Philippe Grimbert

Repair of the lower and middle parts of the face by composite tissue allotransplantation in a patient with massive plexiform neurofibroma: a 1-year follow-up study

BACKGROUND The risk to benefit ratio of face transplantation with a composite tissue allograft remains debatable, although this procedure is technically feasible. We report here a 1-year follow-up of a patient who underwent face transplantation with a composite tissue allograft. METHODS On Jan 21, 2007, a 29-year-old man with neurofibromatosis type 1 underwent resection of a massive plexiform neurofibroma diffusely infiltrating the middle and lower part of his face. The main goal was to restore both the cutaneous appearance and function of the face, including, in particular, control of orbicularis oculi and oris muscle contraction. The issues of immunosuppressive therapy, psychological outcome, and social reintergration were addressed, together with the monitoring of graft rejection by biopsies of the skin and mucosa. FINDINGS The initial postoperative course was uncomplicated. Two episodes of clinical rejection occurred on days 28 and 64. The second episode was associated with cytomegalovirus infection. Both episodes resolved favourably, with no further clinical signs of rejection, making the reduction of immunosuppressive treatment possible. A year after surgery, the functional outcome was very good, with successful sensory and motor reinnervation in the transplanted territory. Psychological recovery was excellent, with complete social reintegration. INTERPRETATION This case demonstrates the feasibility of surgically removing a large part of the face and replacing it with a composite tissue allograft. This facial repair procedure, which seems to have a satisfactory risk to benefit ratio, could be offered in rare and selected cases.

Feasibility, reproducibility, risks and benefits of face transplantation: a prospective study of outcomes.

Composite tissue allotransplantations can be indicated when autologous transfers fail to restore human appearance. We report the reproducibility, difficulties, serious adverse events and outcomes of our patients. Five patients were included in a registered clinical research protocol after thorough screenings assessed by an independent expert committee systematically discussing the alternative options. One patient suffered from plexiform neurofibromas, two from third degree burns and two from gunshot injuries. They were included on a national waiting list with a dedicated face procurement procedure. Transplants were harvested from heart beating brain‐dead donors before other tissues and organs. Induction immunosuppressive therapy included antithymocyte globulins, steroids, mycophenolate mophetil and tacrolimus. Maintenance therapy included the last three ones associated with extracorporeal‐photopheresis. Four patients were transplanted with 7‐ to 38‐month follow‐up. One could not due to multiple panel reactive antibodies after 18 months on waiting list. Acute cellular rejections were controlled by conventional treatment. Opportunistic infections affected all patients and lead one patient to die two month after the transplantation. Voluntary facial activity appeared from 3 to 5 month. Face transplantation has been reproducible under conventional immunosuppression. Major improvements in facial aesthetic and function allowed patients to recover social relations and improved their quality of life.

Risk factors and long-term outcome of transplant renal artery stenosis in adult recipients after treatment by percutaneous transluminal angioplasty.

Transplant renal artery stenosis (TRAS) is a common complication of kidney transplantation but attempts to identify predisposing risk factors for TRAS have yielded conflicting results. In order to determine the predisposing factors for transplant (TRAS), we retrospectively reviewed the records of 29 renal allograft recipients with TRAS treated with percutaneous transluminal angioplasty (PTA). The TRAS group was compared with a case‐control group of 58 patients. Predisposing factors for TRAS included CMV infection (41.4% vs. 12.1% p = 0.0018) and initial delayed graft function (DGF) (48.3% vs. 15.5% p = 0.0018), respectively in the TRAS and the control group. Acute rejection occurred more frequently in patients from the TRAS group (48.3%) compared with the control group (27.6%), although the difference was not significant (p = 0.06). In a multivariate analysis, only CMV infection (p = 0.005) and DGF (p = 0.009) appear to be significantly and independently associated with TRAS. The long‐term graft survival was significantly higher in the control group, compared with the TRAS group (p = 0.03). Our study suggests that CMV infection and DGF are two reliable risk factors for TRAS. Despite treatment by PTA with primary successful results, TRAS significantly affects long‐term graft outcome.

Dominant Renin Gene Mutations Associated with Early-Onset Hyperuricemia, Anemia, and Chronic Kidney Failure

Through linkage analysis and candidate gene sequencing, we identified three unrelated families with the autosomal-dominant inheritance of early onset anemia, hypouricosuric hyperuricemia, progressive kidney failure, and mutations resulting either in the deletion (p.Leu16del) or the amino acid exchange (p.Leu16Arg) of a single leucine residue in the signal sequence of renin. Both mutations decrease signal sequence hydrophobicity and are predicted by bioinformatic analyses to damage targeting and cotranslational translocation of preprorenin into the endoplasmic reticulum (ER). Transfection and in vitro studies confirmed that both mutations affect ER translocation and processing of nascent preprorenin, resulting either in reduced (p.Leu16del) or abolished (p.Leu16Arg) prorenin and renin biosynthesis and secretion. Expression of renin and other components of the renin-angiotensin system was decreased accordingly in kidney biopsy specimens from affected individuals. Cells stably expressing the p.Leu16del protein showed activated ER stress, unfolded protein response, and reduced growth rate. It is likely that expression of the mutant proteins has a dominant toxic effect gradually reducing the viability of renin-expressing cells. This alters the intrarenal renin-angiotensin system and the juxtaglomerular apparatus functionality and leads to nephron dropout and progressive kidney failure. Our findings provide insight into the functionality of renin-angiotensin system and stress the importance of renin analysis in families and individuals with early onset hyperuricemia, anemia, and progressive kidney failure.

Renal transplantation from extended criteria cadaveric donors: problems and perspectives overview.

The critical shortage of organs available for renal transplantation has led to the consideration of alternative strategies for increasing the donor pool. Recently, the cadaveric kidney donor pool extended to donors who might have been deemed unsuitable in early times, leading to the concept of marginal donors and more recently to the notion of expanded criteria donors. Such organs are eligible for organ donation but, because of extreme age and other clinical characteristics, are expected to produce allograft at risk for diminished post‐transplant function. Thus, the challenge is now to reduce the difference between graft outcome from patients grafted with marginal and ‘optimal’ donors. This implies appropriate transplantation strategies during pre‐, peri‐ and post‐transplantation phases including reduction of cold ischemia time, recipient selection, adaptation of immunosuppressive drug regimens, increase in nephron mass by dual kidney transplantation, and improvement in the graft selection process using histological criteria. This review summarizes current definition of a marginal donor and provides some guidance for clinical management of such transplant.

Truncation of C-mip (Tc-mip), a new proximal signaling protein, induces c-maf Th2 transcription factor and cytoskeleton reorganization.

Several arguments suggest that minimal change nephrotic syndrome (MCNS) results from yet unknown systemic disorder of T cell function. By screening a cDNA library from T cell relapse, we identified a new pleckstrin homology (PH) domain-containing protein encoded by a gene located on chromosome 16q24. Two alternative transcripts were identified. The first species (c-mip) was expressed in fetal liver, kidney, and peripheral blood mononuclear cells (PBMCs), but weakly detected in PBMCs from MCNS patients. The second form (Tc-mip, standing for truncated c-maf inducing protein), corresponds to subtracted transcript and lacks the NH2-terminal PH domain. The expression of Tc-mip was restricted to fetal liver, thymus, and MCNS PBMCs where it was specifically recruited in CD4+ T cells subset. Overexpression of Tc-mip in T cell Jurkat induced c-maf, transactivated the interleukin 4 gene and down-regulated the interferon γ expression, characteristic of a Th2 commitment. Moreover, the overexpression of Tc-mip induced Src phosphorylation, T cell clustering, and a cellular redistribution of the cytoskeleton-associated L-plastin, by a PI3 kinase independent pathway. Tc-mip represents therefore the first identified protein, which links proximal signaling to c-maf induction.

Clinical and morphologic spectrum of renal involvement in patients with mixed cryoglobulinemia without evidence of hepatitis C virus infection.

Hepatitis C virus (HCV) infection represents, by far, the major cause of mixed cryoglobulinemia (MC). The renal disease associated with this pathological condition is now well described. By contrast, renal involvement in patients with MC not associated with HCV has been only poorly described, and few cases have been reported. We analyzed the demographic, clinical, and laboratory features and outcome in patients presenting with renal disease associated with MC not related to HCV infection. Records of 20 patients with MC and renal disease, with no evidence of HCV by serology and polymerase chain reaction analysis, were retrospectively analyzed. Renal biopsies and extensive searches for lymphoproliferative disorder were performed in all patients at presentation. MC was related to primary Sjögren Syndrome (pSS) in 9 patients, and to non-Hodgkin lymphoma in 1 patient, while MC was classified as essential in the remaining 10 cases. Renal involvement was characterized by microscopic hematuria in all patients, nephrotic range proteinuria in 75% of patients, hypertension in 80% of patients, and renal failure in 85% of patients (mean glomerular filtration rate, 46 mL/min per 1.73 m2). Membranoproliferative glomerulonephritis with subendothelial deposits was observed in all kidney specimens. Skin vasculitis was the main extrarenal manifestation. In all patients, cryoglobulinemia was classified as type II MC, characterized by monoclonal IgM&kgr; and polyclonal IgG. Most patients (17/20) were treated with steroids or immunosuppressive agents, or both. Initial renal remission was observed in 94% of patients. However, renal relapse occurred in most patients, with 10% reaching end-stage renal disease. Three patients with essential MC developed B-cell lymphoma 36-48 months after the diagnosis of MC. Unexpectedly, B-cell lymphoma induced by Epstein-Barr virus infection occurred in only 1 of the 9 pSS patients. Forty percent of patients died as a result of extrarenal causes. Renal disease associated with MC unrelated to HCV is characterized by the high prevalence of pSS (45%), the finding of CD20+ B-lymphocyte nodular infiltrates in the kidney interstitium, and a high incidence of overt B-cell lymphoma during follow-up. These findings emphasize the need for repetitive clinical evaluation in those patients. Abbreviations: GFR = glomerular filtration rate, HCV = hepatitis C virus, HIV-1 = human immunodeficiency virus-1, MC = mixed cryoglobulinemia, pSS = primary Sjögren syndrome.

Acute Renal Infarction: A Case Series

BACKGROUND AND OBJECTIVES Renal infarction is an arterial vascular event that may cause irreversible damage to kidney tissues. This study describes the clinical characteristics of patients with renal infarction according to underlying mechanism of vascular injury. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study retrospectively identified 94 patients with renal infarction diagnosed between 1989 and 2011 with the aim of highlighting potential correlations between demographic, clinical, and biologic characteristics and the etiology of renal infarction. Four groups were identified: renal infarction of cardiac origin (cardiac group, n=23), renal infarction associated with renal artery injury (renal injury group, n=29), renal infarction associated with hypercoagulability disorders (hypercoagulable group, n=15), and apparently idiopathic renal infarction (idiopathic group, n=27). RESULTS Clinical symptoms included abdominal and/or flank pain in 96.8% of cases; 46 patients had uncontrolled hypertension at diagnosis. Laboratory findings included increase of lactate dehydrogenase level (90.5%), increase in C-reactive protein level (77.6%), and renal impairment (40.4%). Compared with renal injury group patients, this study found that cardiac group patients were older (relative risk for 1 year increase=1.21, P=0.001) and displayed a lower diastolic BP (relative risk per 1 mmHg=0.94, P=0.05). Patients in the hypercoagulable group had a significantly lower diastolic BP (relative risk=0.86, P=0.005). Patients in the idiopathic group were older (relative risk=1.13, P=0.01) and less frequently men (relative risk=0.11, P=0.02). Seven patients required hemodialysis at the first evaluation, and zero patients died during the first 30 days. CONCLUSIONS This study suggests that the clinical and biologic characteristics of patients can provide valuable information about the causal mechanism involved in renal infarction occurrence.

Extracorporeal photopheresis: from solid organs to face transplantation.

Composite tissue allotransplantations (CTA), were introduced with the first successful hand transplantation and are now a part of reconstructive surgery armamentarium. These reconstructive procedures for non life-threatening indications remain rare due to adverse effects of the associated lifelong immunosuppressive therapy. Indeed, despite recent progress, immunosuppressive therapies remain non-specific to the type of donor and still bear significant risks of serious side effects. Extracorporeal photopheresis (ECP), also called photochemotherapy, has been introduced in the composite tissue allotransplantation field as a part of acute rejection treatment in face transplantations. ECP has been performed after solid organ transplantations as a supportive therapy for acute rejection episodes. It has also been used to treat graft versus host diseases, which can occur after bone marrow or stem cell transplantations. ECP is also used to treat dermatologic diseases, such as cutaneous T-cell lymphoma, or autoimmune diseases, such as scleroderma or pemphigus vulgaris. The principle of ECP is to induce leucocyte apoptosis with UVA radiation after their presentation by psoralens. These leucocytes are immediately re-infused into the patient, where they undergo early apoptosis. Following apoptosis, the leucocytes are engulfed by macrophage or other antigen-presenting cells, such as immature dendritic cells, in an anti-inflammatory cytokine environment. The anti-inflammatory cytokine secretion pattern, with a switch from TH1 to TH2 for CD4+ lymphocytes, and the engulfment by immature cells without co-stimulatory molecules induces anergy, by deleting effector T-cells that responded to the presented antigens. An increase in regulatory T-cells (T-regs) is also induced after ECP and may contribute to allograft acceptance by the recipient. ECP has already been used for the great majority of solid organ transplantations to cure acute rejection episodes or in an attempt to prevent or cure chronic rejections, such as bronchitis obliterans, which occurs after lung transplantation. Considering composite tissue allotransplantations, ECP was used in two face transplantations after the occurrence of second rejection episodes triggered by viral infections. ECP therapy, associated with maintenance immunosuppressive therapy and doses of methylprednisolone, and the control of viral infection, succeeded to reverse the rejection process without the development of other side effects. Despite the fact that the mechanism of action of ECP has not been fully elucidated, this therapy could be a useful supportive therapy during the treatment of acute rejection episodes in composite tissue allotransplantations. In this review, we introduce the interest of ECP implementation in CTA in face allotransplantations.

Long-term outcome of kidney transplantation in patients with systemic lupus erythematosus : A multicenter study

Background. The outcome of 60 renal transplantations in 53 patients with end-stage renal disease (ESRD) because of lupus nephritis was studied retrospectively and compared with 106 controls matched for age, sex, maximum panel-reactive antibody (PRA) level, and date of transplantation. Methods. The patients received their transplants over a 260-month period (21.5 years) between October 1971 and August 1993. The population was predominantly women (90%), and the mean age at the time of the transplantation was 33.2 years (range: 21-54 years). Fifty-six transplants (93%) were from cadaveric donors, and 4 (7%) were from living-related donors; 46 patients (86%) had primary allografts, and 7 (14%) received a second allograft. The duration of disease before transplantation was 93.6±6.2 months, and the duration of dialysis before transplantation was 48±6 months. Results. No patient had clinically active systemic lupus erythematosus (SLE) at the time of transplantation. The 1-year graft and patient survival rates were 83% and 98%, and the 5-year graft and patient survival rates were 69% and 96%. Actuarial graft and patient survival rates in SLE patients were not significantly different from those of the matched control group. Chronic rejection was the major risk factor for graft loss. Lupus nephritis recurred in the graft of one patient 3 months after transplantation, and there were extrarenal manifestations of SLE in four others. Conclusions. The present study confirms that patients with SLE can receive transplants with excellent graft and patient survival rates and a low rate of clinical recurrent lupus nephritis.