Alkaline Phosphatase: Potential cure for acute kidney injury?

Acute kidney injury (AKI) affects 20-50% of all hospitalized patients. It is characterized by an increase in serum creatinine and decreased urine output. AKI has mortality rate of >50%. Many factors are responsible for AKI like trauma, cardiovascular surgery, administration of nephrotoxic drugs, but sepsis associated AKI is the prominent one. Current treatment plans include hemodynamic support and antibiotic treatment. Rightfully so, the primary concern with the onset of AKI is to maintain the homeostatic perturbations. But this treatment strategy has countereffect-excess fluid administration can cause renal impairment. And treatment with aminoglycosides antibiotics like gentamicin leads to proximal cellular death in kidney.

As we mentioned above, sepsis induced AKI is the most prevalent in hospitalized patients. Whatever the causative factor is associated with AKI host response is always initiated in the body. Currently, improved scientific findings into host response has led to the identification of potential targets for AKI. One of them is alkaline phosphatase (ALP). ALP has shown considerable renal protection via stimulating anti-inflammatory effects, attenuating tubular injury and pro-apoptotic markers. Let’s understand what ALP does in our body before diving deep into mechanistic details of its action.

ALP is an enzyme expressed in bone and in physiological barrier tissues such as intestinal tract and kidney tubules. There are four isoenzymes of ALP, and they are named after their site of expression. Their basic function is dephosphorylation of proteins. Among placental ALP(PALP), Intestinal ALP(IALP) and tissue non-specific ALP(TALP). IALP plays an important role in maintaining gut homeostasis. This enzyme has been studied extensively and has superior enzymatic activity. Owing to its potential therapeutic effects it has been proposed to be beneficial in inflammatory disorders, ulcers and AKI.  Till now three mechanism(s) of action has been proposed:

1. Anti-inflammatory property of ALP: The lipopolysaccharide (LPS) is a major component of outer membrane of gram-negative bacteria. The most potent component in the structure of LPS was lipid A subunit. This subunit contains two phosphate group for its activation. The study conducted by Peters et al., (1) observed that LPS mediated kidney damage was alleviated by administration of ALP. They observed that ALP administration increased the release of organic phosphate (Pi). It was grossly assumed that ALP is responsible for removing phosphate group from LPS. However, these claims can never be proved by evidence. Komazin et al (2) suggested that ALP nonspecific for LPS. Most likely ALP does not directly detoxify LPS via removing phosphate group. The therapeutic effect of ALP mediated by other mechanisms.
2. Modulation of purines and pyrimidines receptors substrates:  ALP can convert nucleotide to nucleoside and these nucleosides have completely different effect than original nucleotides. The adenosine and uridine mainly form the basis purine and pyrimidine signaling. Adenosines have an affinity for receptors like A1, A2a, and A3. Adenosines activate regulatory T cells in ischemia reperfusion injury in kidney transplantation. The interesting fact is that therapeutic effects of ALP in IRI were abolished by A2a receptor antagonist. Conversely, in LPS induced AKI A2a receptor antagonist was not able to completely nullify the effects of ALP. These findings suggested that ALP renoprotective effects are not executed by single pathway. Although it can be inferred that ALP can regulate the substrate for purine and pyrimidine receptors.
3. Impact on tight junction proteins (TJP):  ALP is important for integrity of endothelium and epithelium. ALP has a close relationship with tight junctions. Researchers demonstrated that exogenous supplementation of ALP increases TJP mRNA. Thus, ALP can prohibit the leakage of endotoxin into circulation. Eventually attenuating TLRs signaling. This later mechanism of action is very crucial in identifying ALP therapeutic effects. Because currently, considerable attention is given to paracrine effects among cells in sepsis induce AKI. Davidson et al (3) suggested that administration of ALP in pigs going through cardiopulmonary bypass showed lower incidence of AKI and brush border epithelium was restored by maintaining the expression of TJP. Thus, to understand the real renoprotective effects of ALP in clinical trials must harness this unique therapeutic effect of ALP. Evaluating barrier hypothesis to determine tubular and vascular injury.

Clinical trials: Uptill now seven clinical trials have been conducted related to ALP. Five trials reported renal outcomes, four were conducted in patients with sepsis induced AKI, one in kidney transplant and two with cardiothoracic surgery. Among all the clinical trial REVIVAL was of primary importance. This trial recruited 649 patients and it was phase 3 level trial to estimate the efficacy and safety of ALP. As previous results showed improvement in survival and reduction in major adverse kidney events by 90 days. ALP did not improve survival in critically ill patients. Although significant reduction in the requirement for dialysis was observed in ALP treated groups. However, the trial was terminated owing to the futility of analysis.

ALP administration in vivo shows considerable therapeutics effects. However, definitive clinical trial results were not obtained. There can be two primary reasons for it:

1. There could be multitude reasons for sepsis in clinical trials. Gram negative bacteria can be one of the many reasons. The heterogeneity in causative organism makes sepsis induced AKI difficult to treat.
2. Most of the results obtained in animals’ model of AKI have received ALP before or shortly after the LPS administration. This scenario is absent in clinical studies. By the time ALP was infused in patients the kidney was already injured.

ALP treatment in living donor kidney patients showed no effect on glomerular filtration rate as compared to placebo group. Although, expression of biomarkers of kidney injury were lowered. These results suggested that intrarenal inflammation might be reduced by the ALP. If we truly want to evaluate the renoprotective effects of ALP the future clinical trials should try to treat patients before or shortly after the AKI(4).

Dr. Isha Sharma, Ph.D.

Sources

1. Peter E, Geraci S, Heemskerk S et al. Alkaline phosphatase protects against renal inflammation through dephosphorylation of lipopolysaccharide and adenosine triphosphate. Br j pharmacol 2015; 172:4932-45.
2. Komazin G, Maybin M, Woodard RW et al. Substrate structure activity relationship reveals a limited lipopolysaccharide chemotype range for intestinal alkaline phosphatse. J Biol Chem 2019; 294:19405-23.
3. Davidson JA, Khailova L, Treece A et al. Alkaline phosphatase treatment of acute kidney injury in an infant piglet model of cardiopulmonary bypass with deep hypothermic circulatory arrest. Sci Rep 2019; 9:14175.
4. Steenvoorden TS, Rood JAJ, Bemelman FJ et al. Alkaline phosphatase treatment of acute kidney injury-an update. Nephrol Dial Transplant. 2024;0:1-9.

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