Recurent and de novo membranous glomerulopathy after kidney transplantation.

The aim of this study was to compare the clinical characteristics of recurrent and de novo membranous glomerulopathy (MG) among a cohort of 614 recipients transplanted between 1989 and 2006. Lupus nephritides were excluded. The diagnosis was established on protocol biopsies performed 1, 2, 4, or 8 years after transplantation or because of proteinuria/nephrotic syndrome and/or an increased serum creatinine level. HCV infection, cryoglobulinemia, monoclonal gammopathy, skin cancers, Kaposi sarcoma, diabetes mellitus, anti-HLA antibodies, and graft survival were not significantly different between the groups. Seventeen MG were diagnosed in 15 patients (2.45% of the whole group), including 6 recurrent MG (35%) and 11 de novo MG (75%). Recurrent MG occurred earlier than de novo MG (15.58 +/- 19.13 vs 49.27 +/- 32.71 months). Recipients with de novo MG were more frequently infected with HCV, which seemed to be the main etiologic factor for de novo MG, and may be linked to a Th2 polarization of the immune response.

Rheumatoid arthritis-induced pseudotumoral AA amyloidosis of the bladder with vesico-peritoneal fistula.

Rheumatoid arthritis-induced AA amyloidosis of the bladder is rare, with fewer than 25 cases reported so far. This localization may be life-threatening with a mortality rate of about 60%, most often due to massive hematuria or multiorgan failure as a result of systemic amyloidosis. We report the case of a 72-year-old woman with a long history of rheumatoid arthritis who developed gross hematuria that induced severe anemia. Ultrasonography and tomodensitometry revealed a large mass localized in the upper part of the bladder. Cystoscopy showed a congestive inflammatory area with a large vesicoperitoneal fistula. Biopsies revealed amyloidosis, and immunohistochemical staining of the specimens defined the process as AA amyloidosis. The amyloid deposits were also found in the rectum, duodenum, uterus and kidneys. This case of rheumatoid arthritis-induced AA amyloidosis of the bladder is characterized by its pseudotumoral aspect and the existence ofa vesico-peritoneal fistula: only 2 cases have been reported so far. Treatment was symptomatic, and the patient died from cachexia. The pseudotumoral forms of AA amyloidosis, including amyloidosis of the bladder, deserve an early correct diagnosis. Otherwise, an incorrect diagnosis, especially cancer, may prompt inappropriate treatments.

Detection of Foxp3+ cells on biopsies of kidney transplants with early acute rejection.

This retrospective study was conducted to examine whether the presence of Foxp3+ cells in biopsies of kidney transplants displaying early acute rejection (AR) predicted the outcome of the episode. Seventeen biopsies showing AR included in this study were obtained at 42 +/- 30 days after transplantation. Lesions were graded according to the Banff classification. Foxp3 staining was performed on paraffin-embedded sections with a monoclonal antibody after antigen retrieval. We evaluated relationships between the number and the location of Foxp3+ cells, the type of rejection, and the serum creatinine value at 1 year. Foxp3+ cells were detected in 11 of 17 biopsies with AR (9.5 +/- 13.3 cells/mm(2)). These elements were mixed with other interstitial inflammatory cells. Intraepithelial tubular Foxp3+ cells were seen in 9 biopsies (1.5 +/- 2.5 cells/mm(2)). Foxp3+ cells were associated with borderline lesions (25.5 +/- 22.4/mm(2)); type 1 AR (7.18 +/- 9/mm(2)) and type 2 AR (1.99 +/- 3.46/mm(2)). The average number of cells per field was not different in C4d(+) and C4d(-) AR (6 +/- 8.35 vs 8.5 +/- 14.7/mm(2)). Graft loss within the first year was higher among the group of recipients without Foxp3+ cells (3/6) than those with Foxp3+ cells (0/11). All AR with intraepithelial tubular Foxp3 cells had favorable outcomes. Foxp3 has been proposed as a relevant marker of CD4(+)CD25(+) regulatory T cells. This study showed that Foxp3+ cells can be detected in kidney transplant biopsies with AR. The absence of Foxp3+ cells, especially in epithelial tubular cells, might indicate a poor prognosis following an AR episode.

Recurrence of IgA nephropathy with crescents in kidney transplants.

Crescentic IgA nephropathy is an uncommon finding in native kidneys (3%-5%) and in renal transplants. This study was performed to determine the frequency of relapsing crescentic IgA nephropathy after kidney transplantation. Over a 15-year period, 42 patients (25 men, 17 women) of age range 17 to 59 years with biopsy-proven IgA nephropathy in their native kidneys were entered into this retrospective study, because they had undergone kidney transplantation and had sequential allograft biopsies during their follow-up. Mean follow-up after transplantation was 8.9 years (range, 1-15 years). In their native kidneys, 5 patients (12%) had more than 20% crescents, and only 2 (5%) had more than 50% of glomeruli involved. As expected, 52.4% of recipients showed recurrent mesangial IgA deposits in their kidney grafts. The 2 patients with diffuse crescentic IgA nephropathy in their native kidneys experienced acute graft dysfunction at 15 and 47 months. Graft biopsy showed recurrent IgA deposits with cellular crescents in 30% and 20% of glomeruli, respectively. Despite corticosteroid pulse therapy, graft failures occurred 2 and 27 months later. No crescentic proliferation was observed during follow-up in any other case. Only 5 other grafts failed because of chronic allograft nephropathy, without any relationship to the relapse of IgA deposits. These data suggested for the first time that only diffuse crescentic IgA nephropathy in the native kidneys was associated with the occurrence of crescents in the kidney transplants, a finding that raises the possibility of a particular subgroup of IgA nephropathies.

Anti-donor DR103 Immunization in a DRB1*0101 kidney allograft recipient.

Posttransplant appearance of donor-specific anti-HLA antibodies is correlated with poor graft survival. Herein, we have provided evidence that an HLA-DRB1*0101 kidney allograft recipent developed anti-DR103 antibody after receiving a transplant from a HLA-DRB1*0103 cadaveric donor, resulting in graft loss. HLA-DRB1*0103 is a rare allele in Caucasian populations. It differs from DRB1*0101 only by three amino-acid substitutions and may play a central role in allorecognition. Nevertheless, our data showed that it induced alloimmunization in a DRB1*0101 recipient. Therefore, this new possibility of immunization must be taken into account before transplantation as well as after grafting.

Chimerism in lymphoid tissues and donor-specific antibody response after injection of allogenic splenic dendritic cells from Fischer rats to Lewis recipients.

The aim of this work was to study cellular chimerism achieved in lymphoid tissues and production of antidonor lymphocyte antibodies after injection of splenic dendritic cells (DCs) from Fischer F344 rats to Lewis recipients, a model of chronic rejection. DCs isolated from the spleen expressed OX62 (95%), CD80 (70%), and CD86 (80%). Two doses of these nonplasmacytoid splenic DCs from Fischer rats (2 x 10(6) and 5 x 10(6)), which had been labeled ex vivo with a TRITC fluorochrome (PKH26), were injected to Lewis recipients. Using fluorescence microscopy TRITC positive cells were localized at day 15 and day 45 in frozen sections from spleen, thymus, mesenteric lymph nodes, heart, liver, kidney, and skin (n = 5 per group). Donor-specific antibodies were sought with flow cytometric crossmatches in serum samples taken at 7, 15, 30, and 45 days. TRITC-positive DCs were essentially localized in the spleen, the thymus, and lymph nodes of Lewis recipients. The majority of DCs were detected in the spleen (14.9 +/- 3.3 and 14.3 +/- 0.9 DCs/per high power field respectively at day 45). A significant number of DCs was also detected in the thymus and mesenteric lymph nodes at both times. Only some scattered TRITC-positive cells were observed in other organs. The number of DCs was stable over time and did not depend on the injected dose. A positive flow cytometric cross-match was observed at day 30 in all recipients independent of the injected dose. These data showed that 2 x 10(6) mature, nonplasmocytoid DCs from F344 rats injected to Lewis recipients induced stable chimerism in primary and secondary lymphoid organs and a humoral response to donor antigens.

Expression of TGFbeta-1 and Type I TGFbeta-receptor on sequential biopsies of renal transplants with chronic allograft nephropathy.

The aim of this study was to determine the expression of transforming growth factor-beta (TGFbeta)-1 and type I TGFbeta-receptor on sequential biopsies from renal transplants with and without chronic allograft nephropathy. Twenty-four renal transplant recipients entered the study. They underwent sequential biopsies performed before (T1: 1.44 +/- 1.2 months) and 6 months after (T2: 15.96 +/- 7.2 months) transplantation. Lesions were graded according to the criteria of the Banff classification. C4d was detected by fluorescence microscopy. Immunohistochemistry was performed in order to identify cells expressing TGFbeta-1 and type I TGFbeta-receptor. In normal renal tissue (n = 4), TGFbeta-1 is expressed by tubular epithelial cells and endothelial cells lining glomerular and peritubular capillaries, whereas type 1 TGFbeta-receptor is expressed by tubular epithelial cells and smooth muscle cells in the media of arteries. In recipients with chronic allograft nephropathy (group 1, n = 14), diffuse epithelial expression of both molecules was found in more patients at T2 than at T1 (42.8% vs 21.4%). In contrast, this pattern of expression remained stable or decreased over time in recipients with long-term normal transplants (group 2, n = 10). Furthermore, type 1 TGFbeta-receptor was detected on the smooth muscle cells of arteries in 12/14 (85.7%) of recipients in group 1 and only in 4/9 (44.4%) of recipients in group 2. No relationship was noticed with regard to C4d deposits. These data suggest that the synthesis of TGFbeta-1 and type I TGFbeta-receptor increases over time in recipients developing chronic allograft nephropathy. Further studies are in progress in order to quantify mRNA of both molecules with real-time polymerase chain reaction.

Induction of tissue factor expression on human umbilical vein endothelial cells by cell-specific HLA class I antibody: preliminary data.

Donor-specific antibodies may play an important role in the development of chronic allograft rejection process. However, the mechanisms leading to intimal vascular proliferation and fibrosis remain poorly understood. The aim of this study was to examine whether donor-specific HLA antibodies induce overexpression of tissue factor (TF) by endothelial cells. HLA typed human umbilical vein endothelial cells (HUVEC) were incubated for 1 to 12 hours with LPS (10 microg/mL), and increasing concentrations (1 to 500 microg/mL) of anti-HLA A1 antibody specific for an antigen expressed by HUVEC and of an anti-HLA A2 antibody for which A2 was not expressed by the HUVEC. Expression of TF mRNA transcripts was quantified using real time Q-RT PCR and TF activity was tested in cell lysates of cultured HUVEC using a chromogenic TF activity assay. HUVEC-specific anti-HLA A1 antibody at low concentrations (10 microg/mL) induced both a significant increase of TF mRNA transcripts after 1 hour of incubation and TF activity after 3 hours incubation compared to incubation with medium alone or with the nonspecific anti-HLA A2 antibody (n = 4 for all experiments, P < .05). These data show for the first time that specific anti-HLA antibody can induce overexpression of TF on endothelial cells. TF, a transmembrane glycoprotein involved not only in the onset of the coagulation cascade, but also in cell proliferation and anti-apoptotic processes, may play a role in the development of alloantibody-induced chronic rejection.

Alteration in plasma antioxidant capacities in chronic renal failure and hemodialysis patients: a possible explanation for the increased cardiovascular risk in these patients.

OBJECTIVE: The high incidence of cardiovascular diseases in chronic renal failure (CRF) and hemodialyzed (HD) patients is now well established and the involvement of oxidative stress has been hypothesized in these phenomena. The aim of our study was to evaluate the level of oxidative stress in healthy controls (CTL) compared with CRF and HD patients before (pre-HD) and after (post-HD) the dialysis session, carried out on a high biocompatible polyacrylonitrile membrane AN69. METHODS: Several indicators of the extracellular redox status were evaluated in plasma. The ascorbyl free radical (AFR) was directly measured using electron spin resonance spectroscopy (ESR) and expressed with respect to the vitamin C level to obtain a direct index of oxidative stress. Indirect plasma parameters such as vitamin E, thiol and uric acid levels were also quantified. The plasma antioxidant status (PAS) was evaluated by the allophycocyanin test. Nitric oxide (NO) stable-end metabolites: nitrites and nitrates (NO(x)), were measured in plasma. RESULTS: In CRF patients, vitamin C and thiol levels were low, and the AFR/vitamin C ratio high compared with the CTL. On the other hand, PAS and uric acid levels were shown to be higher in CRF patients. After the dialysis session, vitamin C level decreased and AFR/vitamin C ratio increased. The thiol levels were shown to be increased, in return PAS and uric acid levels were significantly lower after the dialysis session. NO(x) levels rose during CRF, but were significantly decreased after the dialysis procedure. No differences in vitamin E status were observed between CTL, CRF and HD patients. CONCLUSION: Our study demonstrates that profound disturbances in the extracellular redox system occur during the course of chronic renal failure and hemodialysis, and may provide an explanation for the cardiovascular complications in these patients.

Foscarnet-induced crystalline glomerulonephritis with nephrotic syndrome and acute renal failure after kidney transplantation.

Foscarnet nephrotoxicity has been reported to be associated with acute tubulointerstitial nephritis. Crystals in glomerular capillary lumens have also been observed in patients with acquired immunodeficiency syndrome who were treated with foscarnet for cytomegalovirus disease. We describe a kidney transplant recipient who developed a nephrotic syndrome with microscopic hematuria and nonoliguric acute renal failure within 15 days after starting foscarnet therapy for cytomegalovirus infection. A kidney biopsy specimen showed the presence of crystals in all glomeruli and in proximal tubules. Fourier transform infrared microscopy analysis demonstrated that crystals were made from several forms of foscarnet salts: mixed calcium and sodium salts, and unchanged trisodium foscarnet salts. Renal function and proteinuria spontaneously improved, and a second transplant biopsy performed 8 months after the first one revealed fibrotic organization of half of the glomeruli and of interstitial tissue, and crystal vanishing. We were thus able to provide proof of the possible precipitation of foscarnet in a transplanted kidney.

Peripheral blood stem cell transplantation in a multiple myeloma patient with end-stage renal failure.

Multiple myeloma with IgG kappa monoclonal gammopathy and oliguric renal failure requiring hemodialysis was diagnosed in a 49-year-old man. Conventional therapy with VAD (vincristin, adriamycin, dexamethasone) failed to induce a complete response (CR) but this was subsequently obtained following two cycles of high-dose intravenous melphalan (70 mg/m2). A relapse occurred 8 months after CR which was treated by intensive myeloablative therapy combining total body irradiation (6 Gy over 2 days) and high-dose intravenous melphalan (140 mg/m2) followed by supportive PBSC transplantation. Hemodialysis was performed every other day during the myeloablative therapy and subsequent aplasia. Fluid subtraction allowed 1500 Cal/day intravenous alimentation and the only adverse event observed was a severe mucositis. A second CR was obtained which lasted 14 months. This observation indicates that multiple myeloma patients with end-stage renal failure can receive intensive myeloablative therapy without major toxicity.

Acute renal failure following collective intoxication by Cortinarius orellanus.

Twenty-six young men with no previous medical history all ingested mushroom soup, exclusively made with Cortinarius orellanus. They were hospitalized 10-12 days after the incident. On admission, 12 patients presented with acute tubulointerstitial nephritis with acute renal failure; 8 required haemodialysis. In addition to symptomatic treatment, 9 patients were given corticosteroids. In this group of 12 patients, 8 recovered rapidly, and the other 4 suffered from chronic renal failure for several months. In the other group of 14 patients, initial leukocyturia was observed in 12 cases, although renal function remained normal during a one-year follow-up. Hepatic acetylation and hydroxylation tests performed after 6 months in 22 patients did not provide any explanation for the strong individual sensitivity to the renal toxicity of this fungus.

Miller-Fisher syndrome and pontine abnormalities on MRI: a case report.

The authors report a patient with Miller-Fisher syndrome in whom MRI of the brain stem showed increased signal density on T2 sequence anterior to the fourth ventricle, on the right and the left. The authors discuss the relation between these MRI abnormalities and some clinical features of the syndrome. The authors believe that the cardinal features of Miller-Fisher syndrome are due to peripheral nervous system dysfunction, but that this does not preclude a possible central nervous system involvement.

Hemapheresis in systemic lupus erythematosus.

The place of plasma exchange in treating systemic lupus erythematosus remains to be discussed. Currently available clinical data suggest that PE may be a useful additional therapy only in certain subsets of some severe lupus manifestations such as CNS involvement, crescentic glomerulonephritis, and lupus vasculitis. Using PE could also be of interest in certain manifestations of the anti-phospholipid syndrome. The conflict between the rapid improvement seen in some biological abnormalities (circulating immune complexes, ds-DNA antibodies) and the lack of obvious parallel clinical benefits remains a field of stimulating investigation. Next to plasma exchange associated with conventional corticosteroid or immunosuppressive therapies, other approaches could be of value such as the synchronization of plasma exchange and cyclophosphamide pulses, or the selective removal of assumed pathogenetic antibodies or immune complexes. Insufficient data are presently available to interpret the results of the former. The latter methods could offer the advantage of more precisely establishing the role of selectively removed substances in the pathogenesis of SLE.

Implication of the Epstein-Barr virus in the progression of chronic lymphocytic leukaemia/small lymphocytic lymphoma to Hodgkin-like lymphomas.

Low grade CLL/SLL can evolve to a spectrum of various morphologic higher grade malignancies showing Reed-Sternberg like cells. The evolution towards Hodgkin's disease is rare but frequently associated with the presence of scattered RSL cells within the small lymphocyte proliferation of the CLL/SLL. The evolution towards a Richter's syndrome is more frequent and it can exhibit CD30 positive Reed-Sternberg like cells. In these Richter's syndrome cases, regarding the morphology and the phenotype, it seems likely that there is a spectrum of lesions between true HD and large cell NHL. In the present study, the authors report two cases of transformation of CLL/SLL in non immuno-suppressed patients; one evolved to a morphological and immunohistochemical Hodgkin's disease and the second to a NHL (Richter's syndrome) with numerous Reed-Sternberg like cells. In both cases, EBV has been detected within RSL cells by immunohistochemistry and in-situ hybridization (ISH). So, the role of EBV is suggested in that kind of transformation.

Papillary necrosis: a late complication of nephropathia epidemica?

In the following we describe a case of nephropathia epidemica, which exhibited, a few years after acute infection, arterial hypertension and multiple papillary necrosis. Papillary necrosis was diagnosed by i.v. pyelography and CT Scan. A complete evaluation of the patient failed to show any other etiology for medullary necrosis. If arterial hypertension has already been reported as a complication of nephropathia epidemica, papillary necrosis is exceptional, but may be explained by the severe vascular troubles engendered by Hantavirus infection in kidney medulla.

6-Mercaptopurine pharmacokinetics after use of azathioprine in renal transplant recipients with intermediate or high thiopurine methyl transferase activity phenotype.

Prevention of allograft transplant rejection by the immunosuppressive 6-thiopurine drug azathioprine is limited by haematological toxicity (leucopenia or agranulocytosis). This toxicity is particularly apparent in subjects with low thiopurine methyltransferase activity (TPMTase) phenotype (1% in the Caucasian population). The thiopurine derivative 6-mercaptopurine is the active metabolite of azathioprine, and it would be of interest to measure, after validation of plasma measurements, the mean values of the pharmacokinetic parameters in transplant patients with high or intermediate TPMTase phenotypes (85 and 14% of the Caucasian population, respectively). We measured erythrocyte TPMTase activity in 103 kidney transplant recipients of high or intermediate phenotype and calculated, after a test dose of azathioprine, the mean values of the pharmacokinetic parameters for 6-mercaptopurine. We also compared these values with the same parameters from one subject with low TPMTase activity phenotype. The mean observed area under the plasma concentration-time curve (AUC) was 190+/-140 ng mL(-1) h and the elimination rate constant (Kel) was 1.92+/-1. The pharmacokinetic parameters (AUC, Kel, t1/2el (the elimination half-life)) of 6-mercaptopurine in transplant patients are normally distributed and suitable for acceptance as a gold standard value for this population of Caucasian transplant patients. It seems useful to calculate these parameters, representative of the systemic exposure of individual patients to the drug, before prescribing these subjects azathioprine immunosuppressive treatment. In subjects with low TPMTase phenotype these pharmacokinetic measurements could also be an index of dose reduction.

Aluminium bone deposits in normal renal function patients after long-term treatment by plasma exchange.

The accumulation of aluminium (Al) can cause Al bone deposits, osteomalacia and encephalopathy. As albumin solutions used as replacement fluid in plasma exchange (PE) are contaminated with Al, we studied Al overload in two symptomless patients with normal renal function, treated by long-term plasma exchange (PE). Total Al loading was calculated at 1750 mumol in patient 1 (178 PE sessions) and 2100 mumol in patient 2 (153 PE sessions). Bone biopsy showed Al deposits and low bone formation without osteomalacia in patient 1 and only osteoporosis in patient 2. Plasma Al levels were useless in detecting early Al overload, because the remained in the normal range, even after PE in both patients. Bone biopsy was the best means of recognizing Al intoxication, but cannot be recommended for frequent evaluations. However, the desferrioxamine mobilization test can be proposed as a repetitive non-invasive investigation method.

[Calcific constrictive pericarditis of anginal form complicated by hemopericardium and tamponade during anticoagulant treatment]. / Péricardite constrictive calcifiante à forme angineuse compliquée d'hémopéricarde et de tamponnade au décours d'un traitement anticoagulant

The case-history of a patient with calcified constrictive epicardopericarditis with rapidely progressive aggravation after digestive hemorrage due to excessive dose or oral anticoagulant therapy is reported. The occurrence of a cardiac tamponade has necessitated pericardectomy which has permitted to detect a partitionned hemopericardium. The surgical act was followed by gross improvement of both constrictive phenomenon and angina pectoris which have grounded the prescription of anticoagulant therapy. Anticoagulant therapy is likely responsible of the hemopericardium. Such facts are exceptionals in the course of constrictive pericarditis; diagnostic and therapeutic problems related to this complication are studied. The question of angina pectoris in the course of acute and chronic pericarditis is briefly studied by the way of this observation. Attention is drawed on the danger of the prescription of anticoagulant therapy in the course of some constrictive pericarditides.