-
[show abstract]
[hide abstract]
ABSTRACT: Procalcitonin (PCT) is routinely measured to differentiate autoimmune disorders from infection. There are reports, however, where PCT is high in the absence of infection, i.e. in vasculitis. To investigate the value of PCT in Goodpasture's syndrome, we reviewed the charts of patients with Goodpasture's syndrome who were treated from 1996 to 2006.
PCT (normal range<0.5 ng/ml) was measured with an immunoluminometric assay, C-reactive protein (CRP; normal range<5 mg/l) with nephelometry. Anti-glomerular basement membrane antibodies (normal range<1:10) were measured with ELISA.
During the last 10 years we diagnosed seven patients with Goodpasture's syndrome. Six out of seven patients had biopsy proven crescentic and necrotizing glomerulonephritis. Five patients had a severe manifestation with pulmonary involvement (n=3) and/or severe renal insufficiency (n=4). Mean CRP levels were 145.7 mg/l, mean PCT levels were 34.1 ng/ml. Therapy consisted of plasmapheresis (n=3), pulse cyclophosphamide therapy (n=4) and glucocorticoids (n=6). Remarkably, all patients with elevated PCT levels had life-threatening disease (n=4) and remained dialysis-dependent (as compared to with only one out of three patients with normal PCT). In two out of five patients with severe Goodpasture's syndrome, PCT levels remained high. After thorough exclusion of infection, resumption of high dose glucocorticoids normalized PCT and CRP levels.
The measurement of PCT as a marker of infection in patients with Goodpasture's syndrome is misleading. High PCT values might rather point to a severe form of Goodpasture's syndrome with a more unfavourable prognosis. However, further studies with larger patient numbers are needed to prove this hypothesis.
Nephrology Dialysis Transplantation 09/2007; 22(9):2701-4. · 3.40 Impact Factor
-
Nephrology Dialysis Transplantation 04/2006; 21(3):818. · 3.40 Impact Factor
-
Thrombosis and Haemostasis 11/2005; 94(4):879-80. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Autoantibodies to neutrophil cytoplasmic antigens (ANCA), particularly to proteinase 3 (PR3), are found in the majority of patients with systemic Wegener's granulomatosis. The autoantibodies are widely used as diagnostic markers. Their role in the development and progression of the disease, however, is still under investigation. The primary target of ANCA, PR3, is located in the cytoplasm of polymorphonuclear neutrophils (PMN) or monocytes and is translocated to the cell surface upon stimulation. In patients with Wegener's granulomatosis PR3 is up-regulated most prominently during active disease. Despite the fact that both autoantibodies to PR3 and PMN expressing PR3 are present in patients with Wegener's granulomatosis, there is no evidence for binding of the autoantibodies to PMN. The present study was designed to analyze binding characteristics of autoantibodies to PR3 on PMN.
PMN of patients with active Wegener's granulomatosis (N= 10) were tested for autoantibody binding. Despite high autoantibody titer and PR3 expression on the PMN, no surface-bound IgG was found on PMN ex vivo. When ANCA-containing plasma from patients was incubated with isolated PMN, stimulated to express PR3, again no specific binding of the autoantibody could be detected. Also keeping the samples on ice did not allow surface detection of IgG, ruling out degradation or internalization of the autoantibodies. Only when purified IgG fractions were used, binding to PMN was seen in 14 of 25 patients. Already 1% of plasma, however, was sufficient to greatly reduce the IgG binding. Reduced binding of the IgG fraction was also seen when a larger reaction volume was used.
Our data indicate that autoantibodies to PR3 have a rather low affinity for surface-associated PR3 on PMN. This, in turn, argues against the hypothesis that ANCA contributes to the pathogenesis of the disease by stimulating viable PMN in whole blood.
Kidney International 10/2004; 66(3):1009-17. · 6.61 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: There is increased risk for the occurrence of deep venous thrombosis (DVT) and renovascular thrombosis after kidney transplantation. A disruption of the blood homeostasis caused by surgery and leading to clotting and bleeding malfunctions is widely accepted. However, other causes such as inherited or acquired disorders of the clotting system may further increase the risk of thrombosis. Here, we summarize and review data on possible causes, incidence and ways to prevent the occurrence of DVT and/or renovascular thrombosis after kidney transplantation.
The incidence of DVT after kidney transplantation is 6.2-8.3% and approximately 25% of these patients suffer from pulmonary embolism. The DVT occurs primarily on the side of the transplant with an increased risk throughout the first 5 months after transplantation. Thereby, 2-12% of the patients develop renovascular thromboses, most of which are related directly to the surgery. However, inherited or acquired thrombophilia may also play an important role. A severe course is known for prothrombin gene G20210A polymorphism, which can result in graft loss. A great diversity of prophylactic treatments is available but adjustment to the underlying circumstances is crucial for a favourable outcome. Low-dose heparin prophylaxis for at least 2-3 weeks can be used as standard therapy to prevent the occurrence of DVT after kidney transplantation. However, this may not be sufficient for concurrent disorders of the blood homeostasis such as elevated levels of antiphospholipid antibodies, lupus anticoagulant, prothrombin gene G20210A polymorphism or a combined inherited thrombophilia. These patients may need a prophylactic anticoagulation with coumarins starting prior to transplantation and being continued for at least 1 year or even lifelong. Only randomized trials can answer the question concerning optimal duration and safety of coumarins in this setting.
DVT and/or renovascular thromboses are severe complications after kidney transplantation. Inherited and acquired thrombophilia, apart from surgery and abnormal anatomy itself, have to be considered and proper prophylactic treatment initiated.
Nephrology Dialysis Transplantation 08/2004; 19 Suppl 4:iv64-8. · 3.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: High-dose chemotherapy followed by autologous blood stem cell transplantation induces remission of plasma cell dyscrasia in patients with AL amyloidosis. The impact of this treatment on the glomerular amyloid mass is still unknown.
In the present study, the quantity of the renal amyloid mass before and more than 3 years after high-dose melphalan treatment and autologous blood stem cell transplantation was assessed in two patients. At the time of the second renal biopsy, both patients were in complete remission without detectable serum and urinary monoclonal IgA-lambda and a normal percentage of plasma cells in the bone marrow.
In both patients with biopsy-proven AL amyloidosis, urinary protein excretion decreased from 7 g/24 h to <2 g/24 h more than 3 years after autologous blood stem cell transplantation. In contrast, glomerular amyloid deposits persisted, as shown in the second biopsy.
Despite complete remission of the plasma cell dyscrasia and improvement of glomerular permeability, the amount of glomerular amyloid mass did not regress.
Nephrology Dialysis Transplantation 12/2003; 18(12):2644-7. · 3.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Replicative senescence describes the fact that somatic cells undergo a finite and predictable number of cell divisions before entering an irreversible state of growth arrest. Progressive shortening of the telomeres, a consequence of cell division, is a reliable indicator of replicative senescence.
We analyzed telomere length of DNA derived from T cells of patients suffering from Wegener's granulomatosis by Southern blotting. Moreover, expression of CD28, another marker for replicative senescence, was tested by cytofluorometry.
In patients with disease for more than 5 years, short telomeres were detected in addition to telomeres of normal length, indicating replicative senescence of discrete T-cell clones. Reduced expression of CD28 was noted, particularly on CD8-positive T cells, derived from patients with disease for more than 5 years and short telomeres.
Our data provide evidence that a portion of T cells had undergone replicative senescence, which in turn indicates clonal expansion of T cells as consequence of activation.
Kidney International 07/2003; 63(6):2144-51. · 6.61 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In polymorphonuclear neutrophils (PMN) CD14, one of the receptors for lipopolysaccharides (LPS) is stored intracellularly as a preformed protein, with only few receptors expressed on the surface. We now report that in patients with severe bacterial infections, CD14 expression is profoundly upregulated, as is CD64 (FcgammaRI), the high-affinity receptor for IgG, whereas CD16 (FcgammaRIII) was partly lost from the surface. To further analyze regulation of these receptors, PMN of healthy donors were exposed to low doses of LPS. By brief exposure (10-120 min) to LPS, CD14 was transferred to the surface in a cytochalasin B-sensitive manner, as were CD16 and CD64. Prolonged culture (up to 48 h) resulted in a further upregulation of CD14, sustained expression of CD64, and profound decline of CD16, yielding a similar pattern of receptor expression as seen in the patients. Subsequent studies revealed that LPS induced de novo synthesis of CD14: the increase of surface expression could be inhibited by cycloheximide and by interfering with a known LPS-induced signaling event, the translocation of NFkappaB. Moreover, an up to 10-fold increase of specific mRNA was seen, as was incorporation into CD14 of 35S-methionine. The de novo synthesis prolonged expression of CD14, whereas the CD16 expression declined, generating a PMN phenotype characteristic for severe infection and indicative of escape from apoptosis of a PMN subpopulation.
Shock 02/2003; 19(1):5-12. · 2.85 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cyclosporin A (CsA) has improved patient and organ graft survival, but the dichotomy of benefit and toxicity is still an issue. In a retrospective analysis of 392 renal transplant recipients we documented CsA nephrotoxicity (striped fibrosis, arteriolar wall hyalinosis) in 28 (7.1%) patients (23 male/5 female) in a follow-up of more than one year post transplantation. Median age at renal transplantation was 41 years (13-60) and the period between transplantation and graft biopsy was 42 months (12-122). Median CsA trough levels (ng/ml) at 12 months post transplantation, at time of graft biopsy and at last follow-up were: 114 (71-265), 130 (78-285), 66 (24-115). The following parameters were assessed at 12 months post transplantation, at time of biopsy and at last follow-up: s-creatinine (micromol/l), Doppler resistive index, systolic and diastolic blood pressure (mm Hg) and the number of antihypertensives. Median s-creatinine at 12 months post transplantation was 150.3 (94.6-247.5), at biopsy 225.4 (121.1-353.6) and at last follow-up 160.0 (106.1-247.5) (p < 0.001 for biopsy vs. last follow-up). Resistive index decreased from 0.70 (0.64-0.88) to 0.68 (0.51-0.84) (p < 0.005), systolic blood pressure from 137 (100-168) to 130 (105-144) (p < 0.05) and the number of patients with more than 4 antihypertensives from 10 to 6 between biopsy and last follow-up, with no acute rejection episodes after modification of immunosuppressive therapy (50% of previous CsA trough level and addition of azathioprine or mycophenolate mofetil). Conclusion: CsA nephrotoxicity occurs late after renal transplantation with increased systolic blood pressure and Doppler resistive index. Reduction of CsA improves renal function, reduces graft resistive index and systolic blood pressure.
Nephron 11/2002; 92(2):339-45. · 13.26 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: . Polymorphonuclear neutrophils (PMN) are in the first line of defense against bacterial infections. They are considered to be end-differentiated cells undergoing constitutive apoptosis within hours after release from the bone marrow. During pathological events, however, their life span is extended in conjunction with morphological and functional alterations indicative of a transdifferentiation of mature PMN. To further characterize differentiated PMN, the alterations seen in vivo were reproduced by cultivating PMN of healthy donors with either %-interferon, granulocyte/macrophage colony stimulating factor, or a combination thereof. Thus cultivated cells escaped from apoptosis, and protein synthesis was induced, notably of the major histocompatibility complex (MHC) class II antigens, CD80 and CD86. Moreover, CD83, thought to be specific for dendritic cells was synthesized, while typical markers of PMN, including CD66b, CD11a/CD11b/CD11c, CD15, CD18 were preserved. A profound alteration of both cellular morphology and of function was seen: the cultivated PMN lost their chemotactic activity but had acquired the ability to present to T-cells a peptide antigen in a MHC class II restricted manner. The data lead to the conclusion that mature PMN can differentiate further to cells with characteristics of DCs, thereby connecting PMN to the specific T-cell response.
Journal of Molecular Medicine 07/2001; 79(8):464-474. · 4.67 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Polymorphonuclear neutrophils (PMN) are considered to be short-lived, terminally differentiated cells undergoing spontaneous apoptosis if not appropriately stimulated. In patients with systemic infections and inflammatory disease, however, PMN have an extended life span and acquire new surface receptors and functions. Expression of CD64, the high-affinity receptor for immunoglobulin, has been found, and functionally active elastase and surface-associated fibronectin as well. The latter is of particular interest since fibronectin is known as a multifunctional, multimodal extracellular matrix protein, participating in cell adherence, cell signaling, and cell cycle control. To study the surface-associated fibronectin further, PMN of healthy donors were cultivated to induce de novo synthesis of fibronectin. PMN produced fibronectin, which remained associated with the cell surface, where it was partially cleaved. PMN derived fibronectin exhibited a rare splice pattern: predominantly fibronectin containing the extradomain B (EDB) was generated, but evidently no IIICS domain; the latter is known as a receptor for ş integrins. How the presence of EDB affects the properties of fibronectin is not yet understood. Studies with recombinant EDB have failed to show a membrane-binding site or a direct participation of EDB in the adhesion process. The function of PMN-associated fibronectin is still under investigation. The rapid cleavage by surface-associated proteases suggests that fibronectin acts as a tightly regulated adhesion protein, and probably also as a precursor molecule for fibronectin-derived biologically active mediators.
Journal of Molecular Medicine 07/2000; 78(6):337-345. · 4.67 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In situ production of TNF-, IL-1 and IL-2 receptors in ANCA-positive glomerulonephritis. Humoral and cellular immune mechanisms are thought to be involved in various forms of vasculitis and glomerulonephritis. Recent clinical and experimental results point to a role of cytokines in ANCA-positive vasculitides. We analyzed tumor necrosis factor- (TNF-), interleukin-1 (IL-1) and interleukin-2 receptors (IL-2R) in renal biopsies and in plasma from 22 patients with Wegener's granulomatosis and microscopic polyangiitis. Kidney biopsies were examined by immunocytochemistry, polymerase chain reaction and in situ hybridization. Immunoreactive TNF-, IL-1 and/or IL-2R positive infiltrating cells were observed in 21 of 22 biopsies. TNF-, IL-1 and IL-2R staining was evident in the interstitium and at periglomerular and perivascular sites. The number of positive cells was markedly increased in biopsies with active lesions. Positive cells were also present in cellular and fibrocellular crescents, surrounding tuft necrosis and in the walls of arteries and arterioles with acute vasculitic lesion. Some tubular epithelial cells stained for TNF- and IL-1. TNF-, IL-1 and IL-2R positive infiltrating cells correlated with the presence of histologically active renal lesions. The evaluation of TNF- and IL-1 expression at the mRNA level assessed by the polymerase chain reaction demonstrated specific transcripts for TNF- and IL-1 in all six cases analyzed. In situ hybridization studies showed an increased expression of mRNA for TNF- and IL-1 in infiltrating mononuclear cells, in epithelial cells of Bowman's capsule and in some tubules, predominantly of patients with active renal lesions. The results at the mRNA level correlated with the immunocytochemical findings. Compared to healthy individuals higher TNF- plasma levels were observed in patients with vasculitis (34.4 16.6 pg/ml (sem) VS. 1.9 0.7 pg/ml in controls; P < 0.01). All patients presented a marked increase in SIL-2R plasma levels (3512 485 U/ml vs. 397 21 U/ml in healthy controls; P < 0.001). IL-1 was not detected in most plasma samples. Elevated TNF- and sIL-2R plasma levels were related to active renal lesions. Our study clearly demonstrates that in ANCA-positive vasculitis TNF- and IL-1 are produced in situ by activated infiltrating mononuclear cells and resident renal cells. Intrarenal localization of cytokine producing cells and the correlation between cytokine production and histological signs of activity suggest that TNF- and IL-1 are important locally acting mediators in the vasculitic/glomerulonephritic process.
-
[show abstract]
[hide abstract]
ABSTRACT: PDGF and TGF- contribute to the natural course of human Ig-A glomerulonephritis. PDGF and TGF- are known mediators of mesangial cell proliferation and matrix expansion. The presence of these regulatory factors was examined in 30 renal biopsies from patients with IgA glomerulonephritis (IgA-GN) at the mRNA and protein level. Normal renal tissue served as control. The mRNA expression of PDGF A/B chains, PDGF-R and TGF-1 was evaluated by means of RT/PCR with subsequent Southern blot hybridization and/or non-radiactive in situ hybridization. In addition, PDGF-AB/BB, PDGF-R, TGF- isoforms (1, 1+2, 2+3), the small TGF-1 latency associated peptide (TGF-1 LAP) and the extracellular matrix proteins tenascin and decorin were analyzed by immunocytochemistry. The expression of growth factors was correlated with light microscopic and clinical features. Compared to normal control kidneys, an increased expression of PDGF-BB/PDGF-R mRNAs and the corresponding proteins was observed in all biopsies with IgA-GN. Up-regulation was related to the degree of glomerular proliferation and the extent of fibrosing interstitial lesions. In contrast, there was a discordance between TGF-1 mRNA and protein expression (evaluated by immunocytochemistry). In all biopsies, irrespective of the stage of the disease, abundant TGF-1 transcripts were detected, whereas TGF-1 immunoreactivity was expressed to a lesser degree and disclosed a more variable staining pattern. In patients with significant proliferative glomerular lesions and minor tubulointerstitial alterations, TGF-1 positivity was confined to areas of glomerular proliferation, whereas in cases with more severe histology including sclerosing lesions TGF-1 immunoreactivity was less prominent. The distribution and the intensity of TGF-1 LAP staining commonly exceeded the positivity noted for TGF-1, indicating only limited TGF-1 activation. A decreased reactivity for tenascin accompanied the morphological features of glomerular sclerosis. The staining patterns and the fact that only very few inflammatory cells, particularly CD68 positive monocytes/macrophages, were detected in glomeruli confirm that predominantly resident glomerular cells (mesangial and endothelial cells) are the major source of up-regulated growth factor production in IgA-GN. Since the expression of PDGF-AB/BB paralleled the severity of proliferative glomerular changes, PDGF seems to represent a potential indicator of activity in this condition. It is suggested that an imbalance between PDGF and TGF- (by restricted translation and/or activation) production contribute to the progressive nature of IgA-GN.
