IgG4-related disease in a multi-ethnic community: clinical characteristics and association with malignancy.

BACKGROUND: Immunoglobulin-G4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory condition that can affect multiple organs. Despite growing interest in this condition, the natural history and management of IgG4-RD remain poorly understood. AIM: To describe the clinical characteristics, treatment and outcomes of IgG4-RD in a multi-ethnic UK cohort, and investigate its possible association with malignancy. DESIGN: Retrospective analysis of case-note and electronic data. METHODS: Cases were identified from sub-specialty cohorts and a systematic search of an NHS trust histopathology database using 'IgG4' or 'inflammatory pseudotumour' as search terms. Electronic records, imaging and histopathology reports were reviewed. RESULTS: In total, 66 identified cases of IgG4-RD showed a similar multi-ethnic spread to the local population of North West London. The median age was 59 years and 71% of patients were male. Presenting symptoms relating to mass effect of a lesion were present in 48% of cases and the mean number of organs involved was 2.4. Total of 10 patients had reported malignancies with 6 of these being haematological. 83% of those treated with steroids had good initial response; however, 50% had relapsing-remitting disease. Rituximab was administered in 11 cases and all achieved an initial serological response. Despite this, seven patients subsequently relapsed after a mean duration of 11 months and four progressed despite treatment. CONCLUSIONS: We report a large UK-based cohort of IgG4-RD that shows no clear ethnic predisposition and a wide range of affected organs. We discuss the use of serum IgG4 concentrations as a disease marker in IgG4-RD, the association with malignant disease and outcomes according to differing treatment regimens.

Treatment-limiting renal tubulopathy in patients treated with tenofovir disoproxil fumarate.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is widely used in the treatment or prevention of HIV and hepatitis B infection. TDF may cause renal tubulopathy in a small proportion of recipients. We aimed to study the risk factors for developing severe renal tubulopathy. METHODS: We conducted an observational cohort study with retrospective identification of cases of treatment-limiting tubulopathy during TDF exposure. We used multivariate Poisson regression analysis to identify risk factors for tubulopathy, and mixed effects models to analyse adjusted estimated glomerular filtration rate (eGFR) slopes. RESULTS: Between October 2002 and June 2013, 60 (0.4%) of 15,983 patients who had received TDF developed tubulopathy after a median exposure of 44.1 (IQR 20.4, 64.4) months. Tubulopathy cases were predominantly male (92%), of white ethnicity (93%), and exposed to antiretroviral regimens that contained boosted protease inhibitors (PI, 90%). In multivariate analysis, age, ethnicity, CD4 cell count and use of didanosine or PI were significantly associated with tubulopathy. Tubulopathy cases experienced significantly greater eGFR decline while receiving TDF than the comparator group (-6.60 [-7.70, -5.50] vs. -0.34 [-0.43, -0.26] mL/min/1.73 m2/year, p < 0.0001). CONCLUSIONS: Older age, white ethnicity, immunodeficiency and co-administration of ddI and PI were risk factors for tubulopathy in patients who received TDF-containing antiretroviral therapy. The presence of rapid eGFR decline identified TDF recipients at increased risk of tubulopathy.

An atypical cutaneous presentation of vasculitis with features of Churg-Strauss syndrome, associated with anti-neutrophil cytoplasmic antibodies and anti-glomerular basement membrane antibodies.

We report the case of a 59-year-old woman who presented with a persistent papular and nodular cutaneous eruption and new-onset asthma, with normal renal function but persistent haematuria and proteinuria. Investigations revealed eosinophilia, both antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibodies on serological testing (double-positive vasculitis), and a focal necrotizing glomerulonephritis on renal biopsy. Histological examination of a skin biopsy showed a dense neutrophilic infiltrate with focal fibrinoid necrosis and few eosinophils. The clinical and pathological features suggested a double-positive vasculitis/Churg-Strauss overlap syndrome presenting with a predominantly neutrophilic dermatosis. Specific cutaneous features in patients with double-positive vasculitis have not been documented previously. The patient has responded extremely well to immunosuppressive treatment and her disease is currently in remission.

Impact of new dialysis solutions on peritonitis rates.

Peritonitis remains a major cause of morbidity among patients on peritoneal dialysis (PD), yet there is little information about the effect of new biocompatible dialysis solutions on peritonitis rates and treatment. In our unit, information on each peritonitis episode is prospectively collected. Since 2003, bicarbonate/lactate dialysate has been gradually introduced for new patients and for patients experiencing abdominal pain with conventional lactate solutions. From 2002 to 2005, data from 121 episodes of peritonitis (71 automated PD and 50 continuous ambulatory PD) were analyzed; 107 episodes occurred in patients using standard lactate dialysate and 14 episodes in patients using bicarbonate/lactate solution. Patients using bicarbonate/lactate had a significantly lower peritonitis rate of 1 per 52.5 patient-months compared to those using standard lactate dialysate (1 per 26.9 patient-months) (P=0.0179). Response to treatment, however, was not affected by the type of dialysate; cure rates (71.4 and 69.1%, respectively) and recurrence rates (21.4 and 15.8%, respectively) were not significantly different. Catheter removal was required in three (21.4%) patients using bicarbonate/lactate and 23 (22.4%) patients using lactate solution. Use of biocompatible dialysate appears to reduce the peritonitis rate by 50%, although this has to be confirmed in a randomized study. The type of dialysate, on the other hand, does not affect response to treatment.

Characterization of autoantibodies from patients with Goodpasture's disease using a resonant mirror biosensor.

Goodpasture's disease is characterized by the binding of IgG autoantibodies to the glomerular basement membrane, leading to glomerular inflammation. The autoantigen has been identified as the noncollagenous domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1). We have used the IAsys resonant mirror biosensor to analyse the extent and affinity of binding of anti-GBM antibodies from sera of patients to purified alpha3(IV) NC1. alpha3(IV) NC1 monomers were immobilized to a carboxylate cuvette, with the simultaneous use of a control well. The binding of serum from patients with Goodpasture's disease (n = 12), normal controls (n = 14) and disease controls with vasculitis (n = 14) was analysed. Antibody binding was detected in sera from all patients with Goodpasture's disease but not from controls. IAsys measurements of binding correlated with antibody levels assessed by the standardized ELISA used for clinical assays. Both ELISA and biosensor measurements showed declining antibody levels in serial serum samples from treated patients; however, the biosensor detected antibody recrudescence when ELISA remained negative. Autoantibodies from patients' serum had average affinity constants (Kd) of 6.5 x 10-11M to 52.07 x 10-10M, as determined by an inhibition assay, indicating high affinity. Sips analysis showed that the antibody response was relatively homogeneous (values of 0.46-1). Biosensor techniques can therefore be used to detect and characterize anti-GBM antibodies in serum from patients, with high sensitivity and without need for antibody purification. This technique may be useful in diagnosis and monitoring of patients with Goodpasture's disease, and may be applicable to other autoantibody mediated diseases.

Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression.

BACKGROUND: Anti-glomerular basement membrane (GBM) antibody disease is an autoantibody-mediated disorder that usually presents as rapidly progressive glomerulonephritis, often with pulmonary hemorrhage (the Goodpasture syndrome). It is reported that patients with severe renal failure do not generally recover renal function. OBJECTIVE: To examine the long-term outcome of severe anti-GBM antibody disease. DESIGN: Retrospective review of patients treated for confirmed anti-GBM antibody disease over 25 years. SETTING: A tertiary referral center in the United Kingdom. PATIENTS: 71 treated patients with anti-GBM antibody disease. INTERVENTION: All patients received plasma exchange, prednisolone, and cyclophosphamide. MEASUREMENTS: Patient and renal survival, renal histology, and antibody levels. RESULTS: Patients who presented with a creatinine concentration less than 500 micromol/L (5.7 mg/dL) (n = 19) had 100% patient survival and 95% renal survival at 1 year and 84% patient survival and 74% renal survival at last follow-up. In patients who presented with a creatinine concentration of 500 micromol/L or more (>/=5.7 mg/dL) (n = 13) but did not require immediate dialysis, patient and renal survival were 83% and 82% at 1 year and 62% and 69% at last follow-up. In patients who presented with dialysis-dependent renal failure (n = 39), patient and renal survival were 65% and 8% at 1 year and 36% and 5% at last follow-up. All patients who required immediate dialysis and had 100% crescents on renal biopsy remained dialysis dependent. CONCLUSIONS: Patients with the Goodpasture syndrome and severe renal failure should be considered for urgent immunosuppression therapy, including plasma exchange, to maximize the chance of renal recovery. Patients needing immediate dialysis are less likely to recover.

Nephrotoxicity of intravenous immunoglobulin.

Individual case reports have documented nephrotoxicity of intravenous immunoglobulin (IVIG) preparations, but the true incidence of renal dysfunction is unknown and many data sheets do not include renal impairment as a side-effect of these preparations. We determined the incidence of renal impairment in an unselected cohort of patients receiving two different preparations of IVIG over 20 months, administering 287 courses of IVIG to 119 patients for a variety of indications, including thrombocytopenia, systemic lupus erythematosis, neuropathy, Guillain-Barre syndrome and infections. Two different preparations of IVIG were used, Vigam (BPL) and Sandoglobulin (Novartis), which differ in the concentration of sucrose added as a stabilizer. Eight patients showed deterioration in renal function (6.7%), and in two, no renal recovery occurred (1. 7%). There were no significant differences in the patient characteristics or dose or preparation of IVIG administered to those patients with or without changes in serum creatinine. There was no association between the amount of sucrose in the IVIG and development of renal failure. IVIG (regardless of the sucrose content) is associated with renal impairment which may be irreversible, with a maximum incidence of 6.7%. All patients should have their renal function monitored during the use of IVIG.

The tyrosine phosphatase SHP-1 is a negative regulator of osteoclastogenesis and osteoclast resorbing activity: increased resorption and osteopenia in me(v)/me(v) mutant mice.

Naturally occuring inactivating mutations of the Src homology 2 (SH2) domain-containing tyrosine phosphatase 1 (SHP-1) in mice give rise to the motheaten (me) phenotype. me/me mice have multiple hematopoietic abnormalities, suggesting that this phosphatase plays an important role in hematopoiesis. SHP-1 binds to and is activated by several hematopoietic surface receptors, including the colony-stimulating factor type 1 receptor. We have examined the role of SHP-1 in osteoclastogenesis and osteoclast function using mice with the viable motheaten (me(v)/me(v)) mutation, which has markedly decreased SHP-1 activity. Histomorphometric analysis of 6-week-old me(v)/me(v) mice and control littermates showed a marked osteopenia with an increase in bone resorption indices. The number of formed osteoclast-like cells (OCLs) in cocultures of me(v)/me(v) hematopoietic cells with normal osteoblasts was significantly increased. In contrast, the number of OCLs formed in the coculture of normal bone marrow cells with the me(v)/me(v) osteoblasts was not significantly different from controls. The bone-resorbing activity of me(v)me(v) OCLs and authentic osteoclasts was also found to be increased. Finally, Western blotting of proteins from me(v)/me(v) and control OCLs revealed an overall increase in tyrosine phosphorylation in the me(v)/me(v) lysates. These in vivo and in vitro results suggest that SHP-1 is a negative regulator of bone resorption, affecting both the formation and the function of osteoclasts.

Urological complications after kidney-pancreas transplantation.

PURPOSE: Urological complications are common after kidney-pancreas transplantation. Predictors of urological complication after transplantation have not been established. We studied the impact of urological complications on allograft function. In addition we evaluated age at transplantation, diabetic years before transplantation and preoperative bladder function as predictors of allograft pancreatitis, postoperative retention and urine leaks. MATERIALS AND METHODS: Urological complications in 65 cases (38 men, 27 women, mean diabetic years 21 +/- 6, mean age 33 +/- 7 years) who had transplants between December 1987 and January 1995 were reviewed. Preoperative urodynamics in 50 patients (77%) and voiding cystourethrogram in 40 (62%) were analyzed. Kidney-pancreas transplantation was completed using bladder drainage techniques. RESULTS: Mean followup was 44 +/- 27 months (median 40, range 1 to 93). Urological complications in 51 patients (79%) included urinary tract infection in 59%, hematuria in 26%, allograft pancreatitis in 19%, duodenal leaks in 17%, ureteral lesions in 9% and urethral lesions in 6%. Eleven duodenal leaks (8 leaks in less than 1 month) required surgical treatment. Nine leaks recurred in 7 patients. Allograft pancreatitis occurred 32 times (range 1 to 9) in 12 patients. Three patients had ureteral obstruction and 3 had ureteral leaks. Preoperative urodynamics included detrusor hyperreflexia in 8 patients, detrusor areflexia in 19, indeterminate in 5 and normal in 18. The 1-year patient, kidney and pancreatic allograft survival rates were 92, 91 and 86%; 2-year survival rates were 89, 88 and 80%, and 5-year survival rates were 61, 59 and 55%, respectively. CONCLUSIONS: Urological complications were common after transplantation but did not adversely affect allograft survival in our series. Age at transplantation, diabetic years preceding transplantation and preoperative bladder function were not significantly correlated with allograft pancreatitis, postoperative urinary retention or urine leaks. A prospective analysis of postoperative bladder function should be completed to improve understanding and possibly reduce morbidity of urological complications after transplantation.

Colony-stimulating factor-1 induces cytoskeletal reorganization and c-src-dependent tyrosine phosphorylation of selected cellular proteins in rodent osteoclasts.

Colony-stimulating factor-1 (CSF-1) stimulates motility and cytoplasmic spreading in mature osteoclasts. Therefore, we examined the cellular events and intracellular signaling pathways that accompany CSF-1-induced spreading in normal osteoclasts. To explore the role c-src plays in these processes, we also studied osteoclasts prepared from animals with targeted disruption of the src gene. In normal osteoclasts, CSF-1 treatment induces rapid cytoplasmic spreading, with redistribution of F-actin from a well-delineated central attachment ring to the periphery of the cell. CSF-1 increases membrane phosphotyrosine staining in osteoclasts and induces the phosphorylation of several cellular proteins in cultured, osteoclast-like cells, including c-fms, c-src, and an 85-kD Grb2-binding protein. Src kinase activity is increased threefold after CSF-1 treatment. In src- cells, no attachment ring is present, and CSF-1 fails to induce spreading or a change in the pattern of F-actin distribution. Although c-fms becomes phosphorylated after CSF-1 treatment, the 85-kD protein is significantly less phosphorylated in src- osteoclast-like cells. These results indicate that c-src is critical for the normal cytoskeletal architecture of the osteoclast, and, in its absence, the spreading response induced by CSF-1 is abrogated, and downstream signaling from c-fms is altered.

Mapping B cell epitopes in Goodpasture's disease.

The target antigen of the pathogenic autoantibodies in Goodpasture's disease is the noncollagenous domain of the alpha 3 chain of type IV collagen. A panel of membrane-bound peptides was used to identify antibody-binding regions within the protein, and the significance of the binding by inhibition studies using soluble peptides, and by a structural analysis of the antigen, was confirmed. A total of 117 overlapping 12-mer peptides spanning the entire antigen was simultaneously synthesized as individual spots on a cellulose membrane. All nine patients' sera bound to the membrane, with a conserved pattern of peptides recognized by all sera. Inhibition studies were performed using a panel of overlapping 20-mer peptides, also spanning the entire antigen. Peptides from the regions that bound IgG were able to inhibit the binding of autoantibodies to native antigen. Predictions of the secondary structure of the noncollagenous domain of the alpha 3 chain of type IV collagen were performed by a conventional hydropathy plot and by multiple alignment of homologous alpha chains of type IV collagen and comparison with a structural data base. The core peptides binding and inhibiting Goodpasture's antibodies were predicted to be surface exposed and antigenic. Thus, the conformational epitope(s) of the Goodpasture antigen can be mapped using linear peptides.

Modified pudendal-thigh flap for correction of penoscrotal transposition.

OBJECTIVES: In patients with penoscrotal transposition, an occasional postoperative problem has been a deficiency of skin on the proximal penile shaft that results in penoscrotal fusion and tethering. METHODS: We describe a new operation using a modified neurovascular pudendal-thigh flap for correction of incomplete penoscrotal transposition. RESULTS: This procedure has been used in 6 children, and an excellent cosmetic and functional result has been achieved in each patient. CONCLUSIONS: The flaps provide a reliable blood supply, maintain normal innervation, and correct the problem of postoperative penoscrotal fusion and tethering. This technique preserves sufficient penile skin for a tension-free second-stage urethroplasty.

Hypertension after surgical management of renal duplication associated with an upper pole ureterocele.

PURPOSE: Duplicated upper pole systems associated with a ureterocele frequently have areas of segmental renal dysplasia. Since dysplasia has been related to the development of renin mediated hypertension, we hypothesized that preservation of functional upper pole moieties may result in an increased incidence of high blood pressure. MATERIALS AND METHODS: We evaluated 115 patients with a history of renal duplication and an ipsilateral upper pole ureterocele. Patients were separated into group 1-nonfunctional upper pole managed by partial nephrectomy, group 2-functional upper pole moiety managed by partial nephrectomy and group 3-functional upper pole moiety managed by a nephron sparing procedure. All charts were reviewed for hypertension, febrile urinary tract infection, vesicoureteral reflux and renal scarring. RESULTS: At a median followup age of 15 years (range 1 to 33) hypertension developed in 13 of the 115 patients (11%), including 8 of the 87 (9%) with nonfunctional upper pole systems managed by partial nephrectomy, 1 of the 12 (8%) with a functional upper pole moiety managed by partial nephrectomy and 4 of the 16 (25%) with a functional upper pole system managed by an upper pole salvage procedure. Statistical evaluations failed to reveal any relationship between hypertension and preservation of the upper pole system or between hypertension and vesicoureteral reflux. Rather, elevation in blood pressure was found to be related to development of a renal scar after a febrile urinary tract infection. CONCLUSIONS: Hypertension in patients with a history of renal duplication associated with a ureterocele is directly related to renal scarring.

Genitourinary neurofibromatosis mimicking posterior urethral valves.

A 12-year-old boy, examined after an episode of acute urinary retention, was found to have neurofibromatosis of the bladder neck and prostatic urethra. His symptoms of bladder outlet obstruction and radiographic findings of a dilated prostatic urethra mimicked posterior urethral valves. Complete urologic investigation, including cystourethroscopy, revealed that the dilatation of the prostatic urethra was secondary to neural involvement of the external sphincter and posterior urethra without mechanical obstruction or posterior urethral valves.

Still a role for plasma exchange in rapidly progressive glomerulonephritis?

Plasmapheresis combined with immunosuppression dramatically improved the survival of patients with Goodpasture's disease in the late 1970's. The presence of circulating pathogenic autoantibodies in this disease provided a logical rationale for the use of plasma exchange therapy. Careful analysis of the response to treatment has suggested that patients presenting with a serum creatinine < 600 mumol/I have the most benefit from plasma exchange. Subsequently plasmapheresis has been tried in a variety of other nephritides, predominantly those causing rapidly progressive glomerulonephritis, with variable success. Initial studies failed adequately to distinguish patients with a number of quite distinct causes of crescentic nephritis. However it has become clear that plasma exchange significantly improves the outcome of patients with pauci-immune crescentic glomerulonephritis who present with severe renal failure requiring dialysis, but not those with less severe renal disease.

Identification of a novel 135-kDa Grb2-binding protein in osteoclasts.

The tyrosine kinase receptor for macrophage colony-stimulating factor and the non-receptor tyrosine kinase c-Src play critical roles in osteoclast differentiation and function. Since the ubiquitously expressed adaptor protein Grb2 plays an important role in several tyrosine kinase signal transduction pathways, we used a filter binding assay to identify osteoclast proteins that bind to Grb2. In osteoclasts, there were three major Grb2-binding proteins, two of which, mSos and c-Cbl (p120), have been previously identified as Grb2-binding proteins in many cell types. The third protein, p135, had a restricted pattern of expression and was present at high levels in authentic osteoclasts and osteoclast-like cells formed in an in vitro co-culture system. In addition to binding Grb2 in the filter binding assay, p135 was isolated in complexes with endogenous Grb2 from osteoclast cell extracts. The association of p135 and Grb2 was dependent on an intact Src homology 3 domain and furthermore, was shown to preferentially interact with the N-terminal Src homology 3 domain of Grb2, which is similar to the interaction of mSos and Grb2 in other cell types. p135 was not recognized by antibodies against several known Grb2-binding proteins and thus may be a novel Grb2-binding protein.

c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption.

The primary defect in mice lacking the c-src gene is osteopetrosis, a deficiency in bone resorption by osteoclasts. Osteoclasts express high levels of the c-Src protein and the defect responsible for the osteopetrotic phenotype of the c-src-deficient (src-) mouse is cell-autonomous and occurs in mature osteoclasts. However, the specific signalling pathways that require c-Src expression for normal osteoclast activity have not been elucidated. We report here that the proto-oncogene product c-Cbl is tyrosine-phosphorylated in a Src-dependent manner in osteoclasts, where the two proteins colocalize on some vesicular structures. In vitro bone resorption by osteoclast-like cells (OCLs) is inhibited by both c-src and c-cbl antisense oligonucleotides. Furthermore, tyrosine phosphorylation of c-Cbl and the localization of c-Cbl-containing structures to the peripheral cytoskeleton are impaired in resorption-deficient c-src- OCLs, as well as in wild-type OCLs that have been treated with c-src antisense oligonucleotides. These results indicate that c-Cbl may act downstream of c-Src in a signalling pathway that is required for bone resorption.