Effects of donor stem cells on aging kidneys from a Parkinson's disease trial

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 of approximately −1 mL/min/1.73 m² [12, 13]. As a result, more than half of individuals over 70 years have an eGFR of less than 60 mL/min/1.73 m², a level of function that is defined as CKD stage [14].

Renal senescence is characterized by multiple interconnected mechanisms, including telomere shortening, cellular senescence and apoptosis, mitochondrial and lysosomal dysfunction, changes in the sirtuin and Klotho signaling pathways, degeneration of the renin–angiotensin–aldosterone axis, and chronic inflammation [15, 16]. Recent findings in animal models suggest that chronic inflammation serves as an initial trigger of kidney aging, with Tumor Necrosis Factor (TNF)-α and interleukin (IL)−6 potentially dysregulating the pentose phosphate pathway and leading to increased oxidative stress, a known driver of cellular aging and damage [17]. This hypothesis is further supported by longitudinal studies demonstrating that both the levels and the rate of increase of TNFα and IL-6 correlate with kidney dysfunction in aging [18 –23]. While inflammation plays a key role, it is not the only mechanism contributing to renal aging. Additional pathways, including the restoration of sirtuin activity, modulation of WNT/β-catenin signaling, and activation of mitogen-activated protein kinase (MAPK) pathways, have also been implicated in kidney aging and represent important therapeutic targets in regenerative research [24].

In addition to the physiological changes associated with aging, the increasing prevalence of noncommunicable chronic diseases contributes to the rising incidence of CKD, affecting 27.5% of older adults with hypertension [25] and 40% of those with diabetes [26]. However, aging itself has been proposed as an independent contributor to kidney dysfunction in hypertensive patients [27], potentially accelerating the decline in eGFR in individuals already at risk due to hypertension and other chronic diseases [28]. No existing therapies effectively halt the natural progression of kidney aging or the unfavorable course of age-related kidney diseases. This unmet need has driven research into regenerative medicine, including the potential application of stem cell-based therapies to mitigate age-related renal decline and restore kidney function [29].

Mesenchymal stem cells (MSCs) are multipotent progenitor cells derived from various tissues, including bone marrow, adipose tissue, umbilical cord, and peripheral blood. These cells exhibit a diverse range of therapeutic properties, including anti-apoptotic, antioxidant, anti-inflammatory, antifibrotic, and immunomodulatory effects [30 –33]. They have also been proven to be minimally immunogenic [34], have low tumorigenesis risk [35], are easy to procure and expand, and raise few ethical concerns compared to other stem cell products, making them highly promising candidates for regenerative medicine and a wide array of therapeutic applications [29]. MSCs have the ability to transition between a proinflammatory (MSC1) and an anti-inflammatory phenotype (MSC2), a process primarily driven by elevated levels of IFN-γ, IL-6, and TNF-α [36, 37]. This phenotypic plasticity may influence key pathways involved in aging beyond inflammation, including sirtuin regulation, WNT/β-catenin modulation, and MAPK signaling, thereby offering a multifaceted approach to targeting renal senescence and preserving kidney function in older adults [24].

These therapeutic properties have translated into early-phase clinical trials, showing the potential of MSC-based therapies in treating acute kidney injury, CKD, diabetic nephropathy, atherosclerotic renovascular disease, and lupus nephritis [38], suggesting that MSCs may help manage established kidney diseases primarily by slowing or, in rare cases, halting the decline in kidney function. However, to date, no interventional studies have evaluated the impact of MSCs in individuals with normal kidney function and no preexisting renal comorbidities.

In this context, we report findings from a Phase 2 clinical trial of allogeneic bone marrow-derived MSCs (allo-hMSC) for PD, demonstrating longitudinal improvements in eGFR and serum creatinine (SCr) levels. These results are based on data from comprehensive metabolic panels used as part of the trial's safety assessment in patients with PD who had normal kidney function at trial enrollment (eGFR > 60 mL/min/1.73 m²).

The results from this trial, which studied elderly patients with PD without preexisting CKD (eGFR > 60 mL/min/1.73 m² at enrollment), provide clinical evidence suggesting that repeated intravenous infusions of allo-hMSCs may help stabilize and possibly improve kidney function in the aging PD population. These findings are based on a secondary safety evaluation of organ function conducted as part of a Phase 2 clinical trial assessing the immunomodulatory effects of allo-hMSCs in patients with PD (NCT02611167)^{in press}. More than 1% of individuals over the age of 65 are diagnosed with PD, a neurodegenerative disorder characterized by dopaminergic neuron loss and driven in part by microglial-mediated neuroinflammation [44]. It is hypothesized that allo-hMSCs reduce brain inflammation by modulating the peripheral immune system through multiple mechanisms [45].

Considering that the average age-related decline in eGFR is approximately −1 mL/min/1.73 m² per year¹³, patients in the placebo arm experienced a more pronounced reduction of –2.92 mL/min/1.73 m²/year. In contrast, those receiving active treatment showed a slower decline with two allo-hMSC infusions (–1.46 mL/min/1.73 m²/year) and a notable improvement with three infusions (+ 3.29 mL/min/1.73 m²/year, Fig. 3). This was accompanied by a slower rise in the rate of change of serum creatinine among patients in the active treatment arms, with a slight decrease of –0.02 mg/dL/year (calculated by totalizing the daily rate of –0.00005 mg/dL/day from the linear model) in the three-infusion group and a modest increase of 0.03 mg/dL/year (0.00008 mg/dL/day) in the two-infusion group, compared to a substantial increase of 0.73 mg/dL/year (0.0002 mg/dL/day) in the placebo group, as shown by the linear modeling in Fig. 2.

Importantly, serum BUN levels remained stable across all groups, suggesting that the observed changes in eGFR and SCr were not attributable to hydration status or nutritional factors. Although this PD-focused study did not include measurements of other freely filtered biomarkers such as Cystatin C, which is unaffected by muscle mass, diet, or sex, prior comparative studies have shown that in individuals with eGFR values between 60 and 89 mL/min/1.73 m², the same range observed in our study population (see Table 1), SCr alone estimates GFR as accurately as Cystatin C or the combined SCr and Cystatin C Eqs. [46].

According to these results, although the two-infusion group showed a slower decline in kidney function relative to placebo, the overall trajectory remained negative, indicating continued deterioration, though to a lesser degree. In contrast, the three-infusion group demonstrated a positive slope, reflecting actual improvement in kidney function over time. This divergence in outcomes between the two and three-infusion groups may reflect a cumulative dose effect or a threshold effect of repeated allo-hMSC administration. While patients were randomized, and measured variables were not different at baseline between groups, PD is a very heterogeneous disease, so there is always a possibility of an unmeasured confounder that could be playing a role in the differential response between groups. It is also possible that this difference was due to underlying variability in cell product batches. Although using the same donor minimizes inter-donor variability, individual infusion bags may still contain heterogeneous cell populations with differing immunomodulatory potency [47, 48]. Consequently, batch-to-batch differences could influence peripheral inflammatory responses and impact treatment efficacy. Future trials will incorporate additional equivalency and potency assays, as differences in therapeutic response may stem not only from dosing frequency but also from variability in the functional quality of stem cell preparations [49]. Establishing standardized potency measures will be critical to ensuring consistency and optimizing the nephroprotective potential of allo-hMSC therapy.

Both IL-6 and TNF-α play central roles in the inflammatory changes associated with aging [50]. Animal studies suggest that chronic inflammation initiates and accelerates age-related renal decline by disrupting metabolic pathways such as the pentose phosphate pathway, leading to impaired antioxidant defenses and increased oxidative stress, a hallmark of cellular senescence [17]. In the kidney, this may manifest as glomerular damage, podocyte loss, tubular atrophy, and interstitial fibrosis, ultimately contributing to eGFR decline [11, 51]. Longitudinal human studies further support this model, demonstrating that elevated levels of circulating IL-6 and TNF-α are independently associated with accelerated eGFR decline in older adults, even after adjusting for traditional risk factors [18 –23].

Understanding how interventions like MSC therapy modulate inflammatory mediators may provide critical insight into their potential anti-aging effects on kidney function. Further correlation between kidney function and inflammatory markers is needed to clarify the mechanisms involved. Additionally, linking these outcomes to the activity of individual cell batches may help identify key features of potency and support the development of more precise assays to evaluate the therapeutic strength of MSC products in kidney-related inflammation. This mechanistic insight could not only be extended to other kidney diseases but may also support the broader use of MSCs as a strategy to counteract natural kidney senescence. Although we did not report inflammatory biomarker data or cell potency results in this manuscript, future work should focus on analyzing available longitudinal patient samples and correlating them with cell-based potency and equivalency assays to better understand and optimize the therapeutic potential of MSCs in the kidney.

This study has several limitations. First and foremost, the findings are based on secondary safety outcomes from a larger clinical trial in aging PD patients, and the study did not include non-PD participants. As a result, the generalizability of the findings may be limited, given the theoretical, though unproven, risk of worsened renal function in this population compared to non-PD aging individuals. In addition, the absence of younger healthy controls limits the ability to assess age-specific effects and establish baseline trajectories of renal aging. Taken together, these limitations prevent the current study design from isolating MSC-specific effects from those related to PD progression or normal aging. Future studies should include both age-matched healthy controls and younger participants to validate and contextualize the renal findings observed here. Additionally, because kidney function was not the primary endpoint of this trial, there may be baseline heterogeneity due to the lack of pretrial stratification focused on renal outcomes. However, the results provide proof-of-concept data that could support future clinical trials targeting anti-aging kidney therapies in asymptomatic individuals without CKD. The second limitation is the relatively small sample size, which may limit the generalizability of the findings. To address this, we used Bayesian analysis, which provides posterior probabilities that support clearer and more informed interpretations. This method is endorsed by regulatory agencies such as the FDA for early-phase trials due to its flexibility and suitability for small sample sizes [52]. Third, the exclusion of patients with significant renal comorbidities limits the applicability of these findings to individuals with more advanced CKD. Fourth, the study did not specifically track exposure to nephrotoxic medications or environmental toxins, which could have influenced kidney function and confounded the results. Finally, all participants were of similar age, preventing comparisons between older and younger individuals to evaluate age-specific effects.

These results suggest that repeated intravenous infusions of 10 × 10⁶ allo-hMSCs/kg may improve eGFR and SCr levels in aging patients with PD without preexisting CKD. This represents an important first step in demonstrating the safety and proof-of-concept efficacy of allo-hMSCs as a potential therapy to stabilize and possibly improve kidney function in an aging PD population. Future studies should include well-designed efficacy trials involving diverse populations across different age groups and comorbidity profiles, with appropriate covariate control. In addition, functional potency assays and mechanistic studies are needed to better characterize the allo-hMSC secretome and understand the biological pathways driving the observed renal benefits.

Additional file 1. Additional file 2.