Ibuprofen-induced HUS.

BACKGROUND: Hemolytic uremic syndrome (HUS) is a disease characterized by nonimmune hemolytic anemia, thrombocytopenia and renal impairment. There are many causes for HUS, but adverse reactions to drugs have been increasingly reported. Even the NSAIDs which have been reported as safe and effective painkillers are described as cause of recurrent HUS. PATIENT CASE: We describe a case of a 44-year-old woman who was admitted to our hospital because of thrombocytopenia and anemia after the use of 8 tablets of 400 mg ibuprofen (NSAIDs). The diagnosis HUS was made and she recovered completely after treatment with fresh-frozen plasma and seven plasma exchanges. CONCLUSION: No cause could be identified except the use of ibuprofen. Recognition of a drug-induced HUS is necessary to avoid reexposure and recurrent HUS.

Banff '05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy ('CAN').

The 8th Banff Conference on Allograft Pathology was held in Edmonton, Canada, 15-21 July 2005. Major outcomes included the elimination of the non-specific term "chronic allograft nephropathy" (CAN) from the Banff classification for kidney allograft pathology, and the recognition of the entity of chronic antibody-mediated rejection. Participation of B cells in allograft rejection and genomics markers of rejection were also major subjects addressed by the conference.

The urokinase plasminogen activator receptor is crucially involved in host defense during acute pyelonephritis.

The urokinase plasminogen activator receptor (uPAR) is expressed at the cell surface of inflammatory cells and plays an important role in neutrophil migration. To investigate the in vivo role of uPAR during urinary tract infection, acute pyelonephritis was induced in uPAR-/- and wild-type (WT) mice by intravesical inoculation with 1 x 10(9) colony-forming units (CFU) of uropathogenic Escherichia coli. Mice were killed after 24 and 48 h, after which bacterial outgrowth and cytokine levels in kidney homogenates were determined. Influx of neutrophils was quantified by myeloperoxidase-enzyme-linked immunosorbent assay. uPAR-/- kidneys had significantly higher numbers of E. coli CFU, accompanied by higher levels of interleukin-1beta (IL-1beta), IL-6, keratinocyte-derived chemokine (KC), macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor-alpha (TNF-alpha). However, the number of infiltrating neutrophils was similar in uPAR-/- and WT mice at both time points, suggesting that uPAR-/- neutrophils have a lower ability to eliminate E. coli. To further investigate this, neutrophil oxidative burst and phagocytosis was measured. The generation of reactive oxygen species upon stimulation with E. coli was not diminished in uPAR-/- neutrophils compared with WT. Interestingly, uPAR-/- neutrophils displayed significantly impaired phagocytosis of E. coli organisms compared with WT neutrophils. We conclude that uPAR is crucially involved in host defense through phagocytosis during E. coli induced acute pyelonephritis.

Renal expression of CD44 correlates with acute renal allograft rejection.

As CD44 is involved in the activation, proliferation, adhesion, and extravasation of lymphocytes, we hypothesized that CD44 could be involved in the pathogenesis of acute renal allograft rejection. Renal biopsies and plasma were collected from patients suffering an episode of acute renal allograft rejection. CD44 and its ligands, hyaluronic acid (HA) and osteopontin, were analyzed retrospectively by immunohistochemistry and, computer-aided, morphometric analysis. Soluble CD44 (sCD44) and osteopontin in the plasma were determined by enzyme-linked immunosorbent assay. During acute rejection episodes, CD44 and its ligands, HA and osteopontin, were upregulated in the renal allograft. Also, increased sCD44 plasma levels were observed, which correlated with both tubular expression of CD44 and the extent of infiltrate. No differences could be detected between the different pathologic grades of rejection. Upregulation of tubular CD44 and increased levels of circulating sCD44 may reflect a common pathogenic mechanism during acute renal rejection and could be useful markers in the diagnosis of acute renal rejection.

Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial.

Until recently, intravenous cyclophosphamide pulses with oral corticosteroids were regarded standard therapy for proliferative lupus nephritis (LN). Azathioprine, a less toxic alternative, was never proven to be inferior. In the first Dutch lupus nephritis study (enrollment between 1995 and 2001), we randomized 87 proliferative LN patients to either cyclophosphamide pulses (750 mg/m(2), 13 pulses in 2 years) combined with oral prednisone (CY) or to azathioprine (2 mg/kg/day in 2 years) combined with intravenous pulses of methylprednisolone (3 x 3 pulses of 1000 mg) and oral prednisone (AZA). After a median follow-up of 5.7 years (interquartile range 4.1-7.2 years), doubling of serum creatinine was more frequent in the AZA group, although not statistically significant (relative risk (RR): 4.1, with 95% confidence interval (95% CI): 0.8-20.4). Relapses occurred more often in the AZA group (RR: 8.8, 95% CI: 1.5-31.8). Creatinine and proteinuria at last visit did not differ between the two treatment arms. Moreover, 88.4% of the patients in the AZA arm were still free of cyclophosphamide treatment. During the first 2 years, the frequency of remission was not different, but infections, especially herpes zoster virus infections (HZV) were more frequent in the AZA group. Parameters for ovarian function did not differ between the two groups. In conclusion, in this open-label randomized controlled trial, cyclophosphamide was superior to azathioprine with regard to renal relapses and HZV. At last follow-up, there were no differences in serum creatinine or proteinuria between the two groups. However, since our study lacked sufficient power, longer follow-up is needed to reveal putative differences.

Proliferating cells in HIV and pamidronate-associated collapsing focal segmental glomerulosclerosis are parietal epithelial cells.

Collapsing focal segmental glomerulosclerosis (cFSGS) is characterized by hyperplasia of glomerular epithelial cells. In a mouse model of FSGS and in a patient with recurrent idiopathic FSGS, we identified the proliferating cells as parietal epithelial cells (PECs). In the present study, we have evaluated the origin of the proliferating cells in cFSGS associated with human immunodeficiency virus (HIV) and pamidronate. We performed a detailed study of glomerular lesions in biopsies of two patients with HIV-associated cFSGS and a nephrectomy specimen of a patient with pamidronate-associated cFSGS. Glomeruli were studied by serial sectioning using light and electron microscopy and immunohistochemistry to determine the epithelial cell phenotype. We used Synaptopodin, vascular endothelial growth factor, and CD10 as podocyte markers, CK8 and PAX2 as PEC markers and Ki-67 as marker of cell proliferation. The newly deposited extracellular matrix was characterized using antiheparan sulfate single-chain antibodies. The proliferating cells were negative for the podocyte markers, but stained positive for the PEC markers and the cell proliferation marker Ki-67. The proliferating PAX-2 and CK8 positive cells that covered the capillary tuft were always in continuity with PAX-2/CK8 positive cells lining Bowman's capsule. The matrix deposited by these proliferating cells stained identically to Bowman's capsule. Our study demonstrates that PECs proliferate in HIV and pamidronate-associated cFSGS. Our data do not support the concept of the proliferating, dedifferentiated podocyte.

Eosinophilic tubulo-interstitial nephritis associated with iridocyclitis and thyreoiditis.

A patient is described with the tubulointerstitial nephritis with uveitis syndrome. The diagnosis can be difficult since it has to be differentiated from sarcoidosis, or infections like tuberculosis and toxoplasmosis. Our patient showed prompt recovery of fever, ocular symptoms and renal function after starting corticosteroids.

Release of urokinase plasminogen activator receptor during urosepsis and endotoxemia.

BACKGROUND: The urokinase receptor (uPAR; CD87) is a multifunctional molecule involved in fibrinolysis, in proteolysis, in renal tubular functions, and in migration and adhesion of inflammatory cells to the site of infection. METHODS: To gain insight into systemic and local release of uPAR and into its regulation during urosepsis, which is one of the leading causes of chronic renal failure, uPAR was measured in urine and plasma of healthy human controls (N = 20), patients with culture-proven urosepsis (N = 30), and healthy human volunteers intravenously injected with endotoxin (N = 7). RESULTS: Patients had elevated uPAR levels in both plasma and urine. Three hours after endotoxin challenge in volunteers, there was also a significant increase of uPAR in plasma and in urine. The urine/plasma ratio for uPAR was highly elevated during urosepsis and experimental endotoxemia, suggesting local production in the kidney. Accordingly, damaged tubuli strongly expressed uPAR during pyelonephritis. Moreover, tubular epithelial cells produced uPAR in vitro, and this secretion was strongly up-regulated after stimulation with interleukin-1 beta or tumor necrosis factor-alpha. CONCLUSIONS: We found that uPAR is released systemically and in the urinary tract during urosepsis and experimental endotoxemia. This systemic and renal production of uPAR during pyelonephritis may play a central role in eliminating the infection and protecting renal function.

In vitro evidence for differential involvement of CTGF, TGFbeta, and PDGF-BB in mesangial response to injury.

BACKGROUND: Connective tissue growth factor (CTGF) is a profibrotic growth factor, which is upregulated in wound healing and renal fibrosis, including anti-Thy-1.1 nephritis. The kinetics of CTGF mRNA expression in anti-Thy-1.1 nephritis suggested that CTGF regulation might contribute to glomerular response to injury downstream of transforming growth factor-beta (TGFbeta). In anti-Thy-1.1 nephritis the initial damage is followed by mesangial repair and limited sclerosis, which involves mesangial cell (MC) activation (alpha-smooth-muscle actin (alphaSMA) expression), proliferation, migration, and extracellular matrix production. The present in vitro study addresses the possible role of CTGF in these different aspects of mesangial response to injury, and how CTGF activity might relate to effects of TGFbeta and platelet-derived growth factor-BB (PDGF-BB). METHODS AND RESULTS: Immunostaining and ELISA showed that alphaSMA expression and transformation of MC into myofibroblast-like cells was induced by TGFbeta, but not affected by PDGF-BB, CTGF, or neutralizing anti-CTGF antibodies. [(3)H]thymidine incorporation and Ki67 staining demonstrated that, unlike PDGF-BB, neither CTGF nor TGFbeta induced the proliferation of MC. In contrast, both CTGF and TGFbeta induced MC migration, as evidenced by approximation of wound edges in scrape-wounded, non-proliferating rat MC monolayers. In addition, fibronectin expression was upregulated by both CTGF and TGFbeta, as measured by dot-blot analysis. Anti-CTGF completely blocked the effect of added CTGF. Moreover, anti-CTGF significantly reduced TGFbeta-induced increase in fibronectin. CONCLUSION: It thus appears that CTGF is specifically involved in a subset of the adaptive changes of MC involved in mesangial repair and sclerosis, which makes it an interesting candidate target for future intervention strategies.

Divergent effects of tumor necrosis factor alpha on apoptosis of human neutrophils.

Apoptosis of neutrophils is a key mechanism to control the intensity of the acute inflammatory response. Previously, the cytokine tumor necrosis factor alpha (TNF-alpha) was reported by some to have pro-apoptotic and by others to have antiapoptotic effects on neutrophils. The aim of this study was to explain these contradictory results. We found that TNF-alpha at low concentrations strongly decreased apoptosis of neutrophils. However, at higher concentrations, TNF-alpha lost its protective effects, and also reversed the protective effects of interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF). This pro-apoptotic effect of TNF-alpha was blocked by anti-CD11b and was absent in neutrophils from patients with chronic granulomatous disease, which cannot produce toxic oxygen metabolites. Under these circumstances, we found that TNF-alpha retained its anti-apoptotic effects even at high concentrations. In conclusion, the protective effects against apoptosis of IFN-gamma, GM-CSF, and TNF-alpha itself are overruled when the concentration of TNF-alpha is high enough to produce a respiratory burst. These dual, concentration-dependent effects of TNF-alpha provide an explanation for previous controversial reports and support a dominant role for TNF-alpha in neutrophil apoptosis.

Beta1 integrin activation on human neutrophils promotes beta2 integrin-mediated adhesion to fibronectin.

Although the importance of beta1 integrin-mediated binding to adhesion molecules and extracellular matrix (ECM) molecules is well established for most types of leukocytes, the expression patterns and functional importance of beta1 integrins on neutrophils have remained controversial. Using flow cytometry, we found that human neutrophils express the alpha4, alpha5, alpha9 and beta1 integrin subunits. To examine whether the integrins VLA-4 (alpha4/beta1) and VLA-5 (alpha5/beta1) have a functional role on neutrophils, we studied adhesion to their ligand fibronectin. Treatment of neutrophils with antibody 8A2, which specifically binds and activates beta1 integrins, resulted in increased binding to fibronectin. However, addition of blocking mAb revealed that 8A2-induced adhesion did not depend on beta1 integrins, but on the beta2 integrin CD11b/CD18. Similarly, activation of beta1 integrins by 8A2 resulted in CD11b-dependent binding of neutrophils to fibrinogen. 8A2 treatment increased expression of an activation epitope of CD11b/CD18, which depended on phosphoinositide 3-OH kinase activity and an adequate concentration of intracellular free Ca2+. These data suggest that engagement of beta1 integrins on neutrophils results in a cross-talk signal that leads to activation of the beta2 integrin CD11b/CD18, followed by CD11b-mediated adhesion. As transmigrated neutrophils are surrounded by both beta1 and beta2 ligands in the ECM, this integrin cross-talk could play a role in modifying migration and cellular activation in inflamed tissues.

What is the difference between IgA nephropathy and Henoch-Schönlein purpura nephritis?

Henoch-Schönlein purpura nephritis (HSPN) and IgA nephropathy (IgAN) are considered to be related diseases since both can be encountered consecutively in the same patient, they have been described in twins, and bear identical pathological and biological abnormalities. Apart from the presence of extrarenal clinical signs found only in HSPN, other differences are noticed between the two diseases. The peak age ranges between 15 and 30 years for a diagnosis of IgAN, whereas HSPN is mainly seen in childhood. Nephritic and/or nephrotic syndromes are more often seen at presentation in HSPN. In contrast to IgAN, HSPN has been described in association with hypersensitivity. Endocapillary and extracapillary inflammations as well as fibrin deposits in the glomerulus are more frequent in HSPN. No major biological differences have been found between the two illnesses, except for a larger size of circulating IgA-containing complexes (IgA-CC) and a greater incidence of increased plasma IgE levels in HSPN. As tissue infiltration by leukocytes is a major feature of HSPN vasculitis, a possible role of a more potent activation of the latter cells by IgA-CC and/or circulating chemokines in HSPN should be considered. Further studies are required to elucidate this possible mechanism as well as the role of hypersensitivity in HSPN.

Renal vascular changes in renal disease independent of hypertension.

INTRODUCTION: Cardiovascular disease is common in patients with renal disease, but little is known about the effect of renal disease and loss of renal function on vascular morphology. Intima proliferation of small renal arteries, which correlates with atherosclerosis in the aorta, is sometimes present in renal disease and has been shown to increase with age and hypertension. We studied the effect of chronic renal disease and renal function, independent of hypertension, on intima proliferation. METHODS: We retrospectively selected renal biopsies of subjects in whom a glomerular filtration rate (GFR) measurement with [(125)I] iothalamate had been performed. To separate the effects of renal disease and renal function, we selected biopsies from (A) normotensive controls undergoing nephrectomy because of renal carcinomas; (B) normotensive patients with renal disease and GFR > 90 ml/min; (C) normotensive patients with GFR 30-90 ml/min, and (D) hypertensive patients with a GFR < 90 ml/min. The area of the arteriolar lumen, intima, and media were measured. RESULTS: No significant changes from control subjects were observed in group B. Intima proliferation was observed when renal function declined (intima/total vessel surface ratio was 0.262 +/- 0.071 in group C, 0.192 +/- 0.032 in group A, and 0.205 +/- 0.035 in group B, P < 0.05). The intima proliferation was aggravated in patients with renal insufficiency and hypertension (0.333 +/- 0.121, P < 0.05). Media surface area was not different between groups. CONCLUSION: Renal disease with preserved GFR does not cause significant intima proliferation of small renal arteries. Loss of renal function is accompanied by intima proliferation, even in the absence of systemic hypertension.

The immune dysregulatory compound mercuric chloride induces integrin-mediated T-lymphocyte adhesion.

Exposure of Brown Norway rats to mercuric chloride induces systemic autoimmunity, involving T- and B-lymphocyte activation, (auto-)antibody production and multiorgan inflammation. Several divalent metal ions, such as Mg2+ and Mn2+, can activate binding of integrins to their ligands, thus causing lymphocyte adhesion. To test the hypothesis that Hg2+ acts in a similar way, we studied the effect of HgCl2 on integrin-mediated T-cell adhesion. HgCl2 induced cell-cell aggregation of human T lymphoblasts. Exposure of a human T-cell clone to HgCl2 for 1 hr enhanced, in a dose-dependent way, cell binding to fibronectin (FN) and to intercellular adhesion molecules (ICAM) -1, -2 and -3. Furthermore, HgCl2 induced strong binding of Jurkat T cells to FN. These effects of HgCl2 were of similar magnitude as the effects of phorbol 12-myristate 13-acetate (PMA) or MnCl2. Studies using blocking antibodies indicated the involvement of CD11a in binding to ICAMs, and of CD49d, CD49e, and CD29 in binding to FN. Adhesion to FN induced by HgCl2 or by PMA, but not by MnCl2, was dependent on temperature and on extracellular Ca2+ or Mg2+. Addition of cytochalasin B enhanced synergistically the FN adhesion induced by MnCl2, whereas the effects of PMA and HgCl2 were not modified. These results indicate that Hg2+ is a potent activator of T-cell adhesion, mediated by several integrins and ligands. In contrast to the effect of MnCl2, HgCl2-induced cell adhesion probably involves an intracellular pathway. Activation of integrins by HgCl2 may play an important role in activation and migration of leucocytes involved in HgCl2-induced immune dysregulation in vivo.

Expression of cancer antigen 125 by peritoneal mesothelial cells is not influenced by duration of peritoneal dialysis.

OBJECTIVE: To investigate the presence of cancer antigen 125 (CA125) on mesothelial cells in the effluent of peritoneal dialysis (PD) patients and to analyze the effect of duration of PD on the number of mesothelial cells in peritoneal effluent, the number of CA125-positive cells, and dialysate CA125 concentration. DESIGN: A cross-sectional study in which long-dwell peritoneal effluents were investigated for mesothelial cells and CA125. SETTING: A university hospital population of chronic PD patients. PATIENTS: 33 stable PD patients who were free of peritonitis during the investigation and during the 4 weeks prior to the study. METHODS: Examination of cytospin preparations of peritoneal effluent stained with May-Grünwald Giemsa, and also with an immunocytochemical double-staining method consisting of anticalretinin (pan-mesothelial cell marker) and OC125. RESULTS: A close relationship was present between the numbers of mesothelial cells counted with the two staining methods (r= 0.998, p < 0.001). On average, 92% of mesothelial cells were positive for CA125, ranging between 75% and 100% in 80% of the patients. Correlations were found between the effluent CA125 concentration and the total number of mesothelial cells (r = 0.64, p < 0.001), and also the number of CA125-positive cells (r = 0.66, p < 0.001). A negative effect of time was seen on the effluent CA125 concentration, the total number of mesothelial cells, and the number of CA125-positive mesothelial cells. However, no effect of time was present on the percentage CA125-positive cells. CONCLUSIONS: On average, 92% of mesothelial cells in peritoneal effluent are positive for CA125. This figure is not dependent on the duration of PD. Long-term PD is associated with low dialysate CA125 concentrations, a low number of mesothelial cells, and a low number of CA125-positive mesothelial cells in effluent. These results support the hypothesis that dialysate CA125 can be used as a marker of mesothelial cell mass in stable PD patients.