Pneumocystis jirovecii pneumonia presenting with severe, refractory hypercalcaemia in an immunosuppressed renal transplant patient: Review of the literature and novel biochemical insights.

Pneumocystis jirovecii pneumonia (PJP) is a rare but serious complication of immunosuppression post-solid organ transplantation. We present a case of refractory, severe hypercalcaemia due to PJP in a renal transplant recipient. Treatment of PJP led to normalisation of the patient's calcium levels, and clinical improvement. To further explore the proposed calcitriol-driven mechanism leading to hypercalcaemia in PJP, we performed biochemical analysis on pre- and post-treatment serum and bronchoalveolar lavage sample at the time of PJP diagnosis. We confirmed high circulating and pulmonary levels of calcitriol in acute, untreated PJP with severe hypercalcaemia. PJP treatment led to reduction of circulating calcitriol to within normal range. We present this case, together with a literature review of similar reported cases, and the novel biochemical evidence supporting extra-renal production of calcitriol by activated pulmonary macrophages as the mechanism underpinning hypercalcaemia in PJP.

Conventional and Novel Approaches to Immunosuppression in Lung Transplantation.

Most therapeutic advances in immunosuppression have occurred over the past few decades. Although modern strategies have been effective in reducing acute cellular rejection, excess immunosuppression comes at the price of toxicity, opportunistic infection, and malignancy. As our understanding of the immune system and allograft rejection becomes more nuanced, there is an opportunity to evolve immunosuppression protocols to optimize longer term outcomes while mitigating the deleterious effects of traditional protocols.

Human T-follicular helper and T-follicular regulatory cell maintenance is independent of germinal centers.

The monoclonal anti-CD20 antibody rituximab (RTX) depletes B cells in the treatment of lymphoma and autoimmune disease, and contributes to alloantibody reduction in transplantation across immunologic barriers. The effects of RTX on T cells are less well described. T-follicular helper (Tfh) cells provide growth and differentiation signals to germinal center (GC) B cells to support antibody production, and suppressive T-follicular regulatory (Tfr) cells regulate this response. In mice, both Tfh and Tfr are absolutely dependent on B cells for their formation and on the GC for their maintenance. In this study, we demonstrate that RTX treatment results in a lack of GC B cells in human lymph nodes without affecting the Tfh or Tfr cell populations. These data demonstrate that human Tfh and Tfr do not require an ongoing GC response for their maintenance. The persistence of Tfh and Tfr following RTX treatment may permit rapid reconstitution of the pathological GC response once the B-cell pool begins to recover. Strategies for maintaining remission after RTX therapy will need to take this persistence of Tfh into account.

"Benign" hypergammaglobulinemic purpura is not benign in pregnancy.

A woman presented at 25 weeks gestation in her first pregnancy with severe preeclampsia and an intrauterine death. It later emerged that she had Waldenstrom's benign hypergammaglobulinemic purpura. We discuss the implications of this diagnosis in pregnancy and explore possible management options during subsequent pregnancies.

Anti-CTLA-4 (CD 152) monoclonal antibody-induced autoimmune interstitial nephritis.

Targeted immune-modulating agents are entering clinical practice in many specialties, providing novel therapeutic possibilities but introducing new potential toxicities. We present the first reported case, to our knowledge, of immune-mediated nephritis following the administration of Tremelimumab (CP-675, 206), an anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody. High-dose steroid therapy led to a rapid improvement in renal function, avoiding the need for renal replacement therapy.

Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake.

Copy number (CN) variation (CNV) has been shown to be common in regions of the genome coding for immune-related genes, and thus impacts upon polygenic autoimmunity. Low CN of FCGR3B has recently been associated with systemic lupus erythematosus (SLE). FcgammaRIIIb is a glycosylphosphatidylinositol-linked, low affinity receptor for IgG found predominantly on human neutrophils. We present novel data demonstrating that both in a family with FcgammaRIIIb-deficiency and in the normal population, FCGR3B CNV correlates with protein expression, with neutrophil uptake of and adherence to immune complexes, and with soluble serum FcgammaRIIIb. Reduced FcgammaRIIIb expression is thus likely to contribute to the impaired clearance of immune complexes, which is a feature of SLE, explaining the association between low FCGR3B CNV and SLE that we have confirmed in a Caucasian population. In contrast, antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV), a disease not associated with immune complex deposition, is associated with high FCGR3B CN. Thus, we define a role for FCGR3B CNV in immune complex clearance, a function that may explain why low FCGR3B CNV is associated with SLE, but not AASV. This is the first report of an association between disease-related gene CNV and variation in protein expression and function that may contribute to autoimmune disease susceptibility.

The quality of information about kidney transplantation on the World Wide Web.

BACKGROUND: Websites on the Internet are used increasingly by patients and those caring for them as a source of medical information. This study investigated the nature and quality of the kidney transplant-related information currently available on the World Wide Web (WWW). METHODS: Four common search engines were used to explore the Internet using the keywords "kidney transplantation." Each website was assessed on the following categories: source, language, accessibility, presence of kitemarks, and quality/depth of information. Websites were scored independently by four transplant clinicians (two surgeons and two physicians), and a weighted Information Score (IS) was created to assess the overall clinical and educational value of the site. RESULTS: A total of 200 potential websites were identified of which 94 websites were suitable for scoring. The remaining 106 were repetitions or non-accessible links. The overall median weighted IS for the sites assessed was 21 (IQR 0-61). Median weighted IS of sites originating from Europe and USA were 47 (IQR = 21-61) and 45 (IQR = 15-61) respectively (p = 0.27). Websites belonging to academic institutions scored higher with a median weighted IS of 49 (IQR = 20-61) when compared with kitemarked websites (median 21, IQR = 5-45, p = 0.01). However, there was no statistically significant difference in weighted IS of kitemarked, professional (median 22, IQR = 2-53), commercial (median 20, IQR = 0-45), and individual websites (median 9, IQR 3-12). There was a good agreement between the observers who scored the websites with an intraclass correlation coefficient (ICC) of 0.79 and an associated 95% CI (0.73-0.90) for the four observers on the 94 websites. CONCLUSION: The educational material currently available on the WWW about kidney transplantation is often of poor quality and more input is required from transplant clinicians. Quality seals in the form of kitemarks may give a false sense of security. The gaps in validity and accuracy of the information available on complex topics such as kidney transplantation should be filled; otherwise poor quality information will continue to be the norm rather than the exception.