Allogeneic bone marrow-derived mesenchymal stem cells in the aging kidney: secondary results of a Parkinson's disease clinical trial

Abstract

Background Kidney function declines with age, largely due to chronic low-grade inflammation. Mesenchymal stem cells (MSCs) have demonstrated immunomodulatory effects in certain immune-mediated kidney diseases, but their role in preserving renal function in aging individuals without chronic kidney disease (CKD) remains unclear. This study presents secondary outcome findings from a randomized clinical trial in Parkinson's disease (PD), evaluating the impact of allogeneic human bone marrow-derived MSCs (allo-hMSCs) on kidney function in an aging population with PD with preserved renal function. Methods Subjects with PD aged 50–79 years with baseline estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 were randomized to receive either three allo-hMSC infusions, one placebo followed by two allo-hMSC infusions, or three placebo infusions at 18-week intervals. Kidney function was assessed using eGFR, serum creatinine (SCr), and blood urea nitrogen (BUN) at baseline, 9 weeks after the first two infusions, and at weeks 40 and 88. eGFR was calculated using the 2021 CKD-EPI equation. A Bayesian modeling approach was used to estimate posterior probabilities (PP) of treatment effects. Results Of 45 randomized patients, 44 were analyzed; 43 completed infusions, and 40 completed the 88-week follow-up. The three-infusion group (N=16) showed an average annual eGFR increase of 3.29 mL/min/1.73 m2, versus declines of –1.46 and –2.92 in the two-infusion (N=14) and placebo (N=15) groups. SCr decreased by –0.12 mg/dL at both weeks 40 (PP: 93.9%) and 88 (PP: 86.2%) in the three-infusion group versus placebo, with no significant SCr differences between the two-infusion and placebo groups. BUN levels did not differ significantly between treatment and placebo groups. Conclusion In older adults with PD and preserved kidney function, repeated allo-hMSC infusions were associated with improved kidney function measures. While promising, these findings are preliminary and may be specific to PD. Further studies are needed to assess potential benefits in the broader aging population. Trial Registration ClinicalTrials.Gov. NCT04506073. November 09, 2020. https://clinicaltrials.gov/study/NCT04506073

1. Introduction

The aging population is a growing demographic challenge, with individuals aged 65 and over expected to comprise 23% of the population by 2054 [1]. This demographic shift is accompanied by an increasing prevalence of age-related neurodegenerative diseases, particularly Parkinson's disease (PD), which affects approximately 1% of individuals over age 65 and more than 5% of those over 85 [2]. In parallel, chronic kidney disease (CKD), present in 39.4% of individuals over age 60 [3], has also been independently associated with higher PD prevalence [4]. While this link was initially attributed to uremic toxicity in the basal ganglia [5], emerging evidence supports the existence of a "kidney–brain axis" [6] in which impaired renal clearance of circulating alpha-synuclein may contribute to its accumulation and propagation in the brain, ultimately leading to dopaminergic neurodegeneration and the development of PD motor and non-motor symptoms [7].

More recently, researchers have proposed a potential reverse relationship: that PD itself, particularly its autonomic features, may negatively impact kidney function. Cardiovascular and urinary autonomic dysfunction commonly seen in PD, such as orthostatic hypotension, supine hypertension, and neurogenic bladder, may impair renal perfusion, increase the risk of infection, and contribute to kidney injury [8]. Similar patterns in related synucleinopathies like pure autonomic failure, where patients show significantly lower eGFR, support this possible link [9]. However, the absence of large, prospective studies following PD patients with preserved renal function means there is no clear evidence that PD independently increases the risk of CKD, and it is not currently recognized as a formal risk factor. Aging itself, however, is associated with structural and functional changes in the kidneys, including glomerular senescence and tubular atrophy [10, 11]. These changes contribute to an annual glomerular filtration rate (GFR) decline.