Improved prediction of long-term kidney outcomes in people with type 2 diabetes by levels of circulating haematopoietic stem/progenitor cells

Diabetologia https://doi.org/10.1007/s00125-023-06002-6 ARTICLE Improved prediction of long‑term kidney outcomes in people with type 2 diabetes by levels of circulating haematopoietic stem/ progenitor cells Benedetta Maria Bonora1,2 Gian Paolo Fadini1,2 · Mario Luca Morieri1 · Marella Marassi1 · Roberta Cappellari1 · Angelo Avogaro1 · Received: 23 April 2023 / Accepted: 25 July 2023 © The Author(s) Abstract Aim/hypothesis We examined whether prediction of long-term kidney outcomes in individuals with type 2 diabetes can be improved by measuring circulating levels of haematopoietic stem/progenitor cells (HSPCs), which are reduced in diabetes and are associated with cardiovascular risk. Methods We included individuals with type 2 diabetes who had a baseline determination of circulating HSPCs in 2004–2019 at the diabetes centre of the University Hospital of Padua and divided them into two groups based on their median value per ml of blood. We collected updated data on eGFR and albuminuria up to December 2022. The primary endpoint was a composite of new-onset macroalbuminuria, sustained ≥40% eGFR decline, end-stage kidney disease or death from any cause. The analyses were adjusted for known predictors of kidney disease in the population with diabetes. Results We analysed 342 participants (67.8% men) with a mean age of 65.6 years. Those with low HSPC counts (n=171) were significantly older and had a greater prevalence of hypertension, heart failure and nephropathy (45.0% vs 33.9%; p=0.036), as evidenced by lower eGFR and higher albuminuria at baseline. During a median follow-up of 6.7 years, participants with high vs low HSPC counts had lower rates of the composite kidney outcome (adjusted HR 0.69 [95% CI 0.49, 0.97]), slower decline in eGFR and a similar increase in albuminuria. Adding the HSPC information to the risk score of the CKD Prognosis Consortium significantly improved discrimination of individuals with future adverse kidney outcomes. Conclusions/interpretation HSPC levels predict worsening of kidney function and improve the identification of individuals with type 2 diabetes and adverse kidney outcomes over and beyond a clinical risk score. Keywords End-stage kidney disease · Inflammation · Non-albuminuric · Regeneration · Stratification Abbreviations BM Bone marrow CKD Chronic kidney disease Benedetta Maria Bonora and Mario Luca Morieri contributed equally. * Gian Paolo Fadini 1 Department of Medicine, University of Padova, Padua, Italy 2 Veneto Institute of Molecular Medicine, Padua, Italy ESKD End-stage kidney disease GLP-1 Glucagon-like peptide-1 HSPC Haematopoietic stem/progenitor cell LSM Least square mean MMRM Mixed model for repeated measures NRI Net reclassification index rIDI Relative integrated discrimination improvement ROC Receiver operating characteristic SGLT2 Sodium–glucose cotransporter 2 UACR Urinary albumin/creatinine ratio 13 Vol.:(0123456789) Diabetologia Introduction Type 2 diabetes is the most important cause of end-stage kidney disease (ESKD) in most countries in the world. Despite declining trends of mortality for CVD in the population with and without diabetes, mortality rates due to ESKD have remained stable over the last decades [1, 2]. Among individuals with type 2 diabetes, chronic kidney disease (CKD) results from a complex interaction of factors not limited to hyperglycaemia and including hypertension, obesity, chronic inflammation and hyperuricaemia, among others. As a consequence, the natural history of kidney disease often deviates from that of traditional diabetic nephropathy, and non-albuminuric CKD may prevail [3]. Notably, non-albuminuric CKD is characterised by an excess cardiovascular burden and shortened survival time [4]. Today, the unprecedented opportunity to prevent kidney disease with sodium–glucose cotransporter 2 (SGLT2) inhibitors mandates a thorough examination of an individual’s renal risk. Indeed, clinical trials show lower RR of adverse kidney outcomes with SGLT2 inhibitors across the spectrum of baseline kidney function but a lower absolute benefit in those with normal kidney function at baseline [5]. Therefore, CKD risk stratification could help resource allocation. The mechanisms responsible for the onset of CKD, its progression and associated mortality among people with type 2 diabetes are incompletely defined [6]. The existence of a common pathway into which the various risk factors converge is fascinating. We and others have previously reported that individuals with type 2 diabetes display a consistent 30–40% reduction in the level of haematopoietic stem/progenitor cells (HSPCs) in the bloodstream [7]. This 13 defect has been attributed to impaired structure and function of the bone marrow (BM), which physiologically releases HSPCs in a controlled way [8]. Notably, the occurrence of multiple risk factors that define the metabolic syndrome acts synergistically to reduce HSPC counts [9]. In different populations of individuals, including those with diabetes and the metabolic syndrome [10, 11], a low level of circulating HSPCs is strongly associated with increased rates of cardiovascular events, cardiovascular death and death from any cause [12]. While earlier studies used functional assays to demonstrate the correlation between circulating progenitor cells and vascular risk [13], recent studies have used flow cytometry to enumerate progenitor cells in the blood [14]. We have previously found that individuals with type 2 diabetes and below-median HSPC levels experienced a greater incidence of nephropathy over almost 4 years than did those with higher HSPC levels [15]. Herein, we evaluated whether HSPCs can predict the long-term occurrence of a broad spectrum of typical kidney outcomes of type 2 diabetes. Additionally, we examined whether adding the HSPC measure to a modern kidney risk assessment score improved patient stratification. Methods Participants The study was conducted according to the principles of the Declaration of Helsinki. All participants provided written informed consent for HSPC analysis and for the re-use of clinical data for research purposes. According to national regulations on observational studies, the protocol was notified to and cleared by the Ethical Committee of the University Hospital of Padua (protocol no. 364n/AO/23). Diabetologia We included individuals who underwent blood sampling for the quantification of circulating HSPCs at the Division of Metabolic Diseases of the University Hospital of Padua from January 2004 to April 2019. All participants were of white European ancestry. The same exclusion criteria applied throughout the study: active solid or haematological cancer; blood cytopenia (white blood cells <3000/μl; erythrocyte count <3,000,000/μl; platelet count <50,000/ μl); acute inflammatory conditions; active autoimmune diseases or use of corticosteroids; advanced dementia; severe liver disease (cirrhosis Child–Pugh class B or C); ESKD (...truncated)