François Paraf

Influence of host-recipient origin on clinical aspects of posttransplantation lymphoproliferative disorders in kidney transplantation

BACKGROUND Posttransplantation lymphoproliferative disorder (PTLD) is a well-known complication of immunosuppression associated with solid organ transplantation. The donor or host origin of PTLD may influence the outcome of the disease as it has been reported that a donor origin may be associated with a better prognosis. The aim of the study was to determine the origin (recipient or donor) of 12 PTLD occurring in kidney transplant recipients and to correlate the results with clinical findings. METHODS Origin of PTLD was determined using HLA DRB1 molecular typing, analysis of multiple short-tandem repeat microsatellite loci, and HLA class I antigen expression by immunohistochemistry. RESULTS Combining the three techniques, we found that eight cases originated from the recipient and four cases originated from the donor. The results of the three techniques were concordant and altogether assigned the origin of the tumors. All the donor-origin PTLD were strictly localized to the kidney graft, developed after a mean time of 5 months after transplantation, and regressed after reduction of immunosuppression. In contrast, seven of the eight recipient-origin PTLD presented as multisystemic disease, occurred a mean time of 75.7 months after the transplantation, and had a worse outcome (mortality, five deaths of eight patients, 62.5%). CONCLUSIONS These results suggest that PTLD originating from the donor arise in the first year after transplantation into the graft, and that recipient-origin PTLD develop later as an invasive disease. Because it permits simultaneously the analysis of cell morphology and tumor origin, immunohistochemistry is a more reliable technique in the case of graft tumors associated with allograft rejection. The determination of the origin of the tumors seems to be of value in the management of PTLD to predict the outcome and to adapt therapy.

Interferon alpha and ribavirin for membranoproliferative glomerulonephritis and hepatitis C infection

Cryoglobulinemic membranoproliferative glomerulonephritis, an extrahepatic manifestation of chronic hepatitis C virus infection, often poses a therapeutic challenge (1). Although glucocorticosteroids and interferon alpha are effective in controlling the acute phase of the disease, a sustained response is unusual after discontinuation of treatment (2,3). The combination of interferon alpha and ribavirin, a nucleoside analog with broad activity against both deoxyribonucleic acid and ribonucleic acid (RNA) viruses, may improve the prognosis of hepatitis C virus infection in patients without renal disease (4,5). The few studies of this combination in patients with hepatitis C virus–associated cryoglobulinemic glomerulonephritis have had variable results (6-8). We report two additional patients who achieved a long-term response with early combination antiviral treatment.

Acute Renal Failure in a Marathon Runner: Role of Glomerular Bleeding inTubular Injury

Hematuria is a well recognized and generally benign consequence of sports activity, especially running a marathon (1). A few cases of acute renal failure in long-distance runners have been described due to rhabdomyolysis or less frequently to hemolysis (march hemoglobinuria) (1-3). We report the case of a marathon runner who presented with gross hematuria and anuric renal failure that we considered to be due to tubular injury from glomerular bleeding, similar to that seen in IgA nephropathy (4).

Molecular study of an IgG1κ cryoglobulin yielding organized microtubular deposits and glomerulonephritis in the course of chronic lymphocytic leukaemia

Glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits (GOMMID) and glomerulonephritis related to type I cryoglobulin are well‐known but rare complications of B cell derived chronic lymphocytic leukaemia. In these disorders, monoclonal Ig have never been studied at the molecular level. We conducted a pathological and molecular analysis in a patient with chronic lymphocytic leukaemia, glomerulonephritis and a single circulating monoclonal Ig. Unusual IgG1κ kidney deposits were observed. The heavy and light chain variable region sequences of that cryoprecipitating monoclonal Ig were characterized. Light microscopy revealed glomerulonephritis typical of cryoglobulinaemia, with neutrophil and macrophage infiltration, endocapillary hyperplasia and few protein thrombi. Electron microscopic study clearly evidenced numerous subepithelial mixed granular and organized deposits with a unique microtubular organization, reminiscent of the GOMMID. The Ig molecule sequence revealed alterations of charge and hydrophobicity potentially promoting a crystal‐like aggregation and the aggregation of microtubules.This description suggests that common mechanisms are involved in various forms of precipitation and/or deposition of complete Ig molecules, with a variable extent of organization and with a possible overlap between pathological patterns of either glomerulonephritis with microtubular deposits or type I cryoglobulinic glomerulonephritis.

Maladie de Hirschsprung : attitude pratique

Resume La maladie de Hirschsprung (1/5 000 naissances) est definie par l’absence congenitale de cellules ganglionnaires neuronales dans les plexus nerveux a l’extremite distale du tube digestif. Le segment atteint est rectosigmoidien dans 80 % des cas, ou plus etendu. La maladie de Hirschsprung est suspectee en cas d’occlusion digestive basse neonatale ou de constipation chronique severe chez l’enfant. Son diagnostic repose sur l’examen anatomopathologique de biopsies rectales comportant la sous-muqueuse. Les cellules neuronales sont recherchees sur sections multiples en coloration standard. La coloration acetylcholinesterasique est pratiquee sur fragment congele afin de rechercher l’hyperplasie des fibres cholinergiques tres evocatrice de la maladie de Hirschsprung. Cette hyperplasie decroit du rectum a l’angle gauche. L’hyperplasie des fibres nerveuses extrinseques et la rarefaction des jonctions neuromusculaires au cours de la maladie de Hirschsprung peuvent etre mises en evidence en immunohistochimie. Le diagnostic differentiel inclut les pseudo-obstructions intestinales chroniques. Le traitement de la maladie de Hirschsprung consiste en l’anastomose du tube digestif normalement innerve au canal anal. Les biopsies per- ou pre-operatoires permettent de guider la chirurgie. Elles sont d’interpretation difficile en zone transitionnelle. L’examen de la piece d’exerese permet de mesurer le segment aganglionnaire et la zone transitionnelle. Differents genes (le plus souvent la gene RET) peuvent etre impliques dans la maladie de Hirschsprung sporadique ou familiale. La maladie de Hirschsprung est associee a d’autres anomalies, digestives ou extra-digestives, dans 5 a 30 % des cas. Les associations lesionnelles peuvent retarder le diagnostic et le traitement de la maladie de Hirschsprung.

Comment et quand rechercher une instabilité des microsatellites dans les cancers colorectaux en 2008

Resume Le cancer colorectal hereditaire non polyposique ou syndrome de Lynch est lie a une mutation germinale d’un des genes de reparation des mesappariements de l’ADN. Cette mutation est associee a un phenotype instable de l’ADN tumoral qui se traduit par la presence d’alleles surnumeraires lors du genotypage de marqueurs microsatellites. A cote du panel de reference de Bethesda, a ete propose un panel alternatif de 5 marqueurs microsatellites mononucleotidiques (BAT25, BAT26, NR21, NR24, NR27) plus sensible et d’utilisation plus rapide sous forme de PCR multiplexe. L’immunohistochimie permet de detecter la perte d’expression dans la tumeur des proteines MLH1, MSH2, MSH6 et PMS2, qui correspond au gene mute. Elle oriente ainsi l’analyse constitutionnelle, sauf dans le cas de la proteine MLH1 dont l’extinction peut correspondre a une mutation germinale du gene MLH1 ou a une inactivation par methylation de son promoteur. Celle-ci est habituellement en rapport avec le vieillissement et s’accompagne le plus souvent dans l’ADN tumoral de la mutation V600E du gene BRAF qui est absente dans le syndrome de Lynch. La combinaison sequentielle de ces 3 analyses somatiques devrait permettre de reduire les indications d’analyse constitutionnelle des genes alteres dans le syndrome de Lynch.

A renal transplant recipient with intraglomerular Candida albicans

A 62-year-old man was admitted for his first renal transplantation in August 2001. Immunosuppressive therapy consisted of anti-thymocyte globulin, ciclosporin A, mycophenolate mofetil and steroids. On Day 1 post-transplantation, haemorrhagic shock occurred, leading to massive blood transfusion, surgical re-intervention and delayed graft function (DGF). A large haematoma developed at the transplant site. One month later, DGF was still present and the patient developed severe sepsis. A renal biopsy was performed and showed isolated acute tubular necrosis, explaining the DGF, and unexpectedly a few glomeruli and tubes contained yeast forms that were characteristic of Candida albicans (Figures ​(Figures11 and ​and2).2). Blood cultures were also positive for C. albicans as were transplant site haematoma cultures. Fig. 1 Silver stain (×400) showing intraglomerular yeast (Candida albicans) (yellow arrows) in two different glomeruli associated with inflammatory reaction in the urinary chamber. Fig. 2 PAS stain (A ×200; B × 320) showing intratubular Candida albicans (black arrows) associated with inflammatory reaction in and around the tube. C. albicans septicaemia was treated with 15-day intravenous amphotericin B together with 1-month treatment with fluconazole and evacuation of the haematoma. One month later (2 months after kidney transplantation), renal function had recovered, and the patient was discharged from the hospital with a plasma creatinine level of 240 μmol/l. To the best of our knowledge, there is only one published report of intraglomerular yeast [1] in an HIV-infected patient. Our own report of severe candidaemia after kidney transplantation associated with the intra-glomerular presence of C. albicans would appear to be the only reported case to date.​date. ​ Conflict of interest statement. None declared.