{'fraction_non_alphanumeric': 0.026248164464023494, 'fraction_numerical': 0.009911894273127754, 'mean_word_length': 5.306712962962963, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Immune tolerance with combined allogeneic haplo‐identical haematopoietic stem cell transplant and renal transplant

Early studies demonstrated that establishment of haematopoietic stem cell (HSC) grafts in minor antigen-histocompatible mice would result in the development of tolerance to transplantation of non-HSC tissues from the same donor. This has led to exploration of HSC transplantation as a mechanism to facilitate solid-organ transplantation. In contrast to other types of transplantation, recipients of HSC transplants can develop tolerance, resulting in a chimaeric state not requiring long-term use of immunosuppressive drugs (IsD). The lack of suitable donors and the regimenrelated toxicities of the HSC transplant procedures has precluded wide-spread adoption of this as a technique to establish tolerance. The goals are to expand the pool of suitable HSC donors and to decrease toxicities of conditioning regimens and from acute and/or chronic graft-versus-host disease (GVHD) while maintaining chimaerism. Herein, we report a successful case of tolerance to a renal allograft following a HSC transplant from the same haplo-identical donor in the treatment of a patient with multiple myeloma (MM) who presented with end stage renal disease. We present the case of a 25-year-old Caucasian male presented to the emergency room with complaints of fatigue, nausea, and intermittent vomiting for six months (Table I). His creatinine was 11 1 mg/dl with a severely reduced estimated glomerular filtration rate (eGFR) which required haemodialysis. His evaluation resulted in the diagnosis of kappa light chain (Bence–Jones) MM, International Staging System 3; renal biopsy demonstrated light chain cast nephropathy. He was started on haemodialysis. He subsequently was initiated on renally adjusted chemotherapy with bortezomib, lenalidomide and dexamethasone (VRd). He responded well to chemotherapy, achieving a partial remission after three cycles with improvement in his serum free kappa light chains from 2,570 to 63 mg/l. Considering his age, response to chemotherapy, and end stage renal disease (ESRD) requiring haemodialysis, the patient was offered allogeneic HSC transplantation to be followed by a future kidney transplant from the same donor. He lacked human leukocyte antigen (HLA)-matched sibling donors. He underwent a haplo-identical transplant from his father, ABO bidirectional incompatible (donor B-positive, recipient A-positive). He received an immunosuppressive conditioning regimen with fludarabine, cyclophosphamide and low-dose total body irradiation, followed by a haplo-identical allogenic bone marrow transplant. The post-transplant IsD consisted of cyclophosphamide 50 mg/kg (days 3 and 4), followed by tacrolimus and mycophenolate mofetil. The mycophenolate mofetil was discontinued at day (d) +30. He achieved 100% donor CD3 cell chimaerism on d +28 and this was maintained at one year post transplant. For persistent cytopenias attributed to poor graft function after a negative viral workup, he received a CD34 cell-enriched stem cell boost from his donor in May 2013. He received approximately 5 9 10 CD34 cells/kg after failing treatments with corticosteroids, immunoglobulin G (IgG), and eltrombopag. His counts recovered approximately threeweeks after the stem cell boost. He did not develop acute GVHD; however, he did experience limited chronic GVHD of his eyes and mouth 14–18 weeks after HSC transplant for which he was started on low-dose prednisone and topical steroids. He continued to have mild chronic GVHD (rash on his hands and dry eyes) for which he received several courses of low-dose steroids over the ensuing months while remaining on tacrolimus. He achieved stringent complete remission of MM. Two years after HSC, he received a renal transplant from his father. He continued to take tacrolimus post transplant due to limited chronic GVHD at the time of the renal allograft, which was slowly tapered off and completely discontinued at nine months after renal transplantation. Six years after his renal transplant, his serum creatinine is 1 32 mg/dl and MM remains in complete remission. Figure 1 depicts his treatment timeline as well as response to treatment. A review of the literature shows that HSC transplantation plays an important role in solid-organ transplant tolerance. Compelling data from preclinical studies provide evidence of the impact of microand macrochimaerism to induce transplant tolerance. Several small clinical trials and case series were done to show the importance of tolerance in solid-organ transplantation, though this remains an important question in the literature. A few of these important studies are outlined below (Table II). Kawai et al. demonstrate a good response in combined HLA-mismatch renal transplant and bone marrow transplant without post-transplant immunosuppression. They used a non-myeloablative conditioning regimen protocol. Results demonstrated transient chimaerism in all 10 patients, with seven patients successfully discontinuing IsD for >4 years (longest period off IsD was 11 4 years). Three of these patients resumed IsD after 5–8 years in response to recurrence of disease or chronic antibody-mediated rejection, and finally three allografts failed as a result of thrombotic microangiopathy or rejection. Spitzer et al. studied 10 patients in whom they performed HLA-matched combined kidney and HSC transplant correspondence