Hermann Joseph Gröne

Expression of A20 in the vessel wall of rat-kidney allografts correlates with protection from transplant arteriosclerosis.

Background. Chronic rejection with development of transplant arteriosclerosis is the major culprit involved in loss of kidney allografts. The allografts’ fate was thought to depend on the intensity of the host immune responses and the potency of immunosuppressive regimens. Recent data suggests that grafts contribute to their own survival by way of up-regulation of “cytoprotective” genes. Methods. We analyzed the expression of four cytoprotective genes, A20, Bcl-2, Bcl-xL and heme oxygenase (HO)-1, in three rat renal allograft models of chronic rejection: Fisher 344–Lewis (F344/Lew), Dark Agouti–Brown Norway (DA/BN), and DA–Wistar-Furth (WF). We chose these genes for their known anti-inflammatory and anti-apoptotic function in endothelial cells (EC) and the atheroprotective function of A20 in smooth muscle cells (SMC). Results. Twenty-eight and 9 weeks following transplantation, F344/Lew and DA/BN transplants had stable graft function. Histopathologic analysis showed moderate tissue damage, minimal cellular infiltrates, and preserved vascular integrity correlating with high expression of A20 in SMC. Conversely, impaired allograft function in the DA/WF combination with substantial transplant arteriosclerosis was noted in 60% of the grafts correlating with absent or decreased A20 expression in EC and SMC. In all combinations, expression of HO-1, Bcl-2, and Bcl-xL colocalized with infiltrating cells and was not informative on the graft status. Conclusions. We demonstrate for the first time a strict correlation between A20 expression in the vessel and the absence of transplant arteriosclerosis in rat kidney-allograft models. This data is similar to data obtained in human kidney allografts and suggests that A20 may represent a novel therapeutic target for the prevention of chronic allograft rejection.

Activation of innate immune defense mechanisms contributes to polyomavirus BK-associated nephropathy

Polyomavirus-associated nephropathy (PVAN) is a significant complication after kidney transplantation, often leading to premature graft loss. In order to identify antiviral responses of the renal tubular epithelium, we studied activation of the viral DNA and the double-stranded RNA (dsRNA) sensors Toll-like receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I) in allograft biopsy samples of patients with PVAN, and in human collecting duct cells in culture after stimulation by the dsRNA mimic polyriboinosinic:polyribocytidylic acid (poly(I:C)), cytokines, or infection with BK virus. Double staining using immunofluorescence for BK virus and TLR3 showed strong signals in epithelial cells of distal cortical tubules and the collecting duct. In biopsies microdissected to isolate tubulointerstitial lesions, TLR3 but not RIG-I mRNA expression was found to be increased in PVAN. Collecting duct cells in culture expressed TLR3 intracellularly, and activation of TLR3 and RIG-I by poly(I:C) enhanced expression of cytokine, chemokine, and IFN-β mRNA. This inflammatory response could be specifically blocked by siRNA to TLR3. Finally, infection of the collecting duct cells with BK virus enhanced the expression of cytokines and chemokines. This led to an efficient antiviral immune response with TLR3 and RIG-I upregulation without activation of IL-1β or components of the inflammasome pathway. Thus, PVAN activation of innate immune defense mechanisms through TLR3 is involved in the antiviral and anti-inflammatory response leading to the expression of proinflammatory cytokines and chemokines.

Expression of interferon-inducible Mx-proteins in patients with IgA nephropathy or Henoch-Schönlein purpura★

Both viral infections and dysregulated cytokine synthesis have been implicated in the pathogenesis of immunoglobulin A nephropathy (IgAN) and Henoch-Schönlein purpura (HSP). Mx proteins are specifically induced by type I interferons (IFN-alpha, -beta, -omega) and are very sensitive in detecting, for example, virus-induced, in vivo production of IFN-alpha/-beta, because the biological half-life of Mx (approximately 3 days) markedly exceeds that of IFN-alpha/-beta (20 to 90 minutes). Mx concentrations in leukocytes were measured by enzyme-linked immunosorbent assay (ELISA) in 79 blood samples of 35 patients with IgAN and five with HSP. No patient showed symptoms of infections at the time of the examination. Compared with normal leukocyte Mx concentrations (<2 mU/1,000 leukocytes), only 3 of 79 samples of IgAN/HSP patients showed mildly elevated Mx concentrations (range, 2.2 to 3 mU/1,000 leukocytes). By contrast, patients with increased endogenous IFN production (lupus erythematosus) or patients treated with IFN-alpha2 showed leukocyte Mx concentrations of up to 35 mU/1,000 leukocytes. In patients with IgAN and HSP, leukocyte Mx concentrations were not correlated with various clinical parameters. Immunohistochemically, no renal Mx expression could be detected in eight renal biopsy specimens of patients with various stages of IgAN, whereas control specimens (skin of patients treated with IFN-alpha2) showed abundant cellular Mx expression. Furthermore, human mesangial cells in vitro showed marked Mx production after exposure to IFN-alpha or IFN-beta. We conclude that, in patients with IgAN/HSP, no evidence of an activation or dysregulation of the type I interferon system can be detected.

Akutes Nierenversagen und Verdacht auf Bronchialkarzinom

Eine 50-jährige Frau wurde aus einem auswärtigen Krankenhaus in die Herz-Thorax-Chirurgie des Universitätsklinikums aufgrund des dringenden Verdachts auf ein zentral-stenosierendes Bronchialkarzinommit Retentionspneumonie verlegt. Die Patientin berichtetete über seit 4 Wochen bestehenden Schnupfen, subfebrile Temperaturen sowie eine Reizhustensymptomatik. Bei Verlegung wird bereits mit Ceftriaxon und Clarithromycin behandelt. An Vorerkrankungen ist eine Struma nodosa bekannt. Medikamente hatte die Patientin bis zur initialen Aufnahme nicht eingenommen. Das Kreatinin bei Verlegung beträgt 89 μmol/l, bei Initialkontakt 54 μmol/l.

Progrediente Niereninsuffizienz und Proteinurie bei einem 74-jährigen Patienten

ZusammenfassungDas Fallbeispiel eines mit Nierenfunktionseinschränkung im Stadium 3 nach KDOQI und Proteinurie zur Nierenbiopsie stationär aufgenommenen 74-jährigen Patienten beschreibt zunächst die durchgeführte Anamnese, den klinischen Befund und die Primärdiagnostik. In der weiterführenden Diagnostik gab die Nierenbiopsie bzw. Beckenkammbiopsie Hinweise auf das Vorliegen einer Infiltration der Niere durch ein niedrigmalignes B-Zell-Non-Hodgkin-Lymphom, welches sich durch computertomographische und hämatologische Untersuchungen bestätigen ließen. AbstractThis case example of a 74-year-old patient with limited kidney function in stage 3 according to KDOQI (Kidney Disease Outcomes Quality Initiative) and proteinuria admitted for in-patient renal biopsy, describes the anamnesis, the clinical findings and the primary diagnostics. In the subsequent diagnostics the kidney biopsy supplied the first evidence of the presence of infiltration of the kidneys by a low malignancy non-Hodgkin B-cell lymphoma which was confirmed by iliac crest biopsy, computed tomography and hematological tests.