Association between irisin and major chronic diseases: a review.

OBJECTIVE: Irisin is a muscle-secreted protein released into the circulation by cleavage of fibronectin type III domain containing protein 5(FNDC5). Since its discovery in 2012, it has been the subject of many researches due to its physiological role. It is believed that understanding irisin's function may be the key to comprehend many diseases and their development. The aim of this study is to perform a systematic review in order to establish whether there is an association of irisin's levels with obesity, diabetes mellitus, non-alcoholic steatohepatitis, chronic kidney disease and cancer in terms of prognosis. MATERIALS AND METHODS: The articles that support these findings were selected from Medline using the keyword "irisin" and filtered with "humans only". The selected articles were in English and with abstract. RESULTS: Higher baseline irisin concentrations are associated with greater reductions in glycemia and insulinemia after weight loss in obese subjects. Besides, it was observed that macrovascular disease, a complication of diabetes, was developed when there were lower levels of irisin. In addition, although not statistically significant, high levels of irisin were associated with portal inflammation and severity of histological lesions. Its concentrations decreased with increasing chronic kidney disease stage, and they were not only independently and positively predicted by renal function and insulin resistance but also associated with sarcopenia and carotid atherosclerosis in patients undergoing peritoneal dialysis. Regarding cancer, irisin reduced the proliferation, viability and migration of malignant breast cells. Finally, it is also related to bone health once its concentration is associated with previous osteoporotic fractures. CONCLUSIONS: In every condition studied, irisin's concentrations were related to the development of the disease.

Nocardia farcinica pericarditis after kidney transplantation despite prophylaxis.

A deceased-donor kidney transplant recipient developed purulent pericarditis caused by Nocardia despite trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis for Pneumocystis jirovecii. She was treated empirically with ceftriaxone and amikacin and subsequently underwent sternotomy with drainage of an intrapericardial abscess. Culture and susceptibility data demonstrated Nocardia farcinica, which was susceptible to SMX and amikacin, although resistant to ceftriaxone. Nocardia asteroides, the more common human pathogen, is generally susceptible to third-generation cephalosporins and TMP-SMX. N. farcinica is rare in the United States, more virulent and resistant than N. asteroides, and is more likely to cause disseminated disease. Successful therapy of disseminated Nocardia infections is dependent upon choice of appropriate empiric antibiotics in addition to surgical drainage of purulent fluid collections. TMP-SMX prophylaxis may not be sufficient to prevent infections due to Nocardia species in all immunosuppressed transplant recipients. Here, a rare complication of this unusual pathogen is discussed.

Human granulocytic ehrlichiosis in a renal allograft recipient: review of the clinical spectrum of disease in solid organ transplant patients.

BACKGROUND: Ehrlichiosis is a recently described zoonotic infection with two major expressions: human granulocytic ehrlichiosis (HGE) and human monocytic ehrlichiosis (HME). The organisms associated with HGE and HME have been detected in a tick vector in several regions of United States and cases of ehrlichiosis have been reported in the general population. METHODS: We report a case of HGE in a renal allograft recipient and review the clinical spectrum of disease in solid organ transplant recipients and the epidemiological basis for risk. RESULTS: Our patient demonstrated the typical epidemiological, clinical and laboratory features of human granulocytic ehrlichiosis and responded to treatment with doxycycline. CONCLUSIONS: Human ehrlichiosis should be considered in the differential diagnosis of patients with solid organ transplants, who present with fever and thrombocytopenia. The incidence of ehrlichiosis in the solid organ transplant population is similar to that in the United States general population. As reported in immunocompetent patients, prompt diagnosis and treatment results in the rapid resolution of symptoms in transplanted individuals.

Regulatory functions of self-restricted MHC class II allopeptide-specific Th2 clones in vivo.

We studied T-cell clones generated from grafts of rejecting and tolerant animals and investigated the regulatory function of Th2 clones in vitro and in vivo. To prevent allograft rejection, we treated LEW strain recipient rats of WF strain kidney grafts with CTLA4Ig to block CD28-B7 costimulation. We then isolated epitope-specific T-cell clones from the engrafted tissue, using a donor-derived immunodominant class II MHC allopeptide presented by recipient antigen-presenting cells. Acutely rejected tissue from untreated animals yielded self-restricted, allopeptide-specific T-cell clones that produced IFN-gamma, whereas clones from tolerant animals produced IL-4 and IL-10. Adoptive transfer into naive recipients of Th1 clones, but not Th2 clones, induced alloantigen-specific delayed-type hypersensitivity (DTH) responses. In addition, Th2 clones suppressed DTH responses mediated by Th1 clones in vivo and blocked Th1 cell proliferation and IFN-gamma production in vitro. A pilot human study showed that HLA-DR allopeptide-specific T-cell clones generated from patients with chronic rejection secrete Th1 cytokines, whereas those from patients with stable graft function produce Th2 cytokines in response to donor-specific HLA-DR allopeptides. We suggest that self-restricted alloantigen-specific Th2 clones may regulate the alloimmune responses and promote long-term allograft survival and tolerance.

Chronic allograft dysfunction: mechanisms and new approaches to therapy.

Renal allograft failure is the most common cause of end-stage renal disease beyond the early posttransplantation period, accounting for 25% to 30% of patients awaiting renal transplantation. Despite recent advances in immunosuppressive therapy, improvements in long-term graft survival have not been commensurate with those observed in 1-year graft survival. The most common cause of chronic allograft loss is an incompletely understood clinicopathological entity sometimes called chronic rejection, chronic allograft dysfunction or in the case of kidneys, chronic allograft nephropathy. Although the precise mechanism(s) responsible for the characteristic pathological changes are still unclear, it is generally agreed that both alloantigen-dependent and alloantigen-independent factors influence the development of chronic allograft nephropathy. This article will address the potential mechanisms responsible for the pathogenesis of chronic dysfunction in solid organ grafts and the current approaches to management, including newer therapies designed to prevent the progression of the disease.

Cellular and humoral mechanisms of vascularized allograft rejection induced by indirect recognition of donor MHC allopeptides.

INTRODUCTION: To investigate the role and mechanisms of indirect allorecognition in allograft rejection, we studied whether priming T cells with donor-derived MHC allopeptides could accelerate rejection in a vascularized allograft model. METHODS: Lewis recipients of fully mismatched Wistar Furth cardiac allografts were immunized before transplantation with donor MHC allopeptides. RESULTS: Animals immunized with immunogenic class II MHC allopeptides rejected their grafts in a significantly accelerated fashion compared with controls. Additional studies demonstrated that a single immunodominant RT1.D (HLA-DR like) allopeptide was responsible for accelerating the rejection process. Histological analysis of rejected allografts revealed marked vascular rejection in the accelerated, although not the control, group as well as severe cellular rejection. Peak production of IgM and IgG donor-specific alloantibodies was detected by flow cytometry 1 week earlier in the sera of the accelerated group compared with the control group. Immunohistological analysis of grafts from the accelerated compared with the control group showed increased endothelial deposition of IgG2b, C3, and fibrin, and up-regulation of class II MHC molecule expression. Increased intragraft expression of interferon-y and the interferon-gamma-induced chemokines, inducible protein-10 and Mig, and infiltration by activated mononuclear cells expressing CXCR3, the receptor for inducible protein-10 and Mig, was also seen. CONCLUSION: These novel data provide evidence of a definitive link between indirect allorecognition of donor-derived MHC class II peptides and the cellular and humoral mechanisms of vascularized allograft rejection.

Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.

Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease.

Inhibition of allorecognition by a human class II MHC-derived peptide through the induction of apoptosis.

The interaction of the T-cell receptor with the major histocomatibility complex (MHC)-peptide complex is central to T-cell activation. Variation in the nature of the peptide bound within the groove of the MHC molecule may result in an altered T-cell response. Because some naturally processed peptides bound within the groove of the class II MHC molecule are derived from the MHC molecules themselves, we studied the inhibitory effects of synthetic class II MHC peptides on alloimmune responses in vitro. Three peptides derived from a highly conserved region of the class II MHC alpha chains inhibited the rat mixed lymphocyte response (MLR) in a dose-dependent manner, with the human HLA-DQA1 peptide also inhibiting the human and mouse MLR. No effect was seen on mitogen-induced T-cell proliferation. HLA-DQA1 inhibited cytolytic T lymphocyte (CTL) generation in a dose-response fashion, with no reduction in preformed CTL killing, suggesting that the inhibitory effect is targeted at CD4(+) T-cell function. Cell-cycle analysis by flow cytometry showed that restimulation of primed T cells in the presence of HLA-DQA1 resulted in increased apoptosis, whereas unstimulated cells were not affected. These data demonstrate that synthetic peptides derived from highly conserved regions of the class II MHC alpha chain can alter CD4(+) T-lymphocyte alloimmune responses in vitro, and this effect is mediated by the induction of apoptosis in activated T cells.

Multiple myeloma and renal failure: one center's experience.

Renal involvement remains a major complication of multiple myeloma, particularly in advanced disease. A retrospective analysis was performed of the modes of presentation, treatment and outcome of all patients with multiple myeloma treated in our renal unit between 1987 and 1996. Thirty-four patients were identified: in 26 (76%) the diagnosis of myeloma was made only after referral. Light chains were the most common paraprotein in both serum and urine. Twenty-one (62%) patients underwent renal biopsy: myeloma cast nephropathy was the predominant histological finding in 16 cases. Thirty-one (91%) patients had severe renal failure (GFR < 20 mL/min), with 28 (82%) requiring dialysis within 2 weeks of admission. Despite treatment of presumed precipitaing causes of acute deterioration in renal function, only 1 of these 28 patients subsequently became independent of dialysis. Most had advanced stage myeloma: 29 (85%) were Durie-Salmon stage II or III. Hypercalcemia, sepsis and pathological fractures were the principal complications. Median survival overall was 5 months. The main causes of death were withdrawal of renal replacement therapy (overwhelming myeloma, severe debilitation) and sepsis. Nineteen (56%) patients received long-term (> 1 month) renal replacement therapy with a median survival of 8 months. However, five of these (26%) have survived for more than 12 months on dialysis and report a good quality of life.

Sensitization to human leukocyte antigen before and after the introduction of erythropoietin.

INTRODUCTION: Antibodies directed against human leukocyte antigens (HLAs) impact adversely on renal transplantation. Measures aimed at preventing such antibody formation are thus important. The introduction of recombinant human erythropoietin (rHuEpo) has permitted the reduction of blood transfusion in patients with chronic renal failure. The impact of rHuEpo on the incidence of sensitization in patients awaiting transplantation was therefore studied. METHODS: A retrospective analysis of the patients awaiting transplantation before (group A) and 4 years after (group B) the introduction of rHuEpo was performed in order to ascertain changing patterns in the use of blood transfusion and causes of sensitization. RESULTS: The total number of transfusions administered to haemodialysis patients decreased by 34% during the study period. This was accompanied by a significant reduction in the ratio of blood transfusion to haemodialysis treatment episodes (0.095 in group A to 0.06 in group B, P = 0.001). The number of patients sensitized as a consequence of blood transfusion decreased from 63% in group A to 28% in group B (P = 0.0004). The overall incidence of sensitization decreased from 50% in group A to 36.5% in group B (P = 0.008). This decrement was associated with a significant reduction in the mean waiting time for transplantation (42.1 +/- 1.1 vs 15.4 +/- 2.4 months, P < 0.0001). The incidence of sensitization due to previous transplantation increased during the study period from 41% in group A to 77% in group B, (P = 0.0004). There was no change in the number of patients sensitized due to pregnancy. CONCLUSION: The introduction of rHuEpo has resulted in a significant decrease in the requirements for blood transfusion among patients awaiting transplantation and is associated with a significant reduction in transfusion-related sensitization and mean waiting time for transplantation.

Comparative strategies to induce long-term graft acceptance in fully allogeneic renal versus cardiac allograft models by CD28-B7 T cell costimulatory blockade: role of thymus and spleen.

Blocking CD28-B7 T cell costimulatory activation by the fusion protein CTLA4Ig prevents rejection and induces long-term graft acceptance in various experimental transplant models. There are reported differences in the efficacy of CTLA4Ig in renal and cardiac rodent allograft models, but it is not clear whether these are due to the strain or species differences investigated in the different studies reported. This study investigates the effect of blocking CD28-B7 T cell costimulation with murine CTLA4Ig in rat models of acute renal and cardiac allograft rejection models, using the same complete major histocompatibility complex-incompatible strain combination. A single injection of murine CTLA4Ig 2 d after engraftment was able to induce long-term graft acceptance (> 100 d) in 54% of Lewis rat recipients of Wistar-Furth kidneys. Transferring this protocol into the acute Wistar-Furth to Lewis heart allograft model resulted in a mean graft survival time of 24.7+/-16.9 d, and all grafts were ultimately rejected. Only concomitant injection of donor cells (4 x 10(7) splenocytes) plus a single injection of CTLA4Ig on the day of transplant could induce long-term graft acceptance in 50% of animals. In both the cardiac and renal transplant models, the thymus and spleen were required for induction of tolerance. The maintenance phase of tolerance, however, did not require an intact thymus but did require the presence of a spleen. These data have important clinical applicability because human studies with T cell costimulatory blockade are being planned.

Interactions between cyclosporine and newer antidepressant medications.

The favorable safety profile of the newer antidepressant drugs recently introduced has lead to their increased use in transplant recipients. These new agents are a chemically diverse group of compounds that have selective serotonin reuptake inhibitory properties. Most of these medications inhibit one or more hepatic microsomal cytochrome p450 isoenzymes. Because cyclosporine is metabolized predominantly by CYP3A3/4 isoenzymes, inhibition of this system can lead to the buildup of toxic levels. Two case reports of cyclosporine toxicity attributable to interactions with the novel antidepressants nefazodone and fluvoxamine are presented. The serum creatinine and whole blood cyclosporine levels were found to be elevated at a routine clinic visit. Although it was subsequently possible to reduce the dose of cyclosporine by between 33% and 50%, the frequency of blood draws and consultations was greatly increased in both patients over several weeks, resulting in considerable patient anxiety. Interestingly, both nefazodone and fluvoxamine are known to potently inhibit the CYP3A3/4 isoenzymes. It is concluded that the introduction of a novel antidepressant to a cyclosporine-treated allograft recipient may be complicated by cyclosporine toxicity. Intensive monitoring of the serum creatinine and cyclosporine level is indicated under such circumstances, with dose reductions performed as indicated.

Developments in the clinical science of transplantation during the 20th century.

Transplantation has become the treatment of choice for end-stage organ failure in the four and a half decades since the first successful kidney transplant procedure was performed in 1954. The achievements of solid organ transplantation can be gauged by the progressive increase in the number of kidney, liver, heart, pancreas and lung transplants that are performed annually. Advances in surgical technique, immunotherapy, control of opportunistic infections and tissue typing have collectively contributed to current 1-year patient survival rates that exceed 95% and current 1-year graft survival rates in excess of 85%. This paper will review some of the major advances that have lead to the current state of transplant immunobiology.

Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction.

BACKGROUND: It has been suggested that T cells primed by processed donor major histocompatibility complex antigen (the "indirect" pathway of allorecognition) may be responsible for mediating chronic allograft rejection. The purpose of this study was to develop a clinically useful assay to study the occurrence of indirect allorecognition during chronic rejection in humans. METHODS: A panel of 20 mer peptides corresponding to the hypervariable regions of HLA-DRB1*0101, DRB1*1501, and DRB1*0301 were synthesized. Lymphocytes obtained from renal allograft recipients were cocultured with these peptides. Proliferation was assayed by DNA incorporation of [3H]thymidine, and positive proliferation was defined by a statistically significant increase in counts per minute over background with a minimum stimulation index of 2. The precursor frequency of allopeptide reactive T cells was determined by limiting dilution analysis. RESULTS: Lymphocytes from 82% of patients who were mismatched for at least one of the three DR molecules and had chronic allograft dysfunction specifically proliferated to the mismatched allopeptides (n=11). Proliferation was seen in only 6% of control subjects (2/33, P<0.0001). The proliferative response was low grade and was best detected on day 7-8 of culture in vitro. The precursor frequency of peptide-specific T cells was more than 10-fold higher compared with controls (P<0.001). CONCLUSIONS: These data demonstrate for the first time that T cells of patients with chronic graft dysfunction are primed to recognize and respond to specific donor-derived major histocompatibility complex allopeptides. Our results support the hypothesis that T cells primed via the indirect pathway of allorecognition may be important mediators of chronic rejection and provide the rationale to develop specific therapeutic strategies to prevent or interrupt this process.

Maintenance pharmacological immunosuppressive strategies in renal transplantation.

Current maintenance immunosuppressive regimens for transplantation are based on three classes of drugs: corticosteroids, immunophilin-binding agents (eg, cyclosporin and tacrolimus), and antimetabolites (eg, azathioprine and mycophenolate). Drugs from the various classes inhibit the immune system at different points and are thus synergistic when used in combination.

Light chain deposition disease complicating familial Mediterranean fever.

Familial Mediterranean fever (fMf) is an inherited condition characterized by polyserositis and is sometimes complicated by AA renal amyloidosis leading to nephrotic syndrome and renal failure. We present a case of a man with fMf who presented with rapidly progressive renal failure caused by light chain deposition disease. This disease association has not previously been described in the medical literature.

Role of indirect allorecognition in experimental late acute rejection.

BACKGROUND: Late acute rejection affects up to 28% of renal allograft recipients and remains a major risk factor for late graft loss. As donor-origin antigen-presenting cells are depleted with time, T-cell recognition of donor-derived alloantigenic peptides presented by self antigen-presenting cells (the "indirect pathway" of allorecognition) may play a key role in the initiation of late acute rejection episodes. METHODS: To test this hypothesis, we developed a clinically relevant experimental model in the rat (Wistar-Furth/Lewis) in which allograft recipients received cyclosporine for 1 month after transplantation and were then allowed to reject the graft upon discontinuation of immunosuppression. Lymphocyte proliferation assays to synthetic class II MHC allopeptides of donor origin and also to intact donor (Wistar-Furth) cells were performed at this time. The effector mechanisms studied included delayed-type hypersensitivity (DTH) responses, lymphocyte-mediated cytotoxicity, and alloantibody production. RESULTS: Lymphocytes from recipients undergoing late acute rejection had marked suppression of mixed lymphocyte reaction proliferation to intact donor cells. Significant proliferation to donor-derived 25-mer polymorphic class II MHC allopeptides was elicited, however. In vivo, significant DTH responses were observed to both MHC allopeptides and intact Wistar-Furth cells. Recipient lymphocytes also exhibited significant killing of donor cells, although not third-party cells, and anti-donor alloantibodies were detected by flow cytometry. CONCLUSION: Our results indicate that T cells primed via the indirect pathway are present during acute rejection that occurs after discontinuation of cyclosporine. Mixed lymphocyte reactivity is markedly reduced at this time. Furthermore, there is an association between such allopeptide-primed T cells and the elicitation of specific DTH responses and provision of help to B cells to produce alloantibodies and activation of CD8+ T cells to become effector cytotoxic cells.