Host-Based Th2 Cell Therapy for Prolongation of Cardiac Allograft Viability

Donor T cell transfusion, which is a long-standing approach to prevent allograft rejection, operates indirectly by alteration of host T cell immunity. We therefore hypothesized that adoptive transfer of immune regulatory host Th2 cells would represent a novel intervention to enhance cardiac allograft survival. Using a well-described rat cardiac transplant model, we first developed a method for ex vivo manufacture of rat host-type Th2 cells in rapamycin, with subsequent injection of such Th2.R cells prior to class I and class II disparate cardiac allografting. Second, we determined whether Th2.R cell transfer polarized host immunity towards a Th2 phenotype. And third, we evaluated whether Th2.R cell therapy prolonged allograft viability when used alone or in combination with a short-course of cyclosporine (CSA) therapy. We found that host-type Th2.R cell therapy prior to cardiac allografting: (1) reduced the frequency of activated T cells in secondary lymphoid organs; (2) shifted post-transplant cytokines towards a Th2 phenotype; and (3) prolonged allograft viability when used in combination with short-course CSA therapy. These results provide further support for the rationale to use “direct” host T cell therapy for prolongation of allograft viability as an alternative to “indirect” therapy mediated by donor T cell infusion

Management of hyperglycaemia after pancreas transplantation: are new immunosuppressants the answer?

Pancreas transplantation is considered the optimal therapy for patients with diabetes mellitus who reach end-stage renal disease. Despite achievement of euglycaemia after this procedure, the progression to impaired pancreatic function and metabolic exhaustion still represents one of the major concerns that increase the risk of graft loss. This paper reviews the possible mechanisms that can induce post-transplant hyperglycaemia, including those related to immunosuppression and those non-related, and the new strategies available for minimising or preventing this complication. Different aetiologies can induce pancreatic dysfunction. Technical complications, acute pancreatitis and delayed graft function, mostly related to impaired insulin secretion, are considered the early causes for abnormal glucose control. In general, acute rejection does not affect the endocrine portion of the pancreas graft because islet destruction occurs later than the inflammation of the exocrine components. Hyperinsulinaemia and insulin resistance represent the main concern for the progression of blood glucose intolerance. The anastomotic techniques of the exocrine portion of the pancreas and the immunosuppressive regimens are of critical importance for the development of impaired glucose metabolism. Hyperinsulinaemia, as a result of the fact that systemic-enteric or systemic-bladder drainages reducing the hepatic clearance of insulin, has led to the introduction of more physiological techniques using portal drainage of the endocrine secretions. Experimental and clinical data have shown that many of the current immunosuppressants account, to a large degree, for the increased risk of the development of post-transplant hyperglycaemia. The most common maintenance regimen in pancreatic transplantation still consists of triple therapy with a combination of corticosteroids, calcineurin inhibitors (either ciclosporin [cyclosporine] or tacrolimus), and mycophenolate mofetil (MMF).The diabetogenic effects of corticosteroids and calcineurin inhibitors have resulted in the need for protocols able to minimise their use. Recent studies have shown the safety and efficacy of steroid-sparing or -free regimens. Sirolimus has shown powerful immunosuppressive potency in absence of nephrotoxicity and diabetogenicity. Multicentre and single-centre reports have demonstrated that both calcineurin inhibitor withdrawal and avoidance were possible when sirolimus was used in a concentration-controlled fashion, with low-dose corticosteroids and MMF. Although the experience with sirolimus in pancreatic transplantation is still limited, the results are promising. Patients affected by diabetic gastroparesis seem to better tolerate a regimen with sirolimus and low-dose tacrolimus than one with tacrolimus in combination with MMF.For successful, long-term results of pancreatic transplantation, it is crucial to combine donor selection, technical aspects, modified anastomotic techniques and new therapeutic approaches designed to minimise the metabolic and non-metabolic adverse effects of the immunosuppressive regimens

Vitamin D status and cholecalciferol supplementation in chronic kidney disease patients: an Italian cohort report

Adamasco Cupisti, Valentina Vigo, Maria Enrica Baronti, Claudia D'Alessandro, Lorenzo Ghiadoni, Maria Francesca Egidi Nephrology, Transplant and Dialysis Division, AOUP, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Abstract: This study investigated the factors associated with hypovitaminosis D, in a cohort of 405 prevalent patients with chronic kidney disease (CKD) stages 2–4, living in Italy and followed-up in tertiary care. The effect of cholecalciferol 10,000 IU once-a-week for 12 months was evaluated in a subgroup of 100 consecutive patients with hypovitaminosis D. Vitamin D deficiency was observed in 269 patients (66.4%) whereas vitamin D insufficiency was found in 67 patients (16.5%). In diabetic patients, 25-hydroxyvitamin D deficiency was detected in 80% of cases. In patients older than 65 years, the prevalence of hypovitaminosis D was 89%. In the univariate analysis, 25-hydroxyvitamin D was negatively related to age, parathyroid hormone (PTH), proteinuria, and Charlson index, while a positive relationship has emerged with hemoglobin level. On multiple regression analysis, only age and PTH levels were independently associated with 25-hydroxyvitamin D levels. No relationship emerged between vitamin D deficiency and renal function. Serum levels of 25-hydroxyvitamin D or prevalence of hypovitaminosis D did not differ between patients on a free-choice diet and on a renal diet, including low-protein, low-phosphorus regimens. Twelve-month oral cholecalciferol administration increased 25-hydroxyvitamin D and reduced PTH serum levels. In summary, hypovitaminosis D is very prevalent in CKD patients (83%) in Italy, and it is similar to other locations. PTH serum levels and age, but not renal function, are the major correlates of hypovitaminosis D. Implementation of renal diets is not associated with higher risk of vitamin D depletion. Oral cholecalciferol administration increased 25-hydroxyvitamin D and mildly reduced PTH serum levels. Oral cholecalciferol supplementation should be recommended as a regular practice in CKD patients, also when serum 25-hydroxyvitamin D determination is not available or feasible. Keywords: CKD, vitamin D, cholecalciferol, calcifediol, hypovitaminosis, PTH, renal disease, CKD-MB

Low-dose synthetic adrenocorticotropic hormone-analog therapy for nephrotic patients: results from a single-center pilot study

Paolo Lorusso, Anna Bottai, Emanuela Mangione, Maurizio Innocenti, Adamasco Cupisti, Maria Francesca Egidi Nephrology Transplant Dialysis Unit (AOUP), Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Introduction: This report describes our experience using a low-dose synthetic adrenocorticotropic hormone (ACTH) analog for patients affected by nephrotic syndrome who had not responded to or had relapsed after steroid and immunosuppressive treatments. Patients and methods: Eighteen adult nephrotic patients with an estimated glomerular filtration rate >30 mL/min were recruited. Histological pictures included ten of membranous nephropathy, three of membranous proliferative glomerulonephritis, three of minimal change, and two of focal segmental glomerular sclerosis. All patients received the synthetic ACTH analog tetracosactide 1 mg intramuscularly once a week for 12 months. Estimated glomerular filtration rate, proteinuria, serum lipids, albumin, glucose, and potassium were determined before and during the treatment. Results: One of the 18 patients discontinued the treatment after 1 month because of severe fluid retention, and two patients were lost at follow-up. Complete remission occurred in six cases, while partial remission occurred in four cases (55.5% responder rate). With respect to baseline, after 12 months proteinuria had decreased from 7.24±0.92 to 2.03±0.65 g/day (P<0.0001), and serum albumin had increased from 2.89±0.14 to 3.66±0.18 g/dL (P<0.0001). Total and low-density lipoprotein cholesterol had decreased from 255±17 to 193±10 mg/dL (P=0.01), and from 168±18 to 114±7 mg/dL (P=0.03), respectively. No cases of severe worsening of renal function, hyperglycemia, or hypokalemia were observed, and no admissions for cardiovascular or infectious events were recorded. Conclusion: Tetracosactide administration at the dosage of 1 mg intramuscularly per week for 12 months seems to be an acceptable alternative for nephrotic patients unresponsive or relapsing after steroid-immunosuppressive regimens. Further studies should be planned to assess the effect of this low-dose ACTH regimen also in nephrotic patients not eligible for kidney biopsy or immunosuppressive protocols. Keywords: ACTH, glomerulonephritis, proteinuria, nephrotic syndrome, CKD, Tetracosactid

Different methods to manage dry weight in hemodialysis patients

Estimating the euvolemia and dry weight of hemodialysis patients still represents a challenge for the nephrologist, since both dehydration and hyperhydration are associated with intradialytic events and cardiovascular complications in the short and long term. Despite the need for a precise and objective definition of the dry weight for the individual patient on dialysis, this is usually determined on a clinical basis. To obtain greater sensitivity the dosage of natriuretic peptides, Bioelectrical Impedance Analysis (BIA) and, more recently, Lung Ultra-Sound (LUS) can all be used. The BIA allows to estimate the subject’s body composition and, in particular, the distribution of body fluids. The presence of hyperhydration, as determined through the BIA, is predictive of an increased mortality in numerous observational studies. In recent years, pulmonary ultrasound has taken on an increasingly important role not only within the cardiology and intensive care units, but also in a nephrology setting, especially in dialysis. The purpose of this article is to analyze the advantages and limitations of the methods that can be used to assess the dry weight of patients undergoing hemodialysis treatment

Use of tocilizumab in amyloid a nephropathy associated with Sweet syndrome: a case report and literature review

Amyloid A nephropathy is a possible complication of chronic inflammatory disease. Proteinuria and kidney failure are the main features of the disease. Tocilizumab (TCZ), an IL6-R antibody approved for rheumatoid arthritis, is a promising choice for histologically demonstrated nephropathy. We describe a case of kidney amyloid associated with Sweet syndrome treated with TCZ. The patient was affected by Sweet syndrome associated with proteinuria. Kidney biopsy showed amyloid deposits. During the follow-up, cutaneous and renal findings were refractory to many immunosuppressive regimen (cyclophosphamide, leflunomide, interferon and steroid). After few years, the patient developed rapidly progressive nephropathy associated with nephrotic syndrome (proteinuria up to 6 g/die). A second kidney biopsy was performed and it showed worsening of amyloid nephropathy. Thus, TCZ was administrated (8 mg/kg once a month) and it stabilized kidney function and induced partial remission of the nephrotic syndrome in the following 2 years