Humoral immunity in late-onset Pre-eclampsia and linkage with angiogenic and inflammatory markers.

PROBLEM: Pre-eclampsia (PE) is a leading cause of maternal and foetal morbidity worldwide. Given the implication of immune mechanisms, we compared markers of humoral immunity in PE and their relationship to circulating markers of inflammation, angiogenic factors, and renal function. METHOD OF STUDY: Serum samples from 88 previously healthy women admitted to hospital with PE and 107 healthy pregnant controls at term were analysed for serum immunoglobulins (Ig), including IgG subclasses and free light chain (sFLC) levels, beta-2 microglobulin (B2-M), high-sensitivity C-reactive protein (HS-CRP), albumin, complement proteins (C3 & C4), creatinine, cystatin-C and the ratio of soluble fms-like tyrosine kinase-1 (sFLT-1) and placental growth factor (PlGF). RESULTS: Compared to the controls, women with PE had significantly reduced renal function, serum IgG (subclass 1 & 3), albumin, and C4 levels, whilst concentrations of total sFLC, HS-CRP, B2-M, and sFLT-1:PlGF were raised. On multivariable analysis, sFLT-1:PlGF ratio (P < 0.001), sFLC (P < 0.001) and IgG1 (P < 0.024) were found to be independently associated with PE, after accounting for renal function, patient age, BMI, ethnicity, and parity. B2-M and sFLT-1:PlGF had comparable diagnostic association with PE (P = 0.184), and correlated strongly with each other (ρ = 0.588, P < 0.001) as well as with renal function and adverse clinical outcome. CONCLUSION: We describe for the first time that PE is independently associated with activation of the humoral immune system independent of deranged kidney function and angiogenic markers. The role of B2-M as a potential predictive marker of PE remains to be determined.

Patients with Wegener's granulomatosis demonstrate a relative deficiency and functional impairment of T-regulatory cells.

An increased proportion of CD4(+) CD25(+) T cells has been reported in Wegener's granulomatosis (WG) and may represent an accumulation of regulatory T cells (Treg). CD25 is also expressed on recently activated effector T cells. We have determined the relative proportion of these subsets in a large patient cohort. The fraction of Treg in peripheral blood mononuclear cells from patients and healthy controls was determined by assessment of Foxp3 expression on CD4(+) CD25(+) T cells. The functional activity of Treg was determined by their ability to suppress proliferation and cytokine production in response to proteinase-3. Although WG patients demonstrated an increased fraction of CD4(+) CD25(+) T cells, the percentage of Foxp3-positive cells was decreased. In addition, the percentage of Treg was inversely related to the rate of disease relapse. CD4(+) CD25(hi) T cells were able to suppress T-cell proliferation to proteinase-3 in healthy controls and anti-neutrophil cytoplasm antibody (ANCA)- negative patients (at time of sampling) but not in ANCA-positive patients. In patients with active disease, an increased proportion of CD4(+) Foxp3(+) cells was associated with a more rapid disease remission. Patients with WG demonstrate abnormalities in the number and function of Treg and this is most pronounced in those with most active disease. This information is of value in understanding the pathogenesis and potential treatment of this disease.

Prediction of ESRD in pauci-immune necrotizing glomerulonephritis: quantitative histomorphometric assessment and serum creatinine.

BACKGROUND: Clinical and pathologic features that predict outcome have important potential application in patients with pauci-immune necrotizing glomerulonephritis (usually antineutrophil cytoplasmic antibody-associated vasculitis). This study examines the predictive value of simple quantitative renal histologic measurements in a large cohort with extended follow-up. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 390 consecutive patients with pauci-immune necrotizing glomerulonephritis at a single hospital (1983-2002); 90 patients underwent repeated kidney biopsy during follow-up. PREDICTORS: Age and serum creatinine concentration at biopsy, antineutrophil cytoplasmic antibody specificity, percentage of normal glomeruli, percentage of glomeruli with active lesions, and index of chronic damage (quantitative measurement of established cortical damage) in the initial kidney biopsy for all patients. The same factors were assessed in both biopsy specimens for patients undergoing an additional biopsy. OUTCOMES & MEASUREMENTS: End-stage renal disease and patient survival. RESULTS: Mortality at 1 and 5 years was 23% and 40%, respectively: standardized mortality ratio, 4.74 (95% CI, 3.62-6.32). End-stage renal disease was reached by 14% and 18% at 1 and 5 years, respectively. In multivariable analysis, serum creatinine level at biopsy and percentage of normal glomeruli in the initial biopsy specimen were the best predictors of kidney survival. C Statistics were 0.80 for creatinine level alone and 0.83 for creatinine level with normal glomeruli. In patients undergoing an additional biopsy, rapid progression in the index of chronic damage and serum creatinine level at the second biopsy were associated with kidney survival in multivariable analysis. LIMITATIONS: Retrospective analysis. External validity of the index of chronic damage requires further assessment. Selection bias may influence repeated biopsy analyses. CONCLUSIONS: Serum creatinine level at biopsy best predicts kidney survival in patients with pauci-immune necrotizing glomerulonephritis overall.

Recurrences and infections during continuous immunosuppressive therapy after beginning dialysis in ANCA-associated vasculitis.

BACKGROUND: Approximately 20% of patients with antineutrophil cytoplasm antibody-associated systemic vasculitis (AASV) develop end-stage renal failure (ESRF). It is not clear whether continuation of immunosuppression, with its associated risks, is beneficial because relapse rates after the development of ESRF are reported to be low. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Single tertiary-care referral center. 46 patients with AASV who developed ESRF from 1971 to 2004. OUTCOMES & MEASUREMENTS: Treatment, relapse rates before and after dialysis therapy, patient outcome after dialysis therapy, and infection (defined as admission to hospital or intravenous antibiotics) were recorded. RESULTS: Patients with AASV on dialysis therapy had 1- and 5-year survival rates of 82% and 55%, equivalent to current 1- and 5-year survival rates of dialysis patients reported by the UK renal registry, respectively. Infection rates in patients with ESRF were high in those with AASV on dialysis therapy; 106 events in 35 patients (dialysis patients with AASV, 0.89 infections/patient-year; confidence interval [CI], 0.74 to 1.08). Eight of 9 patients who died of infection were receiving immunosuppressive therapy. No patient died of active disease. Relapse rates after dialysis commencement were less than those predialysis (6 relapses in 4 patients; 0.05 relapses/patient-year postdialysis; CI, 0.02 to 0.1 compared with 18 relapses in 11 patients; 0.13 relapses/patient-year predialysis; CI, 0.07 to 0.19). LIMITATIONS: This is a retrospective study spread over 3 decades with no control group. CONCLUSIONS: Patients with AASV and ESRF are less likely to experience relapse than before dialysis therapy. Patients with AASV on dialysis therapy have a high rate of infection. These results may not be applicable to patients with pulmonary involvement.

Mycophenolate mofetil in the treatment of resistant idiopathic nephrotic syndrome.

BACKGROUND: A small proportion of patients with initially steroid-sensitive nephrotic syndrome relapse frequently, despite treatment with cyclophosphamide and/or cyclosporin. We investigated the efficacy of mycophenolate mofetil (MMF) in this group. METHODS: Seven patients with nephrotic syndrome due to minimal change nephropathy (MCN) or classical focal segmental glomerulosclerosis (FSGS) who had suffered multiple relapses over many years despite treatment with several different agents were commenced on MMF 1 g twice daily, together with a reducing dose of corticosteroids. RESULTS: Six patients went into complete remission and the seventh into partial remission. At 1 year, five remained in complete remission. The median (range) serum albumin concentration rose from 19 g/l (16-42 g/l) pre-MMF to 42 g/l (25-45 g/l) after 12 months (P=0.023), and the median (range) dose of prednisolone fell from 40 mg/day (30-60 mg/day) to 7.5 mg/day (0-40 mg/day) at 12 months (P=0.0008). CONCLUSION: MMF appears to be of benefit in the treatment of multiply relapsing nephrotic syndrome caused by MCN or FSGS. Controlled trials are required to establish the role of MMF in these disorders.