Circulating Levels of SMPDL3B Define Metabolic Endophenotypes and Subclinical Kidney Alterations in [ME], 2025, Rostami-Afshari, Moreau+

[SNT Gatchaman]

Circulating Levels of SMPDL3B Define Metabolic Endophenotypes and Subclinical Kidney Alterations in Myalgic Encephalomyelitis

Spoiler: Authors

Rostami-Afshari, Bita; Elremaly, Wesam; McGregor, Neil R; Huang, Katherine Jin Kai; Armstrong, Christopher W; Franco, Anita; Godbout, Christian; Elbakry, Mohamed; Abdelli, Rim; Moreau, Alain

Myalgic Encephalomyelitis (ME) is a complex, multisystem disorder with poorly understood pathophysiological mechanisms. SMPDL3B, a membrane-associated protein expressed in renal podocytes, is essential for lipid raft integrity and glomerular barrier function. We hypothesize that reduced membrane-bound SMPDL3B may contribute to podocyte dysfunction and impaired renal physiology in ME.

To investigate this, we quantified soluble SMPDL3B in plasma and urine as a surrogate marker of membrane-bound SMPDL3B status and assessed renal clearance and plasma metabolomic profiles

In a cross-sectional study of 56 ME patients and 16 matched healthy controls, ME patients exhibited significantly lower urine-to-plasma ratios of soluble SMPDL3B and reduced renal clearance, suggesting podocyte-related abnormalities. Plasma metabolomics revealed dysregulation of metabolites associated with renal impairment, including succinic acid, benzoic acid, phenyllactic acid, 1,5-anhydroglucitol, histidine, and citrate.

In ME patients, plasma SMPDL3B levels inversely correlated with 1,5-anhydroglucitol concentrations and renal clearance. Multivariable modeling identified the urine-to-plasma SMPDL3B ratio as an independent predictor of clearance. Female ME patients showed more pronounced SMPDL3B alterations, reduced clearance, and greater symptom severity. Non-linear associations between soluble SMPDL3B and lipid species further suggest systemic metabolic remodeling.

These findings support soluble SMPDL3B as a potential non-invasive biomarker of renal-podocyte involvement in ME, highlighting sex-specific differences that may inform future therapeutic strategies.

Web | PDF | International Journal of Molecular Sciences | Open Access

 

[Peter T]

Again a study where healthy controls my not be the best option, rather sedentary controls or controls with a different activity limiting health condition would clarify whether the observed effect related directly to the ME/CFS or was an indirect consequence of enforced lifestyle changes.

 

[SNT Gatchaman]

The study cohort included 56 individuals diagnosed with ME and 16 sedentary healthy controls (HC).

 

[Peter T]

Thank you for pointing this out, I thought I had read the text carefully, but managed to miss the very point I was considering.

 

[Utsikt]

Participants in the control group were recruited based on the following inclusion criteria: (1) a self-reported sedentary lifestyle, defined as engaging in less than two hours of moderate-intensity physical activity per week; (2) no personal or family history of ME, fibromyalgia (FM), multiple sclerosis (MS), or other chronic illnesses; and (3) no current or recent (within the past month) viral or bacterial infection at the time of enrollment. To minimize potential confounding factors, controls were frequency-matched to the ME cohort based on group-level sex and age distributions.

BMI was equal for both groups, but without knowing the severity of the patients there might be a substantial difference between the physical activity of the groups. Average disease duration was 10 years.

I can’t find any data on the symptom scores.

 

[V.R.T.]

The previous SMPDL3B paper was critiqued on here for methadological/statistical issues - I think it was claimed the differences were not particularly significant?

Does this paper have similar issues?

 

[forestglip]

The previous SMPDL3B paper was critiqued on here for methadological/statistical issues - I think it was claimed the differences were not particularly significant?

Does this paper have similar issues?

Part of the discussion was about how the difference might have been driven by contraceptive use:

This is for the females in the Canadian cohorts (the ME/CFS and healthy controls are lumped together). Look at the very big difference between the group not on contraception and the group that is. It's a much stronger difference than between the ME/CFS and HC individuals in the Canadian sample.

I think it would have made sense to consider contraceptive use in this paper as well, but I don't see that word mentioned.

 

[Hutan]

There were only 16 controls - 8 men and 8 women. So, when the subset analysis of women is done, the comparison is with only 8 controls. That makes for very shaky comparisons. The percentage of females and males in each group was different: 66% female in the ME/CFS group and 50% female in the control group.

However, the urinary-to-plasma ratio of soluble SMPDL3B was significantly reduced in ME patients (2.641 ± 0.32) versus controls (4.552 ± 0.96; p = 0.021) (Figure 1b).

Figure 1b

The mean ratio of urinary to plasma SMPDL3B is lower in the ME/CFS group, but the low number of controls and the impact of the two higher values is a problem. The way the data points are plotted over-emphasises the difference visually - the control markers are bigger and appear as a solid dark colour and are spaced out more on the horizontal axis. Actually both sets of data are mostly in the range 0 to 5.

Looking at figures 1d and 1e, it is clear that plasma levels are pretty much the same in the ME/CFS and control groups (0 to 50 for both). There really aren't enough data points to suggest anything much about the plasma levels versus clearance rates (note the difference in the y axis scale).