cells Article Stem Cell Therapy for Microvascular Injury Associated with Ischemic Nephropathy Stephen C. Textor 1,*, Abdu Abumoawad 2, Ahmed Saad 3 , Christopher Ferguson 1 and Allan Dietz 4 1 Mayo Clinic, Division of Nephrology and Hypertension, Rochester, MN 55905, USA; [email protected] 2 Department of Medicine University of Missouri, Kansas, MO 64108, USA; [email protected] 3 Department of Medicine Creighton University School of Medicine, Omaha, NE 68124, USA; [email protected] 4 Mayo Clinic, Human Cell Therapy Laboratory, Rochester, MN 55905, USA; [email protected] * Correspondence: [email protected] Abstract: Ischemic nephropathy reflects progressive loss of kidney function due to large vessel atherosclerotic occlusive disease. Recent studies indicate that this process is characterized by mi- crovascular rarefaction, increased tissue hypoxia and activation of inflammatory processes of tissue injury. This review summarizes the rationale and application of functional MR imaging to evaluate tissue oxygenation in human subjects that defines the limits of renal adaptation to reduction in blood flow, development of increasingly severe tissue hypoxia and recruitment of inflammatory injury pathways in ischemic nephropathy. Human mesenchymal stromal/stem cells (MSC) are capable of modifying angiogenic pathways and immune responses, but the potency of these effects vary between individuals and various clinical characteristics including age and chronic kidney disease and levels of hypoxia. We summarize recently completed first-in-human studies applying intrarenal Citation: Textor, S.C.; Abumoawad, infusion of autologous adipose-derived MSC in human subjects with ischemic nephropathy that A.; Saad, A.; Ferguson, C.; Dietz, A. demonstrate a rise in blood flow and reduction in tissue hypoxia consistent with partial repair of Stem Cell Therapy for Microvascular Injury Associated with Ischemic microvascular injury, even without restoring main renal arterial blood flow. Inflammatory biomarkers Nephropathy. Cells 2021, 10, 765. in the renal vein of post-stenotic kidneys fell after MSC infusion. These changes were associated with https://doi.org/10.3390/ modest but significant dose-related increments in kidney function. These data provide support a role cells10040765 for autologous MSC in repair of microvascular injury associated with tissue hypoxia. Academic Editor: Pei-Hui Lin Keywords: ischemic nephropathy; renal artery stenosis; tissue oxygenation; chronic kidney disease Received: 7 March 2021 Accepted: 26 March 2021 Published: 31 March 2021 1. Introduction Epidemiologic studies identify loss of kidney function as a major risk factor for Publisher’s Note: MDPI stays neutral cardiovascular events and death. Treatment options for many forms of acute and chronic with regard to jurisdictional claims in kidney disease (CKD) are limited beyond measures to reduce systemic blood pressures published maps and institutional affil- and avoid hyperfiltration injury. Recent studies in rodent models indicate a remarkable iations. potential for mesenchymal stromal/stem cell-based therapies to favorably influence kidney allograft survival and recovery from acute kidney injury (AKI) and some forms of chronic kidney disease including diabetes and lupus nephritis, as has been reviewed [1]. The unique features of kidney microcirculation render the kidney particularly susceptible to Copyright: © 2021 by the authors. ischemic injury. How these data translate to human disorders remains poorly understood. Licensee MDPI, Basel, Switzerland. The aim of this review was to summarize the initial studies utilizing autologous MSC in This article is an open access article human subjects with ischemic nephropathy due to atherosclerotic vascular disease of the distributed under the terms and kidney. conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Cells 2021, 10, 765. https://doi.org/10.3390/cells10040765 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 15 Cells 2021, 10, 765 2 of 15 2. Renovascular Disease and Microvascular Injury Large vessel atherosclerotic renovascular disease (ARVD) is highly prevalent in older 2. Renovascular Disease and Microvascular Injury populations as a result of renal artery stenosis. This process develops gradually over many years Largeand is vesselaccelerated atherosclerotic by dyslipidemia, renovascular diabetes, disease hypertension, (ARVD) is highlysmoking prevalent and other in olderath- populations as a result of renal artery stenosis. This process develops gradually over erosclerotic risk factors. When lumen occlusion reaches a “critical” threshold, usually many years and is accelerated by dyslipidemia, diabetes, hypertension, smoking and other identified as more than 70–80% vessel occlusion, distal perfusion pressures and blood atherosclerotic risk factors. When lumen occlusion reaches a “critical” threshold, usually flows begin to fall measurably [2] (Figure 1). Rich literature on hypertension has linked identified as more than 70–80% vessel occlusion, distal perfusion pressures and blood loss of renal perfusion pressure with activation of multiple pressor pathways that produce flows begin to fall measurably [2] (Figure1). Rich literature on hypertension has linked and accelerate renovascular hypertension, including the renin–angiotensin aldosterone loss of renal perfusion pressure with activation of multiple pressor pathways that produce system [3]. While main renal artery revascularization previously was the primary means and accelerate renovascular hypertension, including the renin–angiotensin aldosterone of treating ARVD and renovascular hypertension, advances in antihypertensive drug system [3]. While main renal artery revascularization previously was the primary means of therapy in recent years have made optimized medical therapy the mainstay of manage- treating ARVD and renovascular hypertension, advances in antihypertensive drug therapy ment and can often achieve target blood pressures successfully. One consequence of suc- in recent years have made optimized medical therapy the mainstay of management and can cessful medical therapy has been a marked reduction in revascularization procedures. As often achieve target blood pressures successfully. One consequence of successful medical atherapy result, many has been individuals a marked now reduction are subjected in revascularization to reduced renal procedures. blood flow As and a result, distal many per- fusionindividuals pressures now for are prolonged subjected periods to reduced of times, renal bloodsometimes flow many and distal years. perfusion Sustained pressures loss of bloodfor prolonged flow and periods subsequent of times, loss sometimes of kidney many function years. have Sustained been designated loss of blood “ischemic flow and nephropathy.”subsequent loss of kidney function have been designated “ischemic nephropathy.” Figure 1. Figure 1. LargeLarge vessel vessel atherosclerotic renovascularrenovascular disease disease (ARVD) (ARVD) produces produces reduction reduction in bloodin blood flow flowand and loss loss of kidney of kidney volume volume and and glomerular glomerular filtration filtration rate rate (GFR). (GFR). These Thes changese changes eventually eventually induce in- ducewidening widening tissue tissue hypoxia. hypoxia. The The upper upper panel panel depicts depicts angiograms angiograms with with moderate moderate stenoses stenoses (left ()left and) andmore more severe severe occlusion occlusion (right (right) associated) associated with with reduced reduced kidney kidney volumevolume and declining declining glomerular glomerular filtrationfiltration rate rate (GFR). (GFR). The The bottom panel imagesimages depictdepict thethe increasing increasing intensity intensity of of tissue tissue deoxygenation deoxygena- tionasmeasured as measured by blood-oxygen-level-dependentby blood-oxygen-level-dependent (BOLD) (BOLD) MRI MRI in post-stenotic in post-steno kidneystic kidneys associated associated with withdecreasing decreasing GFR. GFR. G1: theG1: highestthe highest quartile quartile of 48 of subjects, 48 subjects, GFR: GFR: 51 ± 5112; ± G2:12; G2: middle middle two two quartiles, quartiles, GFR: GFR: 25 ± 6 mL/min; G3: the lowest quartile, GFR: 8 ± 3 mL/min. Data from [4] with permission. 25 ± 6 mL/min; G3: the lowest quartile, GFR: 8 ± 3 mL/min. Data from [4] with permission. Such Such changes characterize ischemic nephropathy and are associated with progressive inflammation changes characterize ischemic nephropathy and are associated with progressive inflammation and and tissue damage (see text). tissue damage (see text). Importantly,Importantly, large large vessel vessel ARVD ARVD leads leads to to di distalstal microvascular microvascular disturbances disturbances with with loss loss ofof medium medium and and small small diameter diameter vessels vessels and and ultimately ultimately with with parenchymal parenchymal fibrosis fibrosis [5,6] [5,6 ] (Figure(Figure 2).2). Loss Loss of of renal renal microvasculature microvasculature integrity integrity has hasbeen been identified identified as a common as a common final pathwayfinal pathway for other for kidney other kidney diseases diseases as well, as including well, including diabetic diabetic nephropathy, nephropathy, obesity obesity and nephrosclerosisand nephrosclerosis [7]. While [7]. While ARVD ARVD initially initially manifests manifests as asa hemodynamic a hemodynamic disorder disorder