Multifocal phaeohyphomycosis caused by Exophiala xenobiotica in a kidney transplant recipient.

In recent years, black fungi have been increasingly reported as causing opportunistic infections after solid organ transplantation. Here, we report a case of insidious, relentless, and multifocal Exophiala xenobiotica infection in a kidney transplant recipient that eventually required multiple surgical excisions along with oral and intravenous antifungal combination therapy using liposomal amphotericin B and posaconazole. We compare the present case with all previously reported cases of Exophiala infection after kidney transplantation.

The Kidney Donor Profile Index (KDPI) of marginal donors allocated by standardized pretransplant donor biopsy assessment: distribution and association with graft outcomes.

Pretransplant donor biopsy (PTDB)-based marginal donor allocation systems to single or dual renal transplantation could increase the use of organs with Kidney Donor Profile Index (KDPI) in the highest range (e.g. >80 or >90), whose discard rate approximates 50% in the United States. To test this hypothesis, we retrospectively calculated the KDPI and analyzed the outcomes of 442 marginal kidney transplants (340 single transplants: 278 with a PTDB Remuzzi score<4 [median KDPI: 87; interquartile range (IQR): 78-94] and 62 with a score=4 [median KDPI: 87; IQR: 76-93]; 102 dual transplants [median KDPI: 93; IQR: 86-96]) and 248 single standard transplant controls (median KDPI: 36; IQR: 18-51). PTDB-based allocation of marginal grafts led to a limited discard rate of 15% for kidneys with KDPI of 80-90 and of 37% for kidneys with a KDPI of 91-100. Although 1-year estimated GFRs were significantly lower in recipients of marginal kidneys (-9.3, -17.9 and -18.8 mL/min, for dual transplants, single kidneys with PTDB score<4 and =4, respectively; p<0.001), graft survival (median follow-up 3.3 years) was similar between marginal and standard kidney transplants (hazard ratio: 1.20 [95% confidence interval: 0.80-1.79; p=0.38]). In conclusion, PTDB-based allocation allows the safe transplantation of kidneys with KDPI in the highest range that may otherwise be discarded.

Trends in immune cell function assay and donor-specific HLA antibodies in kidney transplantation: A 3-year prospective study.

The immune cell function assay (ICFA) and de novo anti-donor-specific HLA antibodies (DSA) have been proposed as assays for immune monitoring in renal transplantation, but longitudinal studies examining the modification of both parameters over time and their relation with clinical events are lacking. We prospectively measured longitudinal changes in ICFA and DSA levels in 55 kidney transplant recipients over 3-year follow-up (534 visits) and analyzed their relation with the risk of developing acute rejections or infections. Seven patients (12.7%) developed biopsy-proven acute rejection, and 20 (36.4%) developed viral infections. At 3 years posttransplant, 28% of the patients had developed de novo DSA. ICFA levels peaked at 1-2 months posttransplant (p = 0.005) and leveled off thereafter. They were not associated with the risk of acute rejections, viral infections or development of de novo DSA. Instead, the incidence of de novo DSA was higher in patients who previously had viral infections (adjusted-odds ratio of de novo DSA associated with prior infections: 6.03 [95% CI, 1.64-22.06; p = 0.007]). Our prospective, longitudinal study does not support using ICFA to quantify the immune risk in kidney transplantation. Further studies are needed to confirm the relationship between viral infections and the subsequent development of de novo DSA.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): state of the art.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA) is a systemic small-vessel vasculitis associated with asthma and eosinophilia. Histology of EGPA shows tissue eosinophilia, necrotizing vasculitis, and eosinophil-rich granulomatous inflammation. EGPA commonly presents with upper airway tract and lung involvement, peripheral neuropathy, cardiac and skin lesions. Antineutrophil cytoplasmic antibodies (ANCA) are positive in ~40% of the cases and more often in patients with clinical manifestations due to small-vessel vasculitis. The pathogenesis of EGPA is multifactorial: the disease can be triggered by exposure to allergens or drugs, but a genetic background has also been recognized, particularly an association with HLA-DRB4. Th2 responses are prominent, with up-regulation of IL-4, IL-13, and IL-5; however, Th1 and Th17 responses are not negligible. Eosinophils are activated, have a prolonged lifespan and probably cause tissue damage by releasing their granule proteins; their tissue recruitment can be regulated by chemokines such as eotaxin-3 and CCL17. Humoral immunity is also dysregulated, as demonstrated by prominent IgG4 and IgE responses. EGPA promptly responds to glucocorticoid therapy, although combinations of glucocorticoids and immunosuppressants (e.g., cyclophosphamide, azathioprine) are eventually required in most cases. Newer therapeutic options include the anti-IL5 antibody mepolizumab, whose efficacy has been described in small clinical trials, and the B-cell-depleting agent rituximab, reported in several case series.

EBV-associated leukoencephalopathy with late onset of central nervous system lymphoma in a kidney transplant recipient.

Central nervous system (CNS) lymphoma is a rare posttransplant lymphoproliferative disorder (PTLD), which usually has a poor outcome. To date, no specific conditions predisposing to this complication have been identified. We here describe the case of a renal transplant patient who was initially diagnosed as having Epstein-Barr virus (EBV)-associated leukoencephalopathy and ultimately developed EBV-positive CNS lymphoma. The patient was a young lady who, 2 years after transplantation, presented with focal neurological and electroencephalographic abnormalities and diffuse white matter lesions on brain magnetic resonance imaging. EBV-DNA was detected in the cerebrospinal fluid (CSF) by polymerase chain reaction. After acyclovir therapy and immunosuppressive drug tapering, the symptoms and electroencephalographic abnormalities subsided, and EBV-DNA disappeared from the CSF. Ten years later, a bulky cerebral mass was found. After excision, a diagnosis of EBV-positive, Hodgkin-like monomorphic B-cell PTLD was made. This case illustrates the potential pathophysiological relationships between EBV infection, leukoencephalopathy and CNS lymphoma; although a long time elapsed from the initial neurological illness to CNS lymphoma, a link between these two conditions cannot be excluded. Therefore, a careful long-term follow-up of EBV-related encephalopathy is advisable.

Chronic periaortitis associated with membranous nephropathy: clues to common pathogenetic mechanisms.

Chronic periaortitis (CP) is a rare disease hallmarked by the presence of a periaortic retroperitoneal fibro-inflammatory tissue which can often cause obstructive uropathy. CP is isolated in most cases but it may also be associated with other sclerosing inflammatory and immune-mediated diseases. We here present the case of a patient who was initially diagnosed as having CP and subsequently developed membranous nephropathy and chronic sclerosing sialoadenitis of the right parotid gland. As these conditions were all characterized by either pronounced infiltration of IgG4-positive plasma cells or marked IgG4 tissue deposition, we hypothesize that they are part of the same disease spectrum, and discuss the immune-mediated pathogenetic mechanisms potentially shared by these conditions. In particular, we consider the role of Th2-mediated immune reactions and of immunogenetic factors such as HLA genotype as common determinants of these disorders.

Natural killer cell cytotoxicity is enhanced by very low doses of rIL-2 and rIFN-alpha in patients with renal cell carcinoma.

Very low doses of recombinant interleukin-2 (rIL-2) and interferon-alpha (rIFN-alpha) induce, in patients with advanced renal cell carcinoma (RCC) clinical response rate and median survival time comparable to other protocols, other than immunological response in terms of expansion of NK cells and cT lymphocytes. The aim of this pilot study was to verify whether very low dose immunotherapy can enhance NK cell cytotoxicity against tumoral target cells. Eight patients with advanced and 13 patients with localised disease received 4-week cycles of rIL-2 (total dose per week 7 MIU/m(2), s.c.) and rIFN-alpha (total dose per week 3.6 MUI/m(2), i.m.) according to the scheme proposed by Buzio et al. Neutrophils, monocytes, eosinophils, NK cells (CD56+bright, CD56+dimmer, CD3-CD56 +), NK-T cells (CD3+CD56+), Th-lymphocytes, cT-lymphocytes, HLA-DR+ and CD25+ lymphocytes and NK cell cytotoxicity were evaluated before and after cycle. The treatment led to the significant expansion of eosinophils (P < 0.001), NK cells (P < 0.001), CD56+bright (P < 0.001), CD56+dimmer (P < 0.001), Th-lymphocytes (P = 0.001), cT-lymphocytes (P = 0.014), HLA-DR+ (P = 0.007) and CD25+(P = 0.002) cells. Neutrophils significantly decreased (P = 0.001), whereas no significant effect was observed on monocytes (P = 0.22) or NK-T cells (P = 0.20). Patients with localised disease responded significantly better to treatment than metastatic patients in terms of the expansion of CD56+bright (P = 0.038), DR+ (P = 0.021), CD25+ (P = 0.006) and Th-lymphocytes (P = 0.014). The NK cell cytotoxicity was significantly increased by the immunotherapy in the whole population (P = 0.021) and similarly in the two groups of patients (P = 0.860); a reverse relation, even if not significant, was seen between the variation of NK-T cells and NK cells cytotoxicity (r = -0.39; P = 0.074).

Peripheral inflammatory arthritis in patients with chronic periaortitis: report of five cases and review of the literature.

OBJECTIVES: Chronic periaortitis (CP) is a rare disease with a potentially immune-mediated pathogenesis. The study aims to report the frequency and the clinical characteristics of peripheral inflammatory arthritis in a cohort of CP patients, and to review the literature regarding the association between arthritis and CP. METHODS: Forty-nine consecutive CP patients were seen at our department between 2000 and 2006; all of them underwent imaging (abdominal computed tomography and magnetic resonance imaging) and laboratory examinations, also including erythrocyte sedimentation rate, C-reactive protein and a panel of autoantibodies. The clinical history of the patients who developed peripheral inflammatory arthritis is reported in detail. A PubMed/Medline search without any date limits was performed for English-language articles reporting the association between CP and arthritis. RESULTS: Five of the 49 enrolled patients developed an inflammatory form of peripheral arthritis: three were diagnosed as having RA, one palindromic rheumatism and one acute reactive arthritis. In all but one case, arthritis became clinically overt months to years after the onset of CP, and its outcome was good, since almost all patients were asymptomatic at the end of follow-up. No patient suffered from ankylosing spondylitis. In the literature review, 20 cases of CP-associated arthritis were found, mainly in the form of case reports: 14 of them were spondyloarthropathies, whereas the remaining ones were RA, juvenile RA or undifferentiated arthritis. CONCLUSIONS: Peripheral inflammatory arthritis, particularly RA or RA-like forms, may develop in CP patients. This overlap strengthens the hypothesis of an autoimmune origin of CP.

Octreotide in the treatment of lymphorrhea after renal transplantation: a preliminary experience.

BACKGROUND: Lymphorrhea is a minor complication after kidney transplantation but may develop into a lymphocele and prolong hospital stay. Treatment is conservative based on percutaneous drainage until lymphatic leakage cessation. It has been reported that octreotide has beneficial effects to treat lymphorrhea after axillary node dissection and excision of lymphatic malformations. The aim of this study was to report preliminary experience about octreotide treatment in lymphorrea after kidney transplantation. MATERIALS AND METHODS: This retrospective study included 20 recipients of cadaveric kidney allografts with posttransplant lymphorrhea including 10 treated with instillation of povidone iodate solution, and the other 10 with octreotide (0.1 mg three times a day subcutaneously). We reviewed the daily amount of fluid collection, duration of lymphorrhea, complications, lymphocele formation, rejection episodes, graft outcomes, and hospital stay. RESULTS: The average duration of lymphorrhea was 8.5 (+/-4.5) and 16.3 (+/-7.3) days for the octreotide versus the povidone groups, respectively (P = .001). No complications occurred among the octreotide group, while three lymphoceles grew among patients treated with povidone solution. No differences were observed for acute rejection episodes or renal function between the groups. No octreotide-related adverse events were noted. CONCLUSION: The mean length of lymphorrhea was lower with octreotide versus iodate povidone solution treatment. There was a shorter hospital stay and minor patient discomfort. In conclusion, lymphatic leakage after kidney transplantation may be successfully managed by octreotide administration.

Post-treatment residual tissue in idiopathic retroperitoneal fibrosis: active residual disease or silent "scar" ? A study using 18F-fluorodeoxyglucose positron emission tomography.

OBJECTIVE: Medical treatment is often effective in idiopathic retroperitoneal fibrosis (IRF) but frequently leads to residual retroperitoneal masses that may represent active disease or simply consist of inactive fibrotic tissue. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is a functional imaging modality that reliably assesses disease activity in a number of inflammatory diseases including IRF. We used 18F-FDG PET to evaluate the metabolic activity of residual masses in a series of IRF patients. METHODS: We studied 7 consecutive IRF patients, all of whom presented constitutional symptoms and/or pain, and had high acute-phase reactant levels; 6 had ureteral involvement. IRF was diagnosed by means of computed tomography (CT), which revealed a peri-aortoiliac mass in all cases. Three patients underwent surgical ureterolysis and 2 received ureteral stents. Subsequently, 5 patients received prednisone, one sequential treatment with prednisone and tamoxifen, and one prednisolone plus methotrexate. All of the patients underwent 18F-FDG PET at varying times after the end of treatment. RESULTS: The presenting signs/symptoms improved in all patients and the levels of acute-phase reactants significantly decreased or normalised. Ureteral obstructive disease resolved in all cases. Post-treatment CT revealed a considerable reduction in the amount of IRF but all of the patients had a residual retroperitoneal mass. PET revealed slight aorto-iliac 18F-FDG uptake in only one patient; all of the others were negative. No patient relapsed during the follow-up. CONCLUSIONS: Post-treatment residual masses are frequent in IRF patients but, in most cases, probably represent metabolically inactive tissue.

ENT Wegener's granulomatosis can hide severe central nervous system involvement.

The clinical manifestations of localised or early systemic forms of Wegener's granulomatosis (WG) do not require immediate treatment to save the patient's life and/or the function of a vital organ. The organs mainly involved are the ear, nose, throat (ENT) and lung, and the results of antineutrophil cytoplasmic antibody (ANCA) assays are frequently negative. We here describe three cases of the ANCA-negative early systemic form of WG with prevalent ENT involvement complicated by severe central nervous system (CNS) disease; in two cases, the only symptom was a mild headache. We conclude that, although apparently mild, the localised and early systemic forms of WG can hide CNS involvement and may require immediate treatment. This complication should be suspected and investigated in the case of patients with localised or early systemic disease especially in the presence of ENT involvement and negative ANCA assays.

Idiopathic and secondary forms of retroperitoneal fibrosis: a diagnostic approach.

Retroperitoneal fibrosis (RPF) is an uncommon disease characterized by a fibrous reaction that takes place in the peri-aortic retroperitoneum and often entraps the ureters causing obstructive uropathy. RPF is idiopathic in the majority of cases, but can also be secondary to malignancies, infections, drugs, radiotherapy, and rare histiocytic disorders such as Erdheim-Chester disease. Idiopathic RPF is an immune-mediated disease, which can either be isolated, associated with other autoimmune diseases, or arise in the context of a multifocal fibro-inflammatory disorder recently renamed as IgG4-related disease. The differential diagnosis between idiopathic, IgG4-related and secondary RPF is crucial, essentially because the therapeutic approaches - especially of idiopathic vs. secondary RPF - can be dramatically different. This review focuses on the clinical, laboratory and imaging features of the different RPF forms, and also provides an overview of the available treatment options.

Renal effects of nifedipine and captopril in patients with essential hypertension and reduced renal reserve.

In this study we investigated the short-term effects of calcium channel blockers and angiotensin-converting enzyme inhibitors on renal hemodynamics and the urinary excretion of proteins with different relative mass in subjects with mild to moderate essential hypertension and apparently normal glomerular filtration rate but reduced renal functional reserve. Sixteen subjects underwent the following four treatments: (1) low-protein meal (0.2 g protein/kg body wt), (2) high-protein meal (1.3 g protein/kg body wt), (3) high-protein meal plus oral nifedipine (20 mg), and (4) high-protein meal plus oral captopril (50 mg). Two urine samples were obtained after meals. Blood samples were drawn at the midpoint of each 120-minute urine collection period. Urine and serum were tested for total protein, immunoglobulin G, albumin, alpha 1-microglobulin, retinol binding protein, and beta 2-microglobulin. Glomerular filtration rate and renal plasma flow were assessed by iothalamate and p-aminohippuric clearance, respectively. Compared with the high-protein meal alone, nifedipine elicited a clear-cut increase in the urinary excretion of total protein (+60%, P < .01), immunoglobulin G (+58%, P < .01), albumin (+25%, P < .05), retinol binding protein (+47%, P < .05), and beta 2-microglobulin (+52%, P < .05); captopril decreased the urinary excretion rate of immunoglobulin G (-26%, P < .05), albumin (-22%, P < .05), and beta 2-microglobulin (-34%, P < .05). The ratio between the clearances of immunoglobulin G and albumin was higher after nifedipine (+21%, P < .01) and unchanged after captopril (-9%, P = NS) compared with the high-protein meal alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Interferon-alpha in combination with ribavirin as initial treatment for hepatitis C virus-associated cryoglobulinemic membranoproliferative glomerulonephritis.

Mixed cryoglobulinemia (MC) and glomerulonephritis are the most important extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. In HCV-infected patients with MC, renal involvement worsens the overall prognosis because of a high incidence of infection or cardiovascular disease. The relationship between MC and HCV infection has prompted the use of antiviral therapy. Two patients with chronic HCV infection, type-II MC and membranoproliferative glomerulonephritis (MPGN), presenting as nephrotic syndrome were treated with interferon (IFN)-alpha (3 MU 3 times per week) and ribavirin (15 mg/kg daily) for 6 months. Laboratory tests included measurement of anti-HCV antibodies, HCV RNA, and HCV genotyping, and characterization of circulating cryoglobulins. A pretreatment renal biopsy was performed, and the histopathologic lesions were scored according to the index of disease activity. Viremia and cryoglobulinemia were suppressed in both patients. However, a complete remission of proteinuria was observed in 1 patient only. The evaluation of the renal biopsy specimens revealed a mild MPGN (activity score: 5/24) in the patient with remission of proteinuria and a severe MPGN (activity score: 15/24) in the patient who maintained a nephrotic-range proteinuria. Although a fully satisfactory treatment is not yet available, we feel that a reasonable therapeutic strategy for HCV-infected patients with MC nephritis could be as follows: (1) antiviral treatment alone for patients with a low-grade kidney involvement, and (2) a short-term course of steroids and cytotoxic drugs followed by antiviral therapy for acute exacerbations and/or rapidly progressive GN.

Retinol binding protein in serum and in urine of glomerular and tubular nephropathies.

RBP behavior was studied in different kidney diseases. Serum RBP was increased in chronic renal diseases when the serum creatinine increased. RBP clearance and RBP clearance as a percentage of albumin clearance increased when GFR decreased; this is more evident in tubular kidney diseases. Urinary RBP loss as a percentage of urinary albumin loss increased especially in kidney diseases with persistent tubular lesions.

Glutathione S-transferases M1-1 and T1-1 as risk modifiers for renal cell cancer associated with occupational exposure to chemicals.

AIMS: To investigate the possible interaction between occupational risk factors and genotype for glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) in renal cell cancer (RCC). METHODS: One hundred patients with RCC and 200 outpatient controls were enrolled at Parma University Hospital. The polymorphisms of glutathione S-transferase M1-1 (GSTM1) and T1-1 (GSTT1) were investigated by PCR; occupational history was collected by a structured questionnaire. RESULTS: Subjects with GSTM1 present genotype showed higher risks for RCC, compared to GSTM1 null subjects, if exposed to metals (OR 2.73; 95% CI 0.91 to 8.22 v 1.14; 95% CI 0.46 to 2.82) or pesticides (OR 3.46; 95% CI 1.12 to 10.74 v 1.59; 95% CI 0.48 to 5.34). The GSTT1 present genotype also enhanced the risk (about twofold) of RCC among subjects exposed to solvents and pesticides, compared with those GSTT1 null. CONCLUSIONS: Results support the hypothesis that GSTM1 and GSTT1 polymorphisms can interact with several occupational exposures to significantly modify the risk of RCC among exposed subjects.

Middle molecules in uremic serum, urine and dialysis fluid.

Gel filtration through Sephadex (g 75 and 15) and ultrafiltration and diafiltration through selective membrances have been carried out on 172 uremic sera, 89 normal sera, uremic and normal urines and hemodialysis fluid. The accumulation in uremic sera of substances wwith molecular weights between 500 and 3,500 (so called "middle molecules") was demonstrated. Molecular weight evaluation was verified on single effluent fractions using different added isotopes. Evaporation of serum to dry weight revealed a 2-3 fold increase in solids compared to normal values. Estimation of the fractional content of individual elements and quantitative amino acid analysis (before and after acid hydrolysis) did not show any difference between normal and uremic subjects, but there was a significant increase of peptides in uremic serum. The accumulation of peptides was confirmed by high voltage electrophoresis. Urinary excretion of substances with comparable molecular weights to those found in uremic serum was demonstrated, but there was no significant difference between urine from normal and from uremic subjects. A steady state of chronic uremia with high urinary volume is therefore consistent with a normal urinary excretion of middle molecules with increased concentrations in serum and glomerular filtrate. Tubular reabsorption may also be decreased because the urinary excretion of middle molecules increases with the development of tubular proteinuria in patients with pyelonephritis. Dialysis treatment removes moderate amounts of middle molecules; their serum concentration decreases slightly after dialysis and they are detectable in dialysis fluid. The identification, metabolism and biological effects of middle molecules are discussed in relationship to uremic toxicity and the effects of different forms of dialysis treatment.

Significance of albuminuria in the follow-up of acute poststreptococcal glomerulonephritis.

The present study was aimed at assessing the diagnostic value of urinary albumin (uA) excretion rate in the long-term follow-up of patients suffering from acute post-streptococcal glomerulonephritis (APSGN). 26 patients, who had presented primarily with nephritic syndrome and showing increased uA without a concomitant rise in total proteinuria (uTP) were followed-up for 131 months on average (range 36-288). At the last check, 14 patients did not show urinary abnormalities, 9 had a persistent increase in uA, 1 increased uTP and 2 renal insufficiency. Urinary and clinical signs of the disease were not seen during observation periods prolonged for 79 months on average (range 20-156) after normalization of uA. No pathological findings were remarked in biopsy specimens obtained in 3 patients when uA was normalized; in contrast, when both uTP and uA (12 cases) or when isolated uA (14 cases) were increased a pattern of diffuse mesangial proliferative glomerulonephritis was constantly observed. These results indicate that the abnormal uA excretion rate during long-term follow-up of APSGN allows to identify a subset of patients with persistent renal disease; conversely, the occurrence of normal uA seems to point to a good diagnostic and prognostic significance.