Patrick T. Coates

Effects of body mass index at transplant on outcomes of kidney transplantation.

Backgound. While obesity increases postoperative complications and cardiovascular risks, its effects on long-term kidney transplant outcomes are less clear. Methods. We used data from the Australian and New Zealand Dialysis and Transplant (ANZDATA) Registry to examine the relationships between body mass index (BMI, classified according to World Health Organization criteria) at transplant and transplant outcome. Patients starting renal replacement therapy from April 1991 and who received a single-organ, primary kidney transplant (when aged ≥16 years) from April 1991 to December 2004 were included, and followed up to death or December 2005. Survival outcomes adjusted for important covariates were analyzed using Cox models, and cause-specific failures by competing risks analysis. Analysis using BMI at various times posttransplant was also performed. Intermediate outcomes were delayed graft function (DGF) and any acute rejection at 6 months. Results. In all, 5684 patients were included. Obese patients had worse graft and patient survival only in univariate analyses, not in multivariate analyses (adjusted hazard ratio [HR] for graft loss: 1.10 [0.94–1.259], P=0.25; for patient death: 1.02 [0.83–1.25], P=0.87). Underweight patients had greater late (≥5 years) death-censored graft loss (adjusted HR: 1.70 [1.10–2.64], P=0.02), mainly due to chronic allograft nephropathy. Obesity was associated with greater odds for DGF (adjusted OR: 1.56 [1.23–1.97], P<0.001) and 6-month risk of acute rejection (adjusted OR: 1.25 [1.01–1.54], P=0.04). Conclusions. Obesity per se was not associated with poorer kidney transplant outcomes, although it was associated with factors that led to poorer graft and patient survival. Underweight was associated with late graft failure, mainly due to chronic allograft nephropathy.

Calcific uraemic arteriolopathy: an update.

Purpose of reviewCalcific uraemic arteriolopathy (CUA) or calciphylaxis is a rare but important cause of morbidity and mortality in patients with chronic kidney disease. The prevalence of CUA is increasing in patients with renal failure, and the condition is also being recognized in nonuraemic patients. Recent findingsThere has been increasing understanding of the molecular basis of vascular calcification, in particular on the important role of the uraemic microenvironment in the factors implicated in the differentiation of vascular smooth muscle cells into osteoblasts. New options for treatment of hyperphosphataemia and secondary hyperparathyroidism in patients with chronic kidney disease have become available in the last few years and these have begun to be used in patients with CUA. These include bisphosphonates, newer noncalcium/nonaluminium-containing phosphate binders and case reports of use of cinacalcet. Other treatments for CUA that are not targeted directly at calcium/phosphate homeostasis include hyperbaric oxygen and the antioxidant cation chelator sodium thiosulphate. SummaryClinicians managing patients with CUA should consider a combination approach of treating deranged calcium/phosphate with newer therapeutic agents and promoting wound healing with other older modalities such as hyperbaric oxygen and sodium thiosulphate infusions. Randomized controlled trials for treatments in CUA are still lacking.

Anti-HLA donor-specific antibodies detected in positive B-cell crossmatches by Luminex predict late graft loss.

The significance of B‐cell crossmatching in kidney transplantation is controversial. Recipients (n = 471) transplanted in a single centre from 1987 to 2005 with complete T‐ and B‐cell crossmatch records were studied. Sera from 83 patients transplanted across a positive B‐cell crossmatch, with concomitant negative T‐cell crossmatch (T–B+) on either current and/or peak sera were studied using Luminex® to determine presence of donor‐specific antibodies (DSA). Clinical outcomes of T–B+ patients were compared with 386 T–B− patients. T–B+ predicted vascular (p = 0.01), but not cellular (p = 0.82) or glomerular (p = 0.14) rejection. IgG HLA DSA were found in 33% (n = 27) of the T–B+ patients and were associated with higher risk of any (p = 0.047), vascular (p = 0.01) or glomerular (p < 0.001) rejection at 6 months. Of 27 patients with DSA, 18/21 (86%) were the complement‐fixing IgG1 and/or IgG3 subclass antibodies. DSA imposed a statistically significant higher risk of graft loss 5 years posttransplant (1.8 [1.0–3.3], p = 0.045). This study showed that only one‐third of positive B‐cell crossmatch (BXM) was caused by DSA and was associated with late graft loss. Thus, using BXM to preclude kidney transplantation may potentially disadvantage >60% of patients in whom BXM is not indicative of the presence of DSA.

Multicenter Australian trial of islet transplantation: Improving accessibility and outcomes

Whilst initial rates of insulin independence following islet transplantation are encouraging, long‐term function using the Edmonton Protocol remains a concern. The aim of this single‐arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end‐point was an HbA1c of <7% and cessation of severe hypoglycemia. Seventeen recipients were followed for ≥12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end‐point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7–39 months) and 6 (35%) remain insulin independent. All recipients were C‐peptide positive for at least 3 months. All subjects with unstimulated C‐peptide >0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation.

Curcumin induces maturation-arrested dendritic cells that expand regulatory T cells in vitro and in vivo.

Dendritic cells (DC) and regulatory T cells (Tregs) are vital to the development of transplant tolerance. Curcumin is a novel biological agent extracted from Curcuma longa (turmeric), with anti‐inflammatory and anti‐oxidant activity mediated via nuclear factor (NF)‐κB inhibition. We investigated the immunomodulatory effects of curcumin on human monocyte‐derived and murine DC. Human monocyte‐derived DC (hu‐Mo‐DC) were generated in the presence (CurcDC) or absence (matDC) of 25 µM curcumin, and matured using lipopolysaccharide (1 µg/ml). DC phenotype and allostimulatory capacity was assessed. CD11c+ DC were isolated from C57BL/6 mice, pretreated with curcumin and injected into BALB/c mice, followed by evaluation of in vivo T cell populations and alloproliferative response. Curcumin induced DC differentiation towards maturation‐arrest. CurcDC demonstrated minimal CD83 expression (<2%), down‐regulation of CD80 and CD86 (50% and 30%, respectively) and reduction (10%) in both major histocompatibility complex (MHC) class II and CD40 expression compared to matDC. CurcDC also displayed decreased RelB and interleukin (IL)‐12 mRNA and protein expression. Functionally, CurcDC allostimulatory capacity was decreased by up to 60% (P < 0·001) and intracellular interferon (IFN‐γ) expression in the responding T cell population were reduced by 50% (P < 0·05). T cell hyporesponsiveness was due to generation of CD4+CD25hiCD127loforkhead box P3 (FoxP3)+ Tregs that exerted suppressive functions on naïve syngeneic T cells, although the effect was not antigen‐specific. In mice, in vivo infusion of allogeneic CurcDC promoted development of FoxP3+ Tregs and reduced subsequent alloproliferative capacity. Curcumin arrests maturation of DC and induces a tolerogenic phenotype that subsequently promotes functional FoxP3+ Tregsin vitro and in vivo.

Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function.

Interferon‐γ (IFN‐γ)‐preactivated mesenchymal stem cells (MSC‐γ) are highly immunosuppressive but immunogenic in vivo due to their inherent expression of major histocompatibility (MHC) molecules. Here, we present an improved approach where we modified human bone marrow‐derived MSC with interleukin‐17A (MSC‐17) to enhance T cell immunosuppression but not their immunogenicity. MSC‐17, unlike MSC‐γ, showed no induction or upregulation of MHC class I, MHC class II, and T cell costimulatory molecule CD40, but maintained normal MSC morphology and phenotypic marker expression. When cocultured with phytohemagglutinin (PHA)‐activated human T cells, MSCs‐17 were potent suppressors of T cell proliferation. Furthermore, MSC‐17 inhibited surface CD25 expression and suppressed the elaboration of Th1 cytokines, IFN‐γ, tumor necrosis factor‐α (TNF‐α), and IL‐2 when compared with untreated MSCs (UT‐MSCs). T cell suppression by MSC‐17 correlated with increased IL‐6 but not with indoleamine 2,3‐dioxygenase 1, cyclooxygenase 1, and transforming growth factor β‐1. MSC‐17 but not MSC‐γ consistently induced CD4+CD25highCD127lowFoxP3+ regulatory T cells (iTregs) from PHA‐activated CD4+CD25− T cells. MSC‐induced iTregs expressed CD39, CD73, CD69, OX40, cytotoxic T‐lymphocyte associated antigen‐4 (CTLA‐4), and glucocorticoid‐induced TNFR‐related protein (GITR). These suppressive MSCs‐17 can engender Tregs to potently suppress T cell activation with minimal immunogenicity and thus represent a superior T cell immunomodulator for clinical application. Stem Cells 2015;33:2850–2863

The immune phenotype may relate to cancer development in kidney transplant recipients.

High regulatory T-cell (Treg) numbers predict recurrent cutaneous squamous cell carcinoma in kidney transplant recipients, and the Treg immune phenotype may identify kidney transplant recipients at risk of developing squamous cell carcinoma and/or solid-organ cancer. To investigate this, a total of 116 kidney transplant recipients, of whom 65 had current or past cancer, were immune-phenotyped and followed up prospectively for a median of 15 months. Higher Treg (CD3+CD4+FOXP3+CD25(Hi)CD127(Lo)) proportion and numbers significantly increased the odds of developing cancer (odds ratios (95% CI) 1.61 (1.17-2.20) and 1.03 (1.00-1.06), respectively) after adjusting for age, gender, and duration of immunosuppression. Class-switched memory B cells (CD19+CD27+IgD-) had a significant association to cancer, 1.04 (1.00-1.07). Receiver operator characteristic (ROC) curves for squamous cell carcinoma development within 100 days of immune phenotyping were significant for Tregs, memory B cells, and γδ T cells (AUC of 0.78, 0.68, and 0.65, respectively). After cancer resection, Treg, NK cell, and γδ T-cell numbers fell significantly. Immune-phenotype profiles associated with both squamous cell carcinoma and solid-organ cancer in kidney transplant recipients and depended on the presence of cancer tissue. Thus, immune profiling could be used to stratify kidney transplant recipients at risk of developing cancers to identify those who could qualify for prevention therapy.

Hyperbaric oxygen as effective adjuvant therapy in the treatmentof distal calcific uraemic arteriolopathy

Calcific uraemic arteriolopathy (CUA), calciphylaxis or uraemia of small-vessel disease is a rare life-threatening complication predominantly affecting patients with end-stage renal disease (ESRD) [1]. It typically occurs in those with secondary hyperparathyroidism and is associated with deranged calcium and phosphate metabolism. Other factors, such as malnutrition, obesity, diabetes mellitus, warfarin therapy and female gender, have been implicated as additional risk factors [2]. CUA presents as severely painful ulcers, usually occurring in the lower limbs. The mechanism of injury appears to be calcification of subcutaneous tissues and small arterioles. At a molecular level, derangement of vascular smooth muscle cell function leading to osteogenic differentiation in conjunction with endothelial cell dysfunction appears to be important [3]. The lesions are slow to heal, with superimposed bacterial infection leading to sepsis, the most common cause of death (in up to 80% of patients). The first case series of CUA was published in 1976 [4]. Subsequently, the incidence of CUA in patients with ESRD has increased markedly [3]. Reports to the Australia and New Zealand Dialysis and Transplantation Registry (ANZDATA) demonstrate that CUA had been identified as a comorbidity or cause of death in 171 patients, from its first documentation in 1985 until March 2005 (Figure ​(Figure1).1). Despite an increasing awareness of this disease and a better understanding of its aetiology, an effective form of treatment remains elusive. Most therapeutic regimens include aggressive wound care, ensuring adequate nutrition, improving calcium–phosphate balance and correcting secondary hyperparathyroidism. The use of bisphosphonates [5], low-molecular weight heparin [1] or sodium thiosulfate [6] has been met with success in a few patients. Fig. 1 The number of patients with ESRD and CUA as a comorbidity or cause of death reported to ANZDATA between 1985 and 2005. Hyperbaric oxygen (HBO) involves breathing 100% oxygen within a pressurized environment. It is first-line therapy for a number of medical conditions, namely decompression sickness and carbon monoxide poisoning [7]. Most recently, HBO has been shown to be of benefit in advancing wound healing, including lesions due to CUA [8]. It is proposed to work by increasing oxygen tension in the ischaemic tissue, although the primary initiating factor of vascular calcification is not altered. We report our experience with the treatment of CUA with HBO, which appears to be well tolerated. We describe the largest, single-centre case series of patients with CUA successfully treated with a combination of therapies including HBO.

Gene therapy to improve pancreatic islet transplantation for Type 1 diabetes mellitus.

Pancreatic islet transplantation is a promising treatment option for Type 1 Diabetics, offering improved glycaemic control through restoration of insulin production and freedom from life-threatening hypoglycaemic episodes. Implementation of the Edmonton protocol in 2000, a glucocorticoid-free immunosuppressive regimen has led to improved islet transplantation success. >50% of islets are lost post-transplantation primarily through cytokine-mediated apoptosis, ischemia and hypoxia. Gene therapy presents a novel strategy to modify islets for improved survival post-transplantation. Current islet gene therapy approaches aim to improve islet function, block apoptosis and inhibit rejection. Gene transfer vectors include adenoviral, adeno-associated virus, herpes simplex virus vectors, retroviral vectors (including lentiviral vectors) and non-viral vectors. Adeno-associated virus is currently the best islet gene therapy vector, due to the vectors minimal immunogenicity and high safety profile. In animal models, using viral vectors to deliver genes conferring local immunoregulation, anti-apoptotic genes or angiogenic genes to islets can significantly improve islet survival in the early post-transplant period and influence long term engraftment. With recent improvements in gene delivery and increased understanding of the mechanisms underlying graft failure, gene therapy for islet transplantation has the potential to move closer to the clinic as a treatment for patients with Type 1 Diabetes.

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

BACKGROUND AND OBJECTIVES The current allocation algorithm for deceased donor kidney transplantation takes into consideration HLA mismatches at the ABDR loci but not HLA mismatches at other loci, including HLA-DQ. However, the independent effects of incompatibilities for the closely linked HLA-DQ antigens in the context of HLA-DR antigen matched and mismatched allografts are uncertain. We aimed to determine the effect of HLA-DQ mismatches on renal allograft outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the association between HLA-DQ mismatches and acute rejections in primary live and deceased donor kidney transplant recipients between 2004 and 2012 using adjusted Cox regression models. RESULTS Of the 788 recipients followed for a median of 2.8 years (resulting in 2891 person-years), 321 (40.7%) and 467 (59.3%) received zero and one or two HLA-DQ mismatched kidneys, respectively. Compared with recipients who have received zero HLA-DQ mismatched kidneys, those who have received one or two HLA-DQ mismatched kidneys experienced greater numbers of any rejection (50 of 321 versus 117 of 467; P<0.01), late rejections (occurring >6 months post-transplant; 8 of 321 versus 27 of 467; P=0.03), and antibody-mediated rejections (AMRs; 12 of 321 versus 38 of 467; P=0.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. HLA-DR was an effect modifier between HLA-DQ mismatches and AMR (P value for interaction =0.02), such that the association between HLA-DQ mismatches and AMR was statistically significant in those who have received one or two HLA-DR mismatched kidneys, with adjusted hazard ratio of 2.50 (95% CI, 1.05 to 5.94). CONCLUSIONS HLA-DQ mismatches are associated with acute rejection, independent of HLA-ABDR mismatches and initial immunosuppression. Clinicians should be aware of the potential importance of HLA-DQ matching in the assessment of immunologic risk in kidney transplant recipients.