AIM: To assess the impact of autologous cell therapy on critical limb ischaemia in people with diabetes and diabetic kidney disease. METHODS: A total of 59 people with diabetes (type 1 or type 2) and critical limb ischaemia, persisting after standard revascularization, were treated with cell therapy in our foot clinic over 7 years; this group comprised 17 people with and 42 without severe diabetic kidney disease. The control group had the same inclusion criteria, but was treated conservatively and comprised 21 people with and 23 without severe diabetic kidney disease. Severe diabetic kidney disease was defined as chronic kidney disease stages 4-5 (GFR <30 ml/min/1.73 m²). Death and amputation-free survival were assessed during the 18-month follow-up; changes in transcutaneous oxygen pressure were evaluated at 6 and 12 months after cell therapy. RESULTS: Transcutaneous oxygen pressure increased significantly in both groups receiving cell therapy compared to baseline (both P<0.01); no significant change in either of the control groups was observed. The cell therapy severe diabetic kidney disease group had a significantly longer amputation-free survival time compared to the severe diabetic kidney disease control group (hazard ratio 0.36, 95% CI 0.14-0.91; P=0.042); there was no difference in the non-severe diabetic kidney disease groups. The severe diabetic kidney disease control group had a tendency to have higher mortality (hazard ratio 2.82, 95% CI 0.81-9.80; P=0.062) than the non-severe diabetic kidney disease control group, but there was no difference between the severe diabetic kidney disease and non-severe diabetic kidney disease cell therapy groups. CONCLUSIONS: The present study shows that autologous cell therapy in people with severe diabetic kidney disease significantly improved critical limb ischaemia and lengthened amputation-free survival in comparison with conservative treatment; however, the treatment did not influence overall survival.

Diabetes Centre Tameside Hospital NHS Foundation Trust and University of Manchester Manchester UK

Institute for Clinical and Experimental Medicine Prague Czech Republic

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Agarwal S, Sud K, Shishehbor MH. Nationwide Trends of Hospital Admission and Outcomes Among Critical Limb Ischemia Patients: From 2003-2011. J Am Coll Cardiol 2016; 67: 1901-1913.

Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg 2007; 33(Suppl. 1): S1-75.

O'Hare AM, Glidden DV, Fox CS, Hsu CY. High prevalence of peripheral arterial disease in persons with renal insufficiency: results from the National Health and Nutrition Examination Survey 1999-2000. Circulation 2004; 109: 320-323.

Herzog CA, Asinger RW, Berger AK, Charytan DM, Diez J, Hart RG et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2011; 80: 572-586.

Rajagopalan S, Dellegrottaglie S, Furniss AL, Gillespie BW, Satayathum S, Lameire N et al. Peripheral arterial disease in patients with end-stage renal disease: observations from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Circulation 2006; 114: 1914-1922.

Biancari F, Arvela E, Korhonen M, Soderstrom M, Halmesmaki K, Alback A et al. End-stage renal disease and critical limb ischemia: a deadly combination? Scand J Surg 2012; 101: 138-143.

Bradbury AW, Adam DJ, Bell J, Forbes JF, Fowkes FG, Gillespie I et al. Multicentre randomised controlled trial of the clinical and cost-effectiveness of a bypass-surgery-first versus a balloon-angioplasty-first revascularisation strategy for severe limb ischaemia due to infrainguinal disease. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial. Health Technol Assess 2010; 14(1-210): iii-iv.

Jude EB, Oyibo SO, Chalmers N, Boulton AJ. Peripheral arterial disease in diabetic and nondiabetic patients: a comparison of severity and outcome. Diabetes Care 2001; 24: 1433-1437.

Collinson DJ, Donnelly R. Therapeutic angiogenesis in peripheral arterial disease: can biotechnology produce an effective collateral circulation? Eur J Vasc Endovasc Surg 2004; 28: 9-23.

Meloni M, Giurato L, Izzo V, Stefanini M, Pampana E, Gandini R et al. Long term outcomes of diabetic haemodialysis patients with critical limb ischemia and foot ulcer. Diabetes Res Clin Pract 2016; 116: 117-122.

Hankey GJ, Norman PE, Eikelboom JW. Medical treatment of peripheral arterial disease. JAMA 2006; 295: 547-553.

Dubsky M, Jirkovska A, Bem R, Fejfarova V, Pagacova L, Nemcova A et al. Comparison of the effect of stem cell therapy and percutaneous transluminal angioplasty on diabetic foot disease in patients with critical limb ischemia. Cytotherapy 2014; 16: 1733-1738.

Pignon B, Sevestre MA, Kanagaratnam L, Pernod G, Stephan D, Emmerich J et al. Autologous Bone Marrow Mononuclear Cell Implantation and Its Impact on the Outcome of Patients With Critical Limb Ischemia- Results of a Randomized, Double-Blind, Placebo-Controlled Trial. Circ J 2017; 81: 1713-1720.

Powell RJ, Marston WA, Berceli SA, Guzman R, Henry TD, Longcore AT et al. Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: the randomized, double-blind, placebo-controlled RESTORE-CLI trial. Mol Ther 2012; 20: 1280-1286.

Teraa M, Sprengers RW, Schutgens RE, Slaper-Cortenbach IC, van der Graaf Y, Algra A et al. Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo-controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial. Circulation 2015; 131: 851-860.

Schaper NC. Diabetic foot ulcer classification system for research purposes: a progress report on criteria for including patients in research studies. Diabetes Metab Res Rev 2004; 20(Suppl. 1): S90-95.

Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound classification system. The contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care 1998; 21: 855-859.

Dubsky M, Jirkovska A, Bem R, Fejfarova V, Pagacova L, Sixta B et al. Both autologous bone marrow mononuclear cell and peripheral blood progenitor cell therapies similarly improve ischaemia in patients with diabetic foot in comparison with control treatment. Diabetes Metab Res Rev 2013; 29: 369-376.

Sykova E, Homola A, Mazanec R, Lachmann H, Konradova SL, Kobylka P et al. Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant 2006; 15: 675-687.

Garimella PS, Balakrishnan P, Correa A, Poojary P, Annapureddy N, Chauhan K et al. Nationwide Trends in Hospital Outcomes and Utilization After Lower Limb Revascularization in Patients on Hemodialysis. JACC Cardiovasc Interv 2017; 10: 2101-2110.

Jaar BG, Astor BC, Berns JS, Powe NR. Predictors of amputation and survival following lower extremity revascularization in hemodialysis patients. Kidney Int 2004; 65: 613-620.

Madaric J, Klepanec A, Valachovicova M, Mistrik M, Bucova M, Olejarova I et al. Characteristics of responders to autologous bone marrow cell therapy for no-option critical limb ischemia. Stem Cell Res Ther 2016; 7: 116.

Pignon B, Sevestre MA, Kanagaratnam L, Pernod G, Stephan D, Emmerich J et al. Autologous Bone Marrow Mononuclear Cell Implantation and Its Impact on the Outcome of Patients With Critical Limb Ischemia- Results of a Randomized, Double-Blind, Placebo-Controlled Trial. Circ J 2017; 81: 1713-1720.

Dubsky M, Jirkovska A, Bem R, Nemcova A, Fejfarova V, Jude EB. Cell therapy of critical limb ischemia in diabetic patients - State of art. Diabetes Res Clin Pract 2017; 126: 263-271.

Rigato M, Monami M, Fadini GP. Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Nonrandomized, and Noncontrolled Studies. Circulation Res 2017; 120: 1326-1340.

Kawarada O, Yokoi Y, Higashimori A, Fujihara M, Sakamoto S, Ishihara M et al. Impact of end-stage renal disease in patients with critical limb ischaemia undergoing infrapopliteal intervention. EuroInterv 2014; 10: 753-760.

Nishio H, Minakata K, Kawaguchi A, Kumagai M, Ikeda T, Shimizu A et al. Transcutaneous oxygen pressure as a surrogate index of lower limb amputation. Int Angiol 2016; 35: 565-572.

Attanasio S, Snell J. Therapeutic angiogenesis in the management of critical limb ischemia: current concepts and review. Cardiol Rev 2009; 17: 115-120.

Fadini GP, Agostini C, Avogaro A. Autologous stem cell therapy for peripheral arterial disease meta-analysis and systematic review of the literature. Atherosclerosis 2010; 209: 10-17.

Lawall H, Bramlage P, Amann B. Stem cell and progenitor cell therapy in peripheral artery disease. A critical appraisal. Thromb Haemost 2010; 103: 696-709.

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