Title: A clinical impact of apoptosis inhibitor of macrophage on feline chronic kidney disease

(The Veterinary Journal, 2026 Feb;315:106545. doi:10.1016/j.tvjl.2026.106545)

Three-sentence summary

1. Feline CKD may be substantially driven by a species-specific defect in AIM function - excessive IgM pentamer binding prevents AIM from clearing cellular waste and DAMPs, promoting chronic inflammation and fibrosis.
2. Intravenous administration of rAIM in Stage 3b CKD cats improved 360-day cumulative survival from 20% to 80-83%, stabilized kidney biomarkers (Cre, IS, SDMA), suppressed uremic toxin accumulation and systemic inflammatory proteins (SAA, LPS-BP), and restored serum sphingomyelin levels.
3. As rAIM therapy works toward regulatory approval, nutritional and supportive management targeting inflammation, oxidative stress, and metabolic dysregulation can play a meaningful role in slowing CKD progression in the interim.

 Introduction

If you follow news about feline medicine, you have probably heard about a potential treatment for feline chronic kidney disease (CKD) being developed by Dr. Toru Miyazaki and his team in Japan. On April 24th, they officially submitted a regulatory approval application for an AIM-based therapy - a milestone that has given genuine hope to the many people caring for cats affected by this disease.

To mark this occasion, this article aims to explain what AIM actually is, and what the recently published study found - as accurately as possible, but in plain language.

 Before We Begin: Key Concepts

This article is written for people who may not have a science background but want to understand what all this means for their cats. The following concepts will make the rest of the discussion much easier to follow.

What blood actually is

The body is not a homogenous bag of liquid. It is composed of trillions of highly specialized cells, each maintaining its position and performing a specific function. For these cells to survive and function, they require a continuous supply of nutrients, oxygen, and signaling molecules. This is the job of blood vessels and blood, the circulatory system.

Blood is far more complex than it appears. It contains red blood cells (which carry oxygen via hemoglobin), white blood cells (immune cells), platelets, and a liquid component called serum, which itself contains hundreds of proteins, metabolites, lipids, electrolytes, and waste products. The kidneys serve as the body’s filtration system, processing the entire blood volume roughly 50 or more times per day to excrete metabolic waste as urine.

What is AIM?

AIM stands for ‘Apoptosis Inhibitor of Macrophage’-  also known by its gene name, CD5L - and is a secreted circulating protein found in the blood stream.

Despite the word ‘inhibitor’ in its name (which refers to its originally described role in suppressing macrophage cell death when AIM was first discovered), AIM is now recognized for a much broader set of functions.

AIM’s core function is to ‘bind to intracellular and extracellular waste materials and tag them for engulfment by macrophages’ - a process analogous to opsonization. Think of it as attaching a ‘remove this’ sticker to garbage that needs to be collected. Its primary targets include dead cells, cell debris, and structures known as ‘DAMPs (Damage-Associated Molecular Patterns) - danger molecular signals released by damaged tissues.

How AIM works under normal conditions?

In healthy state, AIM circulates in the bloodstream non-covalently bound to IgM pentamers (a large, five-armed antibody complex), keeping it in an inactive state. When a pathological event occurs - such as tissue injury or acute kidney injury (AKI) - AIM dissociates from IgM, binds to target waste materials, and facilitates their efficient removal by macrophages. This mechanism prevents acute kidney damage from worsening and becoming chronic.

The fundamental problem in cats

However, cats have a defect in this system. Feline AIM binds to IgM pentamers with abnormally high affinity compared to humans or mice. Specifically, the feline AIM protein exists in two structural variants - one with 3 SRCR (Scavenger-Receptor Cysteine-Rich) domains and one with 4 - and regardless of which variant a cat carries, the excessive IgM binding means AIM cannot efficiently dissociate when needed. As a result, cellular waste and DAMPs accumulate in renal tissue, promoting chronic inflammation and fibrosis, which is hypothesized to contribute significantly to feline CKD development and progression.

The approach proposed by Dr. Miyazaki’s team is intuitive: ‘if there is not enough functional AIM, supplement it from outside the body by administering recombinant AIM (rAIM)’.

Paper Walkthrough

This paper was published earlier this year in The Veterinary Journal and investigates whether intravenous administration of externally produced rAIM can suppress the deterioration of kidney biomarkers and meaningfully improve survival in cats with advanced CKD.

The full text is freely accessible - the walkthrough below follows the paper’s figures, so having it open alongside may help: https://www.sciencedirect.com/science/article/pii/S1090023326000018.

Figure 1: Study design and patient selection

Between December 2019 and June 2024, 216 cats with CKD were screened across 13 private veterinary hospitals. Among these, 128 cats with serum creatinine (Cre) concentrations between 2.9 and 5.0 mg/dL - corresponding to IRIS Stage 3 - were selected as the primary candidate pool. After applying exclusion criteria (elevated Inorganic phosphate, high serum IgE, and serious comorbid conditions), 35 cats remained eligible.

At this point, a key additional biomarker enters the picture: Indoxyl Sulfate (IS).

IS is a uremic toxin produced when gut bacteria metabolize tryptophan; its serum concentration rises as kidney filtration capacity declines. So why did the research team introduce IS as a new stratification marker?

When they performed ROC (Receiver Operating Characteristic) analysis, IS predicted progression from IRIS Stage 3 to Stage 4 with an AUC of 0.750 and an odd ratio of 24.0 (95% CI: 2.1–279.6) - a substantially stronger association than creatinine or inorganic phosphate. The more commonly used SDMA showed a slightly higher AUC of 0.778, but its specificity was lower than IS, and its optimal cut-off value (15.0 µg/dL) actually fell below the typical range seen in IRIS Stage 3 cats (26-38 µg/dL), limiting its practical utility for within-stage risk stratification. IS, by contrast, had a cut-off of 5.4 µg/mL that was directly applicable to identifying high-risk cats within Stage 3.

Using IS as a new stratification marker, the team divided the Stage 3 cats into two subgroups:

1. Stage 3a: serum IS < 5 µg/mL - relatively stable Stage 3 (observational group, n=9)
2. Stage 3b: serum IS ≥ 5 µg/mL - advanced Stage 3 at high risk of progressing to Stage 4 (intervention group, n=26)

 

The higher-risk Stage 3b cats were then further divided into three treatment groups

1. Stage 3b Control: standard CKD care only (n=15)
2. Stage 3b mAIM group: standard care + murine rAIM (n=6)
3. Stage 3b fAIM group: standard care + feline rAIM (n=5)

The dose was set at 2 mg/head - approximately equivalent to the estimated total endogenous AIM content in feline whole blood. mAIM was administrated i.v every two weeks for a total of 6 injections; fAIM was administered i.v every two weeks for a total of 12 injections. All cats were monitored for 360 days.

Figure 3: Survival outcomes

The results were striking.

Median survival time and survival rates:

Kaplan-Meier survival analysis: mAIM vs control p=0.012; fAIM vs control p=0.022.

Notably, rAIM-treated cats maintained a 100% survival rate at 180 days. compared to just 36% in the control group. Furthermore, the overall survival curves of Stage 3b cats treated with rAIM closely resembled those of the more stable Stage 3a cats - suggesting that rAIM administration may genuinely slow the pace of CKD progression itself, not just delay an inevitable decline.

Additionally, 9 Stage 3a cats achieved 100% survival at 360 days without any rAIM treatment, further reinforcing the value of IS as a prognostic marker within IRIS Stage 3.

Figure 4: Kidney biomarker stabilization

To confirm that the improved survival reflection genuine biological effects rather than chances, serum kidney biomarkers were compared between baseline (Day 0) and follow-up (Day 70, or Days 70-112 for the fAIM group).

In the control group, serum concentrations of Cre (p=0.026), IS (p=0.032),and SDMA (p=0.0048) all increased significantly by Day 70 - clear evidence of continued kidney deterioration.

In both the mAIM and fAIM groups, none of these markers showed statistically significant changes - they remained stable. This confirms that rAIM administration suppressed the worsening of kidney biomarkers, and that the survival differences observed in Figure 3 were not due to the random group allocation.

Figure 5: What actually changed inside the body?

The survival and biomarker data established clinical efficacy - but why does rAIM work mechanistically? To answer this, ther researchers performed serum metabolomics (GC-MS) and serum proteomics (LC-MS/MS).

Metabolomics:
In Stage 3b control cats, 38 uremic toxins and related small molecules - including taurine, cystathionine, urea, and aconitic acid - were elevated compared to healthy cats, and continued to accumulate through Day 70. In rAIM-treated cats, the accumulation of many of these toxic metabolites was suppressed or partially reversed. Additionally, several essential amino acids that had declined with CKD progression showed a tendency toward recovery following rAIM treatment.

Proteomics:

Analysis of serum proteins showed that Serum Amyloid A (SAA) - a sensitive marker of systemic inflammation - was markedly reduced in rAIM-treated cats at Day 70. LPS-Binding Protein (LPS-BP) and Complement Factor D were also lower compared to the untreated Stage 3b control group.

Taken together, rAIM administration appears to go beyond simply stabilizing kidney function markers — it actively suppresses the accumulation of uremic toxins and dampens the chronic systemic inflammatory response that drives CKD progression.

Figure 6: Sphingolipid metabolism - an additional layer

One of the more intriguing findings in this paper was the lipidomics analysis.

Sphingomyelins are key structural components of cell membranes and important regulators of the sphingolipid metabolic pathway. Accumulating evidence links declining serum sphingomyelins - and rising ceramide levels - with cardiovascular disease, aging, and renal fibrosis.

In Stage 3b control cats, serum sphingomyelin levels declined progressively through Day 70. In mAIM-treated cats, the pattern was reversed: sphingomyelin levels increased across a broad range of molecular species. Metabolite Set Enrichment Analysis (MSEA) confirmed that the sphingolipid metabolic pathway was the most significantly affected pathway between Day 0 and Day 70 in rAIM-treated cats.

This suggests that rAIM's benefits extend beyond direct waste clearance - it may also positively influence lipid homeostasis and downstream anti-inflammatory signaling pathways in ways that compound its protective effects on the kidney.

 Bonus: Why compare mAIM and fAIM?

You may have wondered why the researchers compared murine AIM (mAIM) and feline AIM (fAIM) separately rather than using just one form. This is directly tied to the binding problem described earlier.

Since feline AIM binds IgM pentamers with abnormally high affinity, a natural concern arises: ‘if you inject fAIM, won't it simply bind back to endogenous IgM and become non-functional again?’

mAIM has normal IgM binding kinetics and can therefore circulate more freely in the feline body, making it more likely to reach and bind damaged tissues effectively. It is the functionally superior option - but comes from another species (xenogeneic). fAIM is biologically compatible with cats but risks functional limitation due to IgM re-binding.

The fact that both forms produced comparable survival improvements - mAIM with 6 injections and fAIM with 12 - suggests that AIM's waste-clearance function is largely conserved across species. Much like porcine insulin working effectively in humans despite structural differences, functional homology can matter more than species identity.

It is also worth noting that while some anti-mouse AIM antibodies developed in mAIM-treated cats, in vitro assays found no significant neutralizing effect, and no anaphylactic events occurred clinically across all repeated administrations.

Conclusion

The core message of this paper is clear. Feline CKD may not be simply a disease of gradual nephron loss - it may be substantially driven by deficient AIM function and the resulting chronic accumulation of cellular waste and DAMPs, which in turn perpetuate inflammation and fibrosis. Restoring even part of that clearance capacity through rAIM appears sufficient to meaningfully alter disease trajectory.

The research team acknowledges the study's limitations honestly:

1. This was a small exploratory, non-pivotal study - of the 216 cats screened, only 26 met Stage 3b criteria and received rAIM or served as controls.
2. Baseline treatments (renal diets, antiproteinuric agents, etc.) were not standardized across groups.
3. Blood pressure measurement and urinalysis were not performed uniformly.
4. Only IRIS Stage 3 cats without major comorbidities were enrolled - leaving open the question of efficacy in the typical CKD cat presenting with concurrent anemia, metabolic acidosis, and electrolyte imbalances.

Future work will benefit from larger cohorts with standardized care protocols, efficacy data across earlier and later CKD stages, and dedicated pharmacokinetic/pharmacodynamic (PK/PD) analyses to optimize dosing and injection intervals.

Personal Thoughts

The results are genuinely encouraging - but rAIM therapy has only just entered the regulatory approval process in Japan, and it will take time before it becomes widely available as a clinical treatment.

That does not mean we should simply wait. The most realistic approach right now is to actively manage the internal environment that this paper shows is so central to CKD progression: uremic toxin accumulation, chronic inflammation, and lipid metabolic dysregulation. Dietary management, hydration support, and nutritional strategies that address these pathological processes may not cure CKD, but they can make a meaningful contribution to slowing its progression.

While we wait for the treatment, why not start managing things with nutritional support now?

About the author Hocheol Shin, Ph.D. B.S./M.S./Ph.D. in Biological Sciences, KAIST (Korea Advanced Institute of Science and Technology) Research background in cancer immunology, tumor microenvironment, and translational oncology. Currently engaged in companion animal health and longevity research.