and without metabolic acidosis, and with metabolic acidosis treated with alkali therapy, revealed similar pathways were affected to those identified in their rodent studies. These included pathways related to cell metabolism, such as transmembrane transport, fatty acid metabolism, and oxidoreductase activity [26].

An additional mechanism identified by Pastor Arroyo et al. that may contribute to kidney protection by alkali therapy is modulation of the immune response. These authors found that ‘Chemokine activity’ was one of the pathways most strongly reversed by alkali treatment in mice [26]. Furthermore, they went on to demonstrate that alkali therapy limited the kidney expression of adhesion molecules in injured kidneys, as well as reduced T-helper cell and monocyte invasion [26]. Inflammation is common in kidney disease and has been linked to progression of CKD in humans [27,28]. If alkali treatment limits kidney inflammation in humans with CKD, this could explain many of the putative benefits of alkali treatment. Of course, one must be cautions when prescribing causation to an observed effect. Activation of any pathway that limited tubular injury would be likely to limit the subsequent immune response. With this in mind, in their study, Pastor Arroyo et al. identify a potential mediator of the immune response that may be directly altered by alkali treatment in the antiaging protein α-Klotho [26]. Klotho is produced by the kidney and nephron loss in CKD is associated with α-Klotho deficiency [29]. Importantly, metabolic acidosis may reduce circulating Klotho levels [30]. Consistent with this, α-Klotho was down-regulated by crystal nephropathy induction in Pastor Arroyo et al.’s study [26]. This down-regulation was almost fully reversed by alkali treatment [26]. As α-Klotho has been shown to reduce the expression of adhesion molecules [31], it is possible that alkali treatment prevented the infiltration of immune cells into the kidney by restoring α-Klotho levels [26]. If restoration of α-Klotho levels can be proven to underly the protective effects of alkali treatment, this would identify alkali therapy as a potential low-cost method to modulate physiological levels of Klotho to promote renal protection. Furthermore, α-Klotho levels may provide a useful biomarker of the early effectiveness of alkali therapy in clinical trials.

In summary, the recent study by Pastor Arroyo et al. provides additional evidence of the protective effects of alkali therapy in CKD [26]. In addition, using an unbiased approach, these authors identify two novel pathways which may underly this beneficial response (Figure 1). The first pathway is through promoting pathways of cell metabolism, which may help remaining functional nephrons adapt to the greater metabolic needs required to maintain kidney function in CKD. The second pathway is by restoration of α-Klotho levels, which may limit the expression of adhesion molecules in the injured kidney. This would limit subsequent inflammation that may drive functional decline of the kidney. Identifying these novel pathways, and confirming similar alterations associated with systemic pH in human kidneys, represents an important step forward in identifying the underlying mechanisms mediating the benefits of alkali therapy in CKD. The identification these mechanisms is likely to be critical in the success of future clinical trials of alkali therapy.

Figure 1
Proposed mechanisms of kidney protection

The results of Pastor Arroyo et al. identify two novel mechanisms, which may underly the kidney-protective effects of alkali therapy. One acts through increasing α-Klotho levels. This may slow chronic kidney disease progression by inhibiting the expression of vascular adhesion molecules and thereby-limiting deleterious inflammation. The other is by promoting pathways of cellular metabolism. This may promote adaptation of uninjured nephrons to allow them to better cope with the higher single nephron glomerular filtration rate and metabolic demands required following nephron loss in chronic kidney disease.

Figure 1
Proposed mechanisms of kidney protection

The results of Pastor Arroyo et al. identify two novel mechanisms, which may underly the kidney-protective effects of alkali therapy. One acts through increasing α-Klotho levels. This may slow chronic kidney disease progression by inhibiting the expression of vascular adhesion molecules and thereby-limiting deleterious inflammation. The other is by promoting pathways of cellular metabolism. This may promote adaptation of uninjured nephrons to allow them to better cope with the higher single nephron glomerular filtration rate and metabolic demands required following nephron loss in chronic kidney disease.

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The authors declare that there are no competing interests associated with the manuscript.

This work was supported by NHLBI [grant number P01HL134604]; NIAID [grant number R21 AI150723 (to P.M.O.)]; American Society of Nephrology KidneyCure; and American Heart Association Pre-doctoral Fellowships (to E.C.M.).

Paul M. O’Connor: Writing—original draft. Elinor C. Mannon: Writing—original draft, Writing—review & editing.

     
  • CKD

    chronic kidney disease

  •  
  • NaHCO3

    sodium bicarbonate

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