Publications by authors named "Phillip Ruiz"

176 Publications

Long-term Persistence of Allosensitization After Islet Allograft Failure.

Transplantation 2021 Jan 20. Epub 2021 Jan 20.

Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL, USA. 1450 NW 10th Avenue, Miami, FL 33136, USA. Division of Biostatistics, Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA. 1450 NW 10th Avenue, Miami, FL 33136, USA. Department of Surgery and Pathology, University of Miami Miller School of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA. 1450 NW 10th Avenue, Miami, FL 33136, USA. Division of Cellular Transplantation, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA. 1450 NW 10th Avenue, Miami, FL 33136, USA.

Background: Allosensitization has been reported after discontinuation of immunosuppression following graft failure in islet transplantation (ITx) recipients, though duration of its persistence is unknown.

Methods: We evaluated 35 patients with type 1 diabetes who received ITx, including 17 who developed graft failure (ITx alone, n=13; ITx plus bone marrow-derived hematopoietic stem cells, n=4) and 18 with persistent graft function. Panel reactive antibody (PRA) was measured yearly for the duration of graft function within 1 year after graft failure at enrollment and yearly thereafter.

Results: In ITx alone graft failure patients, 61% (8/13) were PRA-positive at 6 years postgraft failure, and 46% (6/13) developed donor-specific anti-HLA antibodies (DSA to 2 ± 1 donors) during follow up. The degree of sensitization was variable (cPRA ranging between 22% and 100% after graft failure). Allosensitization persisted for 7 to 15 years. Three subjects (3/13) were not allosensitized. In ITx plus bone marrow-derived hematopoietic stem cell recipients, cPRA-positivity (88% to 98%) and DSA-positivity persisted for 15 years in 75% (3/4) of subjects.

Conclusions: Allosensitization was minimal while subjects remained on immunosuppression but after discontinuation of immunosuppressive therapy the majority of subjects (77%) became allosensitized with persistence of PRA positivity for up to 15 years. Persistence of allosensitization in this patient population is of clinical importance as it may result in longer transplant waiting-list times for identification of a suitable donor in case of requiring a subsequent transplant.
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http://dx.doi.org/10.1097/TP.0000000000003635DOI Listing
January 2021

Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial.

Stem Cells Transl Med 2021 05 5;10(5):660-673. Epub 2021 Jan 5.

Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, Florida, USA.

Acute respiratory distress syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in COVID-19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC-MSC) infusions in subjects with COVID-19 ARDS. A double-blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty-four subjects were randomized 1:1 to either UC-MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC-MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 10 UC-MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion-associated AEs. No serious adverse events (SAEs) were observed related to UC-MSC infusions. UC-MSC infusions in COVID-19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC-MSC-treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P = .015), SAE-free survival (P = .008), and time to recovery (P = .03). UC-MSC infusions are safe and could be beneficial in treating subjects with COVID-19 ARDS.
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http://dx.doi.org/10.1002/sctm.20-0472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046040PMC
May 2021

Direct Actions of AT (Type 1 Angiotensin) Receptors in Cardiomyocytes Do Not Contribute to Cardiac Hypertrophy.

Hypertension 2021 Feb 4;77(2):393-404. Epub 2021 Jan 4.

From the Division of Nephrology, Department of Medicine (M.A.S., F.R., E.D., R.R., T.H., L.B., J.S., S.D.C., T.M.C.), Duke University School of Medicine, Durham, NC.

Activation of AT (type 1 Ang) receptors stimulates cardiomyocyte hypertrophy in vitro. Accordingly, it has been suggested that regression of cardiac hypertrophy associated with renin-Ang system blockade is due to inhibition of cellular actions of Ang II in the heart, above and beyond their effects to reduce pressure overload. We generated 2 distinct mouse lines with cell-specific deletion of AT receptors, from cardiomyocytes. In the first line (C-SMKO), elimination of AT receptors was achieved using a heterologous transgene under control of the promoter, which expresses in cells of smooth muscle lineage including cardiomyocytes and vascular smooth muscle cells of conduit but not resistance vessels. The second line (R-SMKO) utilized a transgene knocked-in to the locus, which drives expression in cardiac myocytes and vascular smooth muscle cells in both conduit and resistance arteries. Thus, although both groups lack AT receptors in the cardiomyocytes, they are distinguished by presence (C-SMKO) or absence (R-SMKO) of peripheral vascular responses to Ang II. Similar to wild-types, chronic Ang II infusion caused hypertension and cardiac hypertrophy in C-SMKO mice, whereas both hypertension and cardiac hypertrophy were reduced in R-SMKOs. Thus, despite the absence of AT receptors in cardiomyocytes, C-SMKOs develop robust cardiac hypertrophy. By contrast, R-SMKOs developed identical levels of hypertrophy in response to pressure overload-induced by transverse aortic banding. Our findings suggest that direct activation of AT receptors in cardiac myocytes has minimal influence on cardiac hypertrophy induced by renin-Ang system activation or pressure overload.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803456PMC
February 2021

Clostridium difficile infection mimics intestinal acute cellular rejection in pediatric multivisceral transplant-A case series.

Pediatr Transplant 2020 02 9;24(1):e13621. Epub 2019 Dec 9.

Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Miami, Miami, FL, USA.

Clostridium difficile infection (CDI) is the most common health care-associated infection in the United States. Thirty-nine percent of intestinal transplant recipients may develop CDI. Induction of rejection has been reported as a rare event. To our knowledge, this will be the second report of an association between CDI and rejection in the literature. We describe our experience with four pediatric MVT recipients, three of whom on treatment of their CDI alone had resolution of biopsy findings of intestinal ACR. Our patients were males aged 2-5 years old who had their first CDI post-MVT occurring from 2 months to 15 months post-transplant. All first episodes of CDI were treated with a 10-14 day course of metronidazole with one additionally receiving vancomycin. All four recipients had recurrent CDI, and two recipients had septic shock as a manifestation of their CDI. Three recipients had biopsies showing mild rejection during episodes of CDI, and treatment of the CDI resulted in resolution of biopsy findings of rejection. Our case series suggests CDI may mimic ACR on intestinal biopsy. Treatment of rejection during active CDI carries the risk of over-suppression and worsening of CDI. Our experience has taught us that surveillance endoscopy for rejection may be deceiving during an active CDI, and if mild acute rejection is noted during active CDI, treatment of rejection can be safely delayed and potentially avoided.
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http://dx.doi.org/10.1111/petr.13621DOI Listing
February 2020

Deletion Exaggerates Kidney Injury in Experimental Mouse Models and Confers the Protective Effect of Cruciferous Vegetables in Mice and Humans.

J Am Soc Nephrol 2020 01 14;31(1):102-116. Epub 2019 Nov 14.

Division of Nephrology, Department of Medicine and

Background: encodes glutathione S-transferase -1 (GSTM1), which belongs to a superfamily of phase 2 antioxidant enzymes. The highly prevalent deletion variant is associated with kidney disease progression in human cohorts: the African American Study of Kidney Disease and Hypertension and the Atherosclerosis Risk in Communities (ARIC) Study.

Methods: We generated a knockout mouse line to study its role in a CKD model (involving subtotal nephrectomy) and a hypertension model (induced by angiotensin II). We examined the effect of intake of cruciferous vegetables and genotypes on kidney disease in mice as well as in human ARIC study participants. We also examined the importance of superoxide in the mediating pathways and of hematopoietic on renal inflammation.

Results: knockout mice displayed increased oxidative stress, kidney injury, and inflammation in both models. The central mechanism for kidney injury is likely mediated by oxidative stress, because treatment with Tempol, an superoxide dismutase mimetic, rescued kidney injury in knockout mice without lowering BP. Bone marrow crosstransplantation revealed that deletion in the parenchyma, and not in bone marrow-derived cells, drives renal inflammation. Furthermore, supplementation with cruciferous broccoli powder rich in the precursor to antioxidant-activating sulforaphane significantly ameliorated kidney injury in knockout, but not wild-type mice. Similarly, among humans (ARIC study participants), high consumption of cruciferous vegetables was associated with fewer kidney failure events compared with low consumption, but this association was observed primarily in participants homozygous for the deletion variant.

Conclusions: Our data support a role for the GSTM1 enzyme in the modulation of oxidative stress, inflammation, and protective metabolites in CKD.
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http://dx.doi.org/10.1681/ASN.2019050449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935006PMC
January 2020

Computed Tomography-Guided Kidney Transplant Biopsy Outcomes: A Single-Center Experience.

Exp Clin Transplant 2020 11 16;18(6):676-681. Epub 2019 Sep 16.

From the Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.

Objectives: Percutaneous kidney transplant biopsy is typically performed using ultrasonographic guidance; computed tomography is an alternative modality used to obtain kidney allografttissuewhen ultrasonographyguided percutaneous kidney transplant biopsy is technically challenging. Studies examining postbiopsy outcomes in kidney transplant patients using a computed tomography-guided approach are scarce. Our goal was to reportthe incidence of nonsevere and severe complications in computed tomographyguided percutaneous kidney transplant biopsies and the potential risk factors.

Materials And Methods: We retrospectively reviewed computed tomography-guided percutaneous kidney transplant biopsies in patients undergoing work-up for kidney allograft rejection between 2013 and 2017. Demographics, comorbidities, laboratory data, history of antiplatelet and/or anticoagulant use, and complications were assessed.

Results: : During the study period, 28 patients underwent computed tomography-guided percutaneous kidney transplant biopsies; mean age was 57.5 ± 15.5 years, and 12 (43%)werewomen.Twenty-three patients (82%) were obese, with a body mass index greater than 30 kg/m². Our cohort of kidney transplant recipients included 21 (75%) from deceased donors and 7 (25%) from living-related donors. At the time of biopsy, 6 patients (21%) had elevated blood pressure (defined as > 160/90 mm Hg). One patient had severe complications, which included a significant decrease in hemoglobin requiring transfusion and a perinephric hematoma with worsening renal function. This was a morbidly obese patient whose blood pressure was elevated at the time of biopsy with a platelet count of 93 × 10³/mm³ and international normalized ratio of 1.21.

Conclusions: A computed tomography-guided percutaneous kidney transplant biopsy is a safe and effective alternative to obtain kidney tissue in the obese population and is associated with low rates of complications. In this study, we highlighted the need to achieve adequate blood pressure control and assess bleeding risk factors, such as platelet count and international normalized ratio, prior to biopsy.
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http://dx.doi.org/10.6002/ect.2019.0111DOI Listing
November 2020

Quality control project of NGS HLA genotyping for the 17th International HLA and Immunogenetics Workshop.

Hum Immunol 2019 Apr 6;80(4):228-236. Epub 2019 Feb 6.

Kashi Clinical Laboratories, Inc., Portland, OR, USA.

The 17th International HLA and Immunogenetics Workshop (IHIW) organizers conducted a Pilot Study (PS) in which 13 laboratories (15 groups) participated to assess the performance of the various sequencing library preparation protocols, NGS platforms and software in use prior to the workshop. The organizers sent 50 cell lines to each of the 15 groups, scored the 15 independently generated sets of NGS HLA genotyping data, and generated "consensus" HLA genotypes for each of the 50 cell lines. Proficiency Testing (PT) was subsequently organized using four sets of 24 cell lines, selected from 48 of 50 PS cell lines, to validate the quality of NGS HLA typing data from the 34 participating IHIW laboratories. Completion of the PT program with a minimum score of 95% concordance at the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 loci satisfied the requirements to submit NGS HLA typing data for the 17th IHIW projects. Together, these PS and PT efforts constituted the 17th IHIW Quality Control project. Overall PT concordance rates for HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-DRB3, HLA-DRB4 and HLA-DRB5 were 98.1%, 97.0% and 98.1%, 99.0%, 98.6%, 98.8%, 97.6%, 96.0%, 99.1%, 90.0% and 91.7%, respectively. Across all loci, the majority of the discordance was due to allele dropout. The high cost of NGS HLA genotyping per experiment likely prevented the retyping of initially failed HLA loci. Despite the high HLA genotype concordance rates of the software, there remains room for improvement in the assembly of more accurate consensus DNA sequences by NGS HLA genotyping software.
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http://dx.doi.org/10.1016/j.humimm.2019.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446570PMC
April 2019

Steroid-Free Immune Suppression Impairs Glycemic Control in a Healthy Cynomolgus Monkey.

Cell Transplant 2019 03 24;28(3):262-268. Epub 2019 Jan 24.

1 Diabetes Research Institute, Miller School of Medicine, University of Miami, FL, USA.

The need for chronic immune suppression (IS) is one of the hurdles precluding widespread use of islet cell transplantation to restore glycemic control in patients with type 1 diabetes. We report the case of a healthy nonhuman primate (NHP) treated on and off for over 2.5 years with steroid-free IS, consisting of daclizumab induction and maintenance therapy with rapamycin and low dose tacrolimus. Treatment for 1 year resulted in a striking destabilization of glycemic control, with concomitant decreases in fasting c-peptide and insulin levels. Although these changes gradually reversed during a wash out period of 7 months, retreatment with the same therapy led to accelerated deterioration in glycemic control. Intravenous glucose tolerance and percentage of glycosylated hemoglobin testing further supported a dramatic effect on metabolic control. IS also led to decreases in weight during treatment. Histological evaluation of the pancreas revealed islet hyperplasia, with varying sizes and endocrine cell ratios that differed from normal islet composition, and parenchymal infiltration with adipose tissue. These deleterious effects of IS on glucose control and endocrine components in the native pancreas of a healthy NHP suggest that IS agents commonly utilized for islet transplantation may contribute to failure in islet allograft function in long-term transplant patients.
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http://dx.doi.org/10.1177/0963689718823505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425109PMC
March 2019

Stable perfluorocarbon emulsions for the delivery of halogenated ether anesthetics.

Colloids Surf B Biointerfaces 2018 Dec 12;172:797-805. Epub 2018 Sep 12.

Cell Transplant Center, Diabetes Research Institute, University of Miami, Miami, FL, United States; DeWitt Daughtry Family Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, United States. Electronic address:

Background: Research into injectable volatile anesthetics has been ongoing for approximately 40 years, with limited success, in an attempt to address the deficiencies of inhalational anesthesia. The purpose of this work was to formulate and optimize volatile anesthetic carrier emulsions based on our prior work in perfluorocarbon emulsions.

Methods: Perfluorocarbons were screened for their volatilty and emulsion stability. Optimal anesthetic emulsions were manufactured by high pressure homogenization of a select, clinically relevant perfluorocarbon, isoflurane and a surfactant-containing aqueous phase. Longitudinal particle size, polydispersity and isoflurane content analysis was performed. Observational studies of in vivo efficacy and safety were performed in 225-300 g Lewis Rats (n = 34) with blood chemistry and post study tissue pathology analysis.

Results: Emulsion particle size and isolflurane content in select emulsions were stable at room temperature greater than 300 days. This stability was depedent on perfluorocarbon molecular weight and boiling point. in vivo, emulsions demonstrated a rapid onset and offset. Variability in onset metrics (loss of righting reflex, pain reflexes and time to recovery) was less than 40% amongst individual emulsion preparations (n = 9) utilized in induction trials. No adverse effects due to the intravenous administration of emulsions were observed in blood chemistry results or post-study pathological examination.

Conclusions: These formulations showed stability, safety and efficacy. In addition to induction and general anesthesia, these emulsions could have utility in global health or in military applications where equipment and resources are limited.
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http://dx.doi.org/10.1016/j.colsurfb.2018.09.024DOI Listing
December 2018

Cardioprotective Effects of Paricalcitol Alone and in Combination With FGF23 Receptor Inhibition in Chronic Renal Failure: Experimental and Clinical Studies.

Am J Hypertens 2019 01;32(1):34-44

Division of Pediatric Nephrology, University of Miami Miller School of Medicine, Miami, Florida, USA.

Background: In uremic animals, vitamin D receptor (VDR) agonists like paricalcitol (Pc) attenuate cardiac hypertrophy, but this effect has not been replicated consistently in humans with chronic kidney disease. Elevated fibroblast growth factor 23 (FGF23) levels cause cardiac hypertrophy with activation of the myocardial calcineurin/nuclear factor of activated T cell (NFAT) axis and may antagonize the cardioprotective effects of VDR agonist therapy. We hypothesized that the effectiveness of Pc may depend on the prevailing circulating levels of FGF23 and could be potentiated by the combined administration of a pan-FGF23 receptor (FGFR) blocker agent (PD173074).

Methods: In rats with 5/6 nephrectomy treated with Pc or PD173074 or both agents concurrently, myocardial mRNA expression of renin-angiotensin system, VDR, FGFR4, and calcineurin/NFAT target genes was determined. In adolescents on hemodialysis, we analyzed sequential echocardiograms, blood pressures and serial FGF23 measurements, and their relations to the cumulative administered dose of parenteral Pc.

Results: The ratio of Pc dose/plasma levels of FGF23 correlated inversely (P < 0.005) with the cardiac mass in uremic rats and in hemodialysis patients, independently of hypertension. Despite persistently elevated FGF23 levels and myocardial FGFR4 activation, Pc suppressed upregulated myocardial calcineurin/NFAT target genes, and the effects were amplified by coadministration of PD173074.

Conclusions: The beneficial effects of Pc on uremic cardiac hypertrophy are counterbalanced by the increased FGF23 levels. Blockade of FGF23-mediated signaling increased the Pc-induced suppression of the myocardial calcineurin/NFAT system. Higher doses of Pc should be considered in the treatment of patients with uremic cardiomyopathy.
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http://dx.doi.org/10.1093/ajh/hpy154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284753PMC
January 2019

Kidney-derived c-kit progenitor/stem cells contribute to podocyte recovery in a model of acute proteinuria.

Sci Rep 2018 10 3;8(1):14723. Epub 2018 Oct 3.

Interdisciplinary Stem Cell Institute, Leonard M Miller School of Medicine University of Miami, Miami, 33136, Florida, USA.

Kidney-derived c-kit cells exhibit progenitor/stem cell properties and can regenerate epithelial tubular cells following ischemia-reperfusion injury in rats. We therefore investigated whether c-kit progenitor/stem cells contribute to podocyte repair in a rat model of acute proteinuria induced by puromycin aminonucleoside (PAN), the experimental prototype of human minimal change disease and early stages of focal and segmental glomerulosclerosis. We found that c-kit progenitor/stem cells accelerated kidney recovery by improving foot process effacement (foot process width was lower in c-kit group vs saline treated animals, P = 0.03). In particular, these cells engrafted in small quantity into tubules, vessels, and glomeruli, where they occasionally differentiated into podocyte-like cells. This effect was related to an up regulation of α-Actinin-4 and mTORC2-Rictor pathway. Activation of autophagy by c-kit progenitor/stem cells also contributed to kidney regeneration and intracellular homeostasis (autophagosomes and autophagolysosomes number and LC3A/B-I and LC3A/B-II expression were higher in the c-kit group vs saline treated animals, P = 0.0031 and P = 0.0009, respectively). Taken together, our findings suggest that kidney-derived c-kit progenitor/stem cells exert reparative effects on glomerular disease processes through paracrine effects, to a lesser extent differentiation into podocyte-like cells and contribution to maintenance of podocyte cytoskeleton after injury. These findings have clinical implications for cell therapy of glomerular pathobiology.
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http://dx.doi.org/10.1038/s41598-018-33082-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170432PMC
October 2018

Antibody-mediated rejection implies a poor prognosis in kidney transplantation: Results from a single center.

Clin Transplant 2018 10 23;32(10):e13392. Epub 2018 Sep 23.

The Lillian Jean Kaplan Renal Transplant Center, Miami Transplant Institute, Miami, Florida.

Two major barriers to achieving long-term graft survival include patient nonadherence in taking the prescribed immunosuppression and antibody-mediated rejection(AMR). We were therefore interested in determining the prognostic impact of developing an AMR component to rejection in a prospective randomized trial of 200 kidney transplant recipients who received dual induction therapy (rATG combined with either daclizumab or alemtuzumab) and planned early corticosteroid withdrawal. With a median follow-up of 96 months post-transplant, 40/200 developed a first BPAR; 9/200 developed a second BPAR. An AMR component to rejection was observed in 70% (28/40) of cases. Percentages having C4d deposition, histopathologic evidence of acute AMR, and presence of DSAs/non-DSAs at the time of first developing the AMR component were 64.3% (18/28), 60.7% (17/28), and 53.6% (15/28), respectively. Development of an AMR component was associated with a significantly higher death-censored graft failure rate following rejection in comparison with the patient state of experiencing BPAR but without developing an AMR component (estimated hazard ratio: 4.52, P = 0.01). The observed percentage developing graft failure following development of an AMR component was 53.6% (15/28) vs only 20.0%(3/15) if it was not observed. Actuarial death-censored graft survival at 60 months following development of an AMR component was 28.3 ± 11.9%. In summary, it appears that more effective AMR prevention/treatment strategies are warranted.
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http://dx.doi.org/10.1111/ctr.13392DOI Listing
October 2018

Podocytes exhibit a specialized protein quality control employing derlin-2 in kidney disease.

Am J Physiol Renal Physiol 2018 03 22;314(3):F471-F482. Epub 2017 Nov 22.

Department of Internal Medicine, Rush University Medical Center , Chicago, Illinois.

Podocytes are terminally differentiated cells of the kidney filtration barrier with a limited proliferative capacity and are the primary glomerular target for various sources of cellular stress. Accordingly, it is particularly important for podocytes to cope with stress efficiently to circumvent cell death and avoid compromising renal function. Improperly folded proteins within the endoplasmic reticulum (ER) are associated with increased cellular injury and cell death. To relieve ER stress, protein quality control mechanisms like ER-associated degradation (ERAD) are initiated. Derlin-2 is an important dislocation channel component in the ERAD pathway, having an indispensable role in clearing misfolded glycoproteins from the ER lumen. With studies linking ER stress to kidney disease, we investigated the role of derlin-2 in the susceptibility of podocytes to injury due to protein misfolding. We show that podocytes employ derlin-2 to mediate the ER quality control system to maintain cellular homeostasis in both mouse and human glomeruli. Patients with focal segmental glomerulosclerosis (FSGS) or diabetic nephropathy (DN) upregulate derlin-2 expression in response to glomerular injury, as do corresponding mouse models. In derlin-2-deficient podocytes, compensatory responses were lost under adriamycin (ADR)-induced ER dysfunction, and severe cellular injury ensued via a caspase-12-dependent pathway. Moreover, derlin-2 overexpression in vitro attenuated ADR-induced podocyte injury. Thus derlin-2 is part of a protein quality control mechanism that can rescue glomerular injury attributable to impaired protein folding pathways in the ER. Induction of derlin-2 expression in vivo may have applications in prevention and treatment of glomerular diseases.
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http://dx.doi.org/10.1152/ajprenal.00691.2016DOI Listing
March 2018

E1841K Mutation Augments Proteinuria and Podocyte Injury and Migration.

J Am Soc Nephrol 2018 01 9;29(1):155-167. Epub 2017 Oct 9.

Department of Medicine, University of Virginia, Charlottesville, Virginia;

Intronic variants of the gene that encodes the nonmuscle myosin heavy chain IIA are associated with diabetic nephropathy in European Americans and with sickle cell disease-associated nephropathy. However, the causal functional variants of have remained elusive. Rare missense mutations in cause macrothrombocytopenia and are occasionally associated with development of nephropathy. The E1841K mutation is among the common missense mutations and has been associated with nephropathy in some carriers. To determine the contribution of the E1841K mutation in kidney disease, we studied the effects of the E1841K mutation in mice subjected to high salt or angiotensin II (Ang II) as models of hypertension and in mice subjected to renal mass reduction as a model of CKD. Despite similar levels of BP among wild-type ( ) mice and mice heterozygous ( ) and homozygous ( ) for the mutation in each model, mice exhibited mildly increased albuminuria in response to high salt; severe albuminuria, nephrinuria, FSGS, and podocyte foot effacement in Ang II-induced hypertension; and early mortality in the renal mass reduction model. Treatment with candesartan during Ang II-induced hypertension attenuated kidney disease development in mice. , isolated primary podocytes from mice exhibited increased lamellipodia formation and reorganization of F-actin stress fibers. Wound healing assays revealed that podocytes had the lowest migration rate, followed by then podocytes. In conclusion, the E1841K variant alters podocyte cytoskeletal structure and renders podocytes more susceptible to injury after a damaging stimulus.
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http://dx.doi.org/10.1681/ASN.2015060707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748898PMC
January 2018

Meeting Report of the XIV International Small Bowel Transplant Symposium: Summary of Presentations, Workshops, and Debates From a Comprehensive Meeting on Intestinal Failure, Rehabilitation, and Transplantation, Buenos Aires, Argentina, June 10-13, 2015.

JPEN J Parenter Enteral Nutr 2018 02 12;42(2):477-489. Epub 2017 Dec 12.

Ronald Reagan UCLA Medical Center, Los Angeles, California, USA.

The 2015 meeting of the Intestinal Transplant Association was held in Buenos Aires, Argentina. This was the 14th International Small Bowel Transplant Symposium, and it was the first meeting organized as a joint venture of the Transplantation Society, the Intestinal Transplant Association, and the Argentinean Transplant Society (Sociedad Argentina de Trasplantes). Innovative aspects of the classic meeting format included workshops sessions, debates, and multicenter studies. This report highlights the most prominent scientific contributions and results of the first such symposium in a Latin American country.
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http://dx.doi.org/10.1177/0148607117701696DOI Listing
February 2018

Impact of antiretroviral therapy on clinical outcomes in HIV kidney transplant recipients: Review of 58 cases.

F1000Res 2016 21;5:2893. Epub 2016 Dec 21.

Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, USA.

Antiretroviral therapy (ART) poses challenging drug-drug interactions with immunosuppressant agents in transplant recipients.  We aimed to determine the impact of specific antiretroviral regimens in clinical outcomes of HIV kidney transplant recipients.  A single-center, retrospective cohort study was conducted at a large academic center. Subjects included 58 HIV to HIV adult, first-time kidney transplant patients. The main intervention was ART regimen used after transplantation.  The main outcomes assessed at one- and three-years were: patient survival, death-censored graft survival, and biopsy-proven acute rejection; we also assessed serious infections within the first six months post-transplant.  Patient and graft survival at three years were both 90% for the entire cohort. Patients receiving protease inhibitor (PI)-containing regimens had lower patient survival at one and three years than patients receiving PI-sparing regimens: 85% vs. 100% ( =0.06) and 82% vs. 100% ( =0.03), respectively. Patients who received PI-containing regimens had twelve times higher odds of death at 3 years compared to patients who were not exposed to PIs (odds ratio, 12.05; 95% confidence interval, 1.31-1602; =0.02).  Three-year death-censored graft survival was lower in patients receiving PI vs. patients on PI-sparing regimens (82 vs 100%, =0.03). Patients receiving integrase strand transfer inhibitors-containing regimens had higher 3-year graft survival. There were no differences in the incidence of acute rejection by ART regimen. Individuals receiving PIs had a higher incidence of serious infections compared to those on PI-sparing regimens (39 vs. 8%, =0.01).  PI-containing ART regimens are associated with adverse outcomes in HIV kidney transplant recipients.
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http://dx.doi.org/10.12688/f1000research.10414.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310378PMC
December 2016

Early primary graft failure after a pediatric heart transplant and successful rescue with plasmapheresis, immunoglobulins, and alemtuzumab.

Ann Pediatr Cardiol 2017 Jan-Apr;10(1):69-71

Department of Pediatrics, Division of Pediatric Cardiology, Holtz Children's Hospital/Jackson Health System, University of Miami Miller School of Medicine, Miami, FL, USA.

Early primary graft failure after pediatric orthotopic heart transplantation (OHT) has a high mortality rate and can occur due to several causes including but not limited to prolonged graft ischemia time, suboptimal preimplant myocardial preservation, hyperacute rejection, and maladaptation of the graft to the host's hemodynamic status. Mechanical circulatory support with either extracorporeal membrane oxygenation (ECMO) or ventricular assist device has been used for the rescue of primary graft failure in pediatric patients after heart transplant. Cardiac arrest before ECMO initiation in these patients is associated with adverse neurologic outcome although those surviving to hospital discharge generally have excellent long-term outcome. We report a case of early primary graft failure after OHT who required ECMO support and successful rescue with plasmapheresis, immunoglobulins, and alemtuzumab.
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http://dx.doi.org/10.4103/0974-2069.197063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241849PMC
February 2017

Randomized trial of rATg/Daclizumab vs. rATg/Alemtuzumab as dual induction therapy in renal transplantation: Results at 8years of follow-up.

Transpl Immunol 2017 02 22;40:42-50. Epub 2016 Nov 22.

The Lillian Jean Kaplan Renal Transplant Center and the Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address:

Our goal in using dual induction therapy is to bring the kidney transplant recipient closer (through more effectively timed lymphodepletion) to an optimally immunosuppressed state. Here, we report long-term results of a prospective randomized trial comparing (Group I,N=100) rATG/Dac (3 rATG, 2 Dac doses) vs. (Group II,N=100) rATG/Alemtuzumab(C1H) (1 dose each), using reduced tacrolimus dosing, EC-MPS, and early corticosteroid withdrawal. Lower EC-MPS dosing was targeted in Group II to avoid severe leukopenia. Median follow-up was 96mo post-transplant. There were no differences in 1st BPAR (including borderline) rates: 10/100 vs. 9/100 in Groups I and II during the first 12mo(P=0.54), and 20/100 vs. 20/100 throughout the study(P=0.90). Equally favorable renal function was maintained in both treatment arms(N.S.). While not significant, more patients in Group II experienced graft loss, 25/100 vs. 18/100 in Group I(P=0.23). Actuarial patient/graft survival at 96mo was 92%/83% vs. 85%/73% in Groups I and II(N.S.). DWFG-due-to-infection(N.S.), EC-MPS withholding-due-to-leukopenia during the first 2mo(P=0.03), and incidence of viral infections(P=0.09) were higher in Group II, whereas EC-MPS withholding-due-to-GI symptoms was higher in Group I(P=0.009). No other adverse event differences were observed. While long-term anti-rejection and renal function efficacy were demonstrated in both treatment arms, slight over-immunosuppression of Group II patients occurred.
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http://dx.doi.org/10.1016/j.trim.2016.11.004DOI Listing
February 2017

CD52-Negative NK Cells Are Abundant in the Liver and Less Susceptible to Alemtuzumab Treatment.

PLoS One 2016 25;11(8):e0161618. Epub 2016 Aug 25.

Division of Liver and Gastrointestinal Transplantation, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States of America.

Background: T-cell depleting strategies have become an integral part of immunosuppressive regimens in organ transplantation. Alemtuzumab is a humanized monoclonal antibody against CD52, a cell-surface antigen on several immune cells. It has been suggested that lymphocyte depletion increases the risk of serious infections. However, this has not been observed with short-term alemtuzumab treatment in an organ transplant setting. For induction therapy using alemtuzumab following liver transplantation, we found that T- and B-cell numbers declined rapidly after alemtuzumab therapy; however, the natural killer (NK) cell number was sustained. NK cells are important effectors of innate immunity. Since the effects of alemtuzumab on NK cell functions, especially those of liver NK cells, are unknown, this study aimed to investigate this in detail.

Methods: To assess the effect of alemtuzumab on NK cells, samples were obtained from 7 organ donors and examined by flow cytometry using Annexin V and propidium iodide. Phenotypical and functional differences within subsets of NK cells with different levels of CD52 expression were determined by flow cytometry and in vitro cytotoxicity assays.

Results: CD52 expression on NK cells was lower than that on other lymphocyte subsets. The liver contained a large number of CD52- NK cells compared with the peripheral blood. In vitro treatment of liver-derived NK cells with alemtuzumab did not result in cell death. In contrast, co-incubation with alemtuzumab induced cell death in peripheral blood mononuclear cells and non-NK cells in the liver. Furthermore, CD52- liver NK cells were more cytotoxic and produced more IFN-γ than CD52+ NK cells after cytokine activation.

Conclusion: The liver contains a large number of CD52- NK cells. These cells are refractory to alemtuzumab and have robust activity. These findings indicate that CD52- NK cells persist and could protect against infection after alemtuzumab-based lymphocyte depletion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161618PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999148PMC
August 2017

Influence of immune activation on the risk of allograft rejection in human immunodeficiency virus-infected kidney transplant recipients.

Transpl Immunol 2016 09 11;38:40-43. Epub 2016 Jun 11.

Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, USA.

Background: HIV infection is associated with high rates of acute rejection following kidney transplantation. The underlying mechanisms for such predisposition are incompletely understood. Pathological immune activation is a hallmark of chronic HIV infection that persists despite effective antiretroviral therapy. We hypothesized that the baseline levels of T cell activation in HIV(+) candidates would correlate with their risk of acute rejection following kidney transplantation.

Methods: Single-center retrospective cohort analysis of HIV(+) adult kidney transplants performed between October 2006 and September 2013. The frequency of CD3(+)HLA-DR(+) cells measured by flow cytometry served as a surrogate marker of immune activation. Patients were categorized into tertiles of activation, and the rates of biopsy-proven acute rejection were compared across groups.

Results: (1) Compared to matched HIV(-) controls, the baseline number of CD3(+)HLA-DR(+) cells was higher in HIV(+) kidney transplant candidates. (2) Abnormally high levels of activation did not decrease with transplant-associated immunosuppression. (3) Patients categorized within the lower and middle CD3(+)HLA-DR(+) tertiles had higher probability of rejection during the first 3years post-transplant compared to those in the higher activation tertile (36.9% vs. 0%; log-rank P=0.04).

Conclusions: Pathological immune activation in HIV(+) transplant candidates does not explain their increased susceptibility to allograft rejection. Paradoxically, those with the highest levels of immune activation seem to be less prone to rejection.
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http://dx.doi.org/10.1016/j.trim.2016.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025357PMC
September 2016

Abdominal transplantation for unresectable tumors in children: the zooming out principle.

Pediatr Surg Int 2016 Apr 28;32(4):337-46. Epub 2015 Dec 28.

Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.

Purpose: To present our experience in abdominal transplantations to manage unresectable abdominal neoplasms in children and to describe the role of extensive surgeries in such cases.

Methods: This is a retrospective study of 22 abdominal transplantations in 21 patients for abdominal tumors over 16 years. Transplantation techniques included liver transplant (LT), multivisceral transplant (MVTx), and intestinal autotransplant (IA). Follow-up intervals ranged from 0.3 to 168 months (median 20 months).

Results: LT alone was performed in 15 patients for primary malignant (11) and benign (4) liver tumors. Pathological classification included HB hepatoblastoma (6), HCC hepatocellular cancer (3), hepatic epithelioid hemangioendothelioma HEH (1), angiosarcoma (1), benign vascular tumors (3), and adenoma (1). IA was performed in four patients for lesions involving the root of the mesentery; tumors of the head of pancreas (3) and mesenteric hemangioma (1). MVTx was performed in 2 patients for malignancies; pancreaticoblastoma (1), recurrent hepatoblastoma (1), and in one patient as a rescue procedure after IA failure. Four of the eleven patients who underwent LT for malignant liver tumor had metastatic disease at presentation. Six of them died of recurrent neoplasm (3), transplant-related complications (2), and underlying disease (1). All LT patients who had benign tumors are alive with functioning grafts. All IA patients survived and are on an oral diet, with one patient requiring TPN supplementation. One of the three patients who underwent MVTx died of metastatic disease.

Conclusions: Allo/auto transplantation for abdominal tumors is a valuable modality when conventional treatments fail or are not feasible.
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http://dx.doi.org/10.1007/s00383-015-3852-3DOI Listing
April 2016

Lessons From Pancreas Transplantation in Type 1 Diabetes: Recurrence of Islet Autoimmunity.

Curr Diab Rep 2015 Dec;15(12):121

Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA.

Type 1 diabetes recurrence (T1DR) affecting pancreas transplants was first reported in recipients of living-related pancreas grafts from twins or HLA identical siblings; given HLA identity, recipients received no or minimal immunosuppression. This observation provided critical evidence that type 1 diabetes (T1D) is an autoimmune disease. However, T1DR is traditionally considered very rare in immunosuppressed recipients of pancreas grafts from organ donors, representing the majority of recipients, and immunological graft failures are ascribed to chronic rejection. We have been performing simultaneous pancreas-kidney (SPK) transplants for over 25 years and find that 6-8 % of our recipients develop T1DR, with symptoms usually becoming manifest on extended follow-up. T1DR is typically characterized by (1) variable degree of insulitis and loss of insulin staining, on pancreas transplant biopsy (with most often absent), minimal to moderate and rarely severe pancreas, and/or kidney transplant rejection; (2) the conversion of T1D-associated autoantibodies (to the autoantigens GAD65, IA-2, and ZnT8), preceding hyperglycemia by a variable length of time; and (3) the presence of autoreactive T cells in the peripheral blood, pancreas transplant, and/or peripancreatic transplant lymph nodes. There is no therapeutic regimen that so far has controlled the progression of islet autoimmunity, even when additional immunosuppression was added to the ongoing chronic regimens; we hope that further studies and, in particular, in-depth analysis of pancreas transplant biopsies with recurrent diabetes will help identify more effective therapeutic approaches.
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http://dx.doi.org/10.1007/s11892-015-0691-5DOI Listing
December 2015

Lower tacrolimus trough levels are associated with subsequently higher acute rejection risk during the first 12 months after kidney transplantation.

Transpl Int 2016 Feb 3;29(2):216-26. Epub 2015 Nov 3.

Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.

The premise that lower TAC trough levels are associated with subsequently higher first BPAR risk during the first 12 mo post-transplant was recently questioned. Using our prospectively followed cohort of 528 adult, primary kidney transplant recipients (pooled across four randomized trials) who received reduced TAC dosing plus an IMPDH inhibitor, TAC trough levels measured at seven time points, 7, 14 days, 1, 2, 3, 6 and 9 months post-transplant, were utilized along with Cox's model to determine the multivariable significance of TAC level(t) (a continuous time-dependent covariate equaling the most recently measured TAC level prior to time t) on the hazard rate of developing first BPAR during the first 12 months post-transplant. The percentage developing BPAR during the first 12 months post-transplant was 10.2% (54/528). In univariable analysis, lower TAC level(t) was associated with a significantly higher BPAR rate (P = 0.00006), and its significance was maintained even after controlling for 2 significant baseline predictors (African-American/Hispanic Recipient and Developed DGF) in Cox's model (multivariable P = 0.0003). Use of a cutpoint, TAC level(t) <4.0 vs. ≥4.0 ng/ml, yielded an even greater association with BPAR rate (univariable and multivariable P < 0.000001), with an estimated hazard ratio of 6.33. These results suggest that TAC levels <4.0 ng/ml should be avoided during the first 12 months post-transplant when TAC is used in combination with fixed-dose mycophenolate with or without corticosteroids and induction therapy.
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http://dx.doi.org/10.1111/tri.12699DOI Listing
February 2016

Multivariable risk of developing new onset diabetes after transplant-results from a single-center study of 481 adult, primary kidney transplant recipients.

Clin Transplant 2015 Apr 18;29(4):301-10. Epub 2015 Feb 18.

Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, USA.

Background: Understanding the relative contributions of baseline demographics and immunosuppressive therapy on NODAT risk may help in developing preventive strategies.

Methods: Using our prospectively followed cohort of 481 adult, primary kidney transplant recipients without pre-transplant diabetes, we determined the significant baseline predictors for the hazard rate of developing NODAT via Cox stepwise regression. The multivariable influence of first BPAR (defined as a time-dependent covariate) was also tested.

Results: Median follow-up was 57 mo post-transplant; the overall percentage who developed NODAT was 22.5% (108/481). Four baseline predictors of a greater NODAT hazard rate were found (by order of selection): higher BMI (p < 0.000001), planned maintenance with SRL (p = 0.0003), non-white recipient (p = 0.0004), and older recipient age (p = 0.0004). Approximately one-half of the 106 patients in the highest demographic risk category (BMI ≥25 kg/m(2) , non-white race, and age at transplant ≥40 yr) developed NODAT; actuarial NODAT risk ranged from 10% to 30% in the lower demographic risk categories. First BPAR was also associated with significantly higher NODAT in multivariable analysis (p = 0.02)-the highly elevated NODAT rate observed during the first few months post-transplant and following first BPAR appears to demonstrate the diabetogenic effect of using high-dose (intravenous) corticosteroids.

Conclusions: The disturbingly high NODAT rate found among patients having multiple demographic risk factors is still an important problem that awaits a better solution.
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http://dx.doi.org/10.1111/ctr.12510DOI Listing
April 2015

Role of innate and acquired immune mechanisms in clinical intestinal transplant rejection.

Transplantation 2015 Jun;99(6):1273-81

1 Department of Surgery, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL. 2 Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL. 3 Jesse Brown VA Medical Center, Chicago, IL. 4 Department of Surgery, University of Miami Miller School of Medicine, Miami, FL. 5 Department of Microbiology-Immunology, University of Miami Miller School of Medicine, Miami, FL. 6 Miami VA Medical Center, Miami, FL. 7 Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, IL.

Background: Long-term outcomes of intestinal transplantation are limited by infection and rejection. To understand the underlying immune mechanisms, graft infiltrating and peripheral blood cells were analyzed using multiple ex vivo assays in intestinal transplantation recipients.

Methods: Infiltrating cells from rejected (graft enterectomy for rejection) and accepted or quiescent (stoma closure in stable transplant recipients) grafts were isolated and phenotypically characterized as to subsets and Toll-like receptor expressions as well as functionally tested for antimicrobial and antidonor immune responses. Multiparameter antidonor immunity was also assessed serially in the peripheral blood.

Results: The graft infiltrating lymphocytes were mostly of recipient origin in all patients tested. In rejecting grafts, the predominant populations were TcRαβ(+)CD3(+)CD8(+) T cells, and CD14(+) monocytes that coexpressed Toll-like receptor-2, receptor-3, receptor-4, receptor-5, and receptor-9, suggesting innate immune activation. In quiescent allografts the major cell subsets were CD13(+)CD14(-) monocytes and CD4(+)CD25(+) T cells with possible regulatory functions. Infiltrating cells from rejected but not quiescent grafts proliferated in response to enteric bacterial and donor antigens as well as killed donor targets. Serial follow-up of peripheral blood indicated donor-specific posttransplant unresponsiveness in micro-cell-mediated lympholysis (m-CML) and mixed lymphocyte reaction (MLR) in recipients with quiescent grafts, but not in recipients with multiple rejection episodes. Enzyme-Linked ImmunoSpot assays yielded parallel results: granzyme-B with micro-cell-mediated lympholysis and interferon-γ with MLR tests.

Conclusion: These results were consistent with the notion that rejection was associated with innate and acquired antimicrobial and antidonor immune reactivity and that patients with stable grafts were free from these deleterious effects.
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http://dx.doi.org/10.1097/TP.0000000000000491DOI Listing
June 2015

Single-centre study of 628 adult, primary kidney transplant recipients showing no unfavourable effect of new-onset diabetes after transplant.

Diabetologia 2015 Feb 1;58(2):334-45. Epub 2014 Nov 1.

Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Highland Professional Building, 1801 NW 9th Avenue, Miami, FL, 33136, USA,

Aims/hypothesis: To better understand the implications of new-onset diabetes after transplant (NODAT), we used our prospectively followed cohort of 628 adult primary kidney transplant recipients to determine the prognostic impact of pretransplant diabetes and NODAT.

Methods: The study cohort consisted of all participants in four randomised immunosuppression trials performed at our centre since May 2000. For each cause-specific hazard analysed, Cox stepwise regression was used to determine a multivariable model of significant baseline predictors; the multivariable influence of having pretransplant diabetes and NODAT (t) (the latter defined as a zero-one, time-dependent covariate) was subsequently tested. Similar analyses of estimated glomerular filtration rate (eGFR) at 36 and 60 months post transplant were performed using stepwise linear regression. Finally, a repeated measures analysis of mean HbA1c as a function of diabetes category (pretransplant diabetes vs NODAT) and randomised trial (first to fourth) was performed.

Results: Median follow-up was 56 months post transplant. Patients with pretransplant diabetes comprised 23.4% (147/628), and 22.5% (108/481) of the remaining patients developed NODAT. Pretransplant diabetes had no prognostic influence on first biopsy-proven acute rejection and death-censored graft failure hazard rates, nor on eGFR, but was associated with significantly higher rates of death with a functioning graft (DWFG) (p = 0.003), DWFG due to a cardiovascular event (p = 0.005) and infection that required hospitalisation (p = 0.03). NODAT (t) had no unfavourable impact on any of these hazard rates nor on eGFR, with actuarial freedom from DWFG remaining at over 90% among patients in pre- and post-NODAT states at 72 months post transplant/NODAT. Mean HbA1c for patients in the first to fourth randomised trials, averaged across diabetes category, decreased by trial (7.28%, 6.92%, 6.87% and 6.64% [56.1, 52.1, 51.6 and 49.1 mmol/mol], respectively; p = 0.02).

Conclusions/interpretation: Less-than-expected post-NODAT risk for graft loss and death may exist in the current climate of tighter glucose monitoring post transplant.
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http://dx.doi.org/10.1007/s00125-014-3428-0DOI Listing
February 2015

Inflammation-driven carcinogenesis is mediated through STING.

Nat Commun 2014 Oct 10;5:5166. Epub 2014 Oct 10.

Department of Cell Biology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida 33136, USA.

Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by mechanisms that are not well understood. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), cisplatin and etoposide induce nuclear DNA leakage into the cytosol that intrinsically activates stimulator of interferon genes (STING)-dependent cytokine production. Inflammatory cytokine levels are subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING(-/-) mice, or wild-type mice adoptively transferred with STING(-/-) bone marrow, are almost completely resistant to DMBA-induced skin carcinogenesis compared with their wild-type counterparts. Our data establish a role for STING in the control of cancer, shed significant insight into the causes of inflammation-driven carcinogenesis and may provide a basis for therapeutic strategies to help prevent malignant disease.
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http://dx.doi.org/10.1038/ncomms6166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998973PMC
October 2014

Differential efficacy of human mesenchymal stem cells based on source of origin.

J Immunol 2014 Nov 1;193(9):4381-90. Epub 2014 Oct 1.

Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403.

Mesenchymal stem cells (MSCs) are useful in tissue repair but also possess immunomodulatory properties. Murine and uncontrolled human trials suggest efficacy of MSCs in treating lupus. Autologous cells are preferable; however, recent studies suggest that lupus-derived MSCs lack efficacy in treating disease. Thus, the optimum derivation of MSCs for use in lupus is unknown. It is also unknown which in vitro assays of MSC function predict in vivo efficacy. The objectives for this study were to provide insight into the optimum source of MSCs and to identify in vitro assays that predict in vivo efficacy. We derived MSCs from four umbilical cords, four healthy bone marrows (BMs), and four lupus BMs. In diseased MRL/lpr mice, MSCs from healthy BM and umbilical cords significantly decreased renal disease, whereas lupus BM MSCs only delayed disease. Current in vitro assays did not differentiate efficacy of the different MSCs. However, differences in MSC efficacy were observed in B cell proliferation assays. Our results suggest that autologous MSCs from lupus patients are not effective in treating disease. Furthermore, standard in vitro assays for MSC licensing are not predictive of in vivo efficacy, whereas inhibiting B cell proliferation appears to differentiate effective MSCs from ineffective MSCs.
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http://dx.doi.org/10.4049/jimmunol.1401636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201962PMC
November 2014

Intrinsic self-DNA triggers inflammatory disease dependent on STING.

J Immunol 2014 Nov 26;193(9):4634-42. Epub 2014 Sep 26.

Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136; and

Inflammatory diseases such as Aicardi-Goutières syndrome and severe systemic lupus erythematosus are generally lethal disorders that have been traced to defects in the exonuclease TREX1 (DNase III). Mice lacking TREX1 similarly die at an early age through comparable symptoms, including inflammatory myocarditis, through chronic activation of the stimulator of IFN genes (STING) pathway. In this study, we demonstrate that phagocytes rather than myocytes are predominantly responsible for causing inflammation, an outcome that could be alleviated following adoptive transfer of normal bone marrow into TREX1(-/-) mice. TREX1(-/-) macrophages did not exhibit significant augmented ability to produce proinflammatory cytokines compared with normal macrophages following exposure to STING-dependent activators, but rather appeared chronically stimulated by genomic DNA. These results shed molecular insight into inflammation and provide concepts for the design of new therapies.
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http://dx.doi.org/10.4049/jimmunol.1401337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003413PMC
November 2014