Previous studies suggested that membranoproliferative glomerulonephritis (MPGN) type II has a worse renal survival and an unacceptable risk of recurrence post transplantation. We hypothesised that other factors may determine this risk. We analysed all cases (n=70) of MPGN diagnosed by renal biopsy in Ireland from 1972 to 1995. We used Cox regression analysis to determine factors that were independently predictive of renal failure. MPGN II had more crescent formation and mesangial proliferation (P<0.05). Mean follow-up duration was 13.8 years, during which time 41 (58.6%) developed end-stage renal failure (ESRF). The median time to ESRF was 8.3 years (95% confidence interval 5.7-10.9) and 5-, 10-, and 20-year probabilities of ESRF were 32, 54, and 70%, respectively. Multivariate analysis revealed that severity of interstitial fibrosis (P<0.05), crescent formation (P<0. 01) and mesangial proliferation (P<0.05) were independently associated with ESRF. Decade of diagnosis, age, MPGN type, and creatinine or complement level at baseline did not predict renal survival in this model. In 21 (49%) of the 43 renal transplants, MPGN recurred. Younger age at initial diagnosis (P<0.01) and the presence of crescents on the original biopsy (P<0.005) were independently associated with recurrence on multivariate analysis. MPGN type was not associated with recurrence in this model. Contrary to previous reports, after controlling for crescent formation, MPGN II was not associated with more ESRF or recurrence in the allograft. It is therefore the more aggressive glomerular changes associated with MPGN II, rather than the disease type per se, that determine outcome.

In patients with late UTIs, renal scarring is a frequent finding. Scarring may occur even in asymptomatic patients without VUR. The lack of an effect on graft survival may reflect successful intervention with prophylactic antibiotics and surveillance urine cultures. Late recurrent UTIs may be damaging to renal allografts, even in the absence of reflux.

Fas ligand (FasL) expression induces apoptosis of activated T cells and has been suggested as a strategy to inhibit graft rejection. Unfortunately, the use of FasL to confer 'immune privilege' in this setting has been hampered by the finding that it may also provoke a destructive granulocytic response. While the Fas/FasL-mediated apoptotic pathways are well defined, the pro-inflammatory effects of FasL are poorly understood. Our aim in this study was to define in vitro the biological effects of FasL on neutrophil recruitment and activation. DAP-3 cells expressing human FasL on the cell membrane (mFasL) potently induced apoptosis in human neutrophils and in activated T lymphocytes. Recombinant human soluble FasL (sFasL), by contrast, was a very weak inducer of apoptosis, even at high concentrations. This latter observation suggests that cleavage of mFasL by naturally occurring matrix metalloproteinases may serve to down-regulate FasL activity in vivo. However, in the presence of a cross-linking antibody, the efficiency of apoptosis-induction by sFasL was greatly increased, suggesting that the lesser pro-apoptotic potency of sFasL reflects an inability to induce trimerization of the Fas receptor. With regard to pro-inflammatory effects, we found that sFasL is a potent neutrophil chemoattractant and, given that it induces little apoptosis, the dominance of sFasL over mFasL may mean that graft-infiltrating neutrophils will survive to mediate inflammation. Neither sFasL nor mFasL produced neutrophil activation as assessed by chemiluminescence assay. This suggests that neutrophils recruited to an inflammatory site by FasL will be activated by mechanisms other than Fas-FasL signalling.

Sensitized patients with lymphocytotoxic immunoglobulin (Ig)G anti-human leukocyte antigen (HLA) antibodies have an increased risk of rejection and poorer graft survival. Little is known, however, about the correlation between IgG antibody subclass and clinical outcomes. We identified 20 sensitized renal transplant recipients (panel reactive antibody >15%), all of whom had anti-HLA class I antibodies of an IgG isotype with known specificity before transplantation but who received a crossmatch negative graft. We analyzed the degree of skewing solely toward IgG1 (n=11) or to other IgG subclasses with or without IgG1 (n=9) and correlated these findings with graft survival. At last follow-up (median follow-up 28 months), 6 of 11 patients (55%) with anti-HLA antibodies skewed toward IgG1 had lost their grafts compared with 0 of 9 patients (0%) with anti-HLA antibodies not skewed toward IgG1 (P =0.01 log-rank test). Anti-HLA antibodies of an IgG1 subclass may be a novel marker predicting poor graft outcome.

Cholesterol embolism is a common but underrecognised complication arising from a variety of vascular insults

Membership of some ethnic groups has an effect on renal transplant outcome but little is known about the impact of Indo-Asian ethnicity, despite this group's high incidence of renal disease. We compared outcomes in Indo-Asians and Caucasians at the Hammersmith Hospital (Indo-Asians, N = 46; Caucasians, N = 90), in the Long-Term Efficacy and Safety Surveillance (LOTESS) database of cyclosporin-treated renal transplant recipients (Indo-Asians, N = 254; Caucasians, N = 4262) and the National Transplant Database held by UK Transplant (Indo-Asians, N = 459; Caucasians, N = 4831). The baseline demographic and co-morbid characteristics of the two ethnic groups were comparable, save for more diabetes in the Indo-Asian community. Following transplantation, the incidence of delayed graft function and steroid-resistant acute rejection were also comparable, as were graft and patient survival (out to 5 years) and graft function. In addition, post-transplant blood pressure, levels of cholesterol and triglycerides and exposure to corticosteroids and cyclosporin were comparable. However, when patients who were not diabetic before transplantation were studied separately, there was an increased incidence of diabetes in the Indo-Asian community (Hammersmith data: Indo-Asians 10.9% vs. Caucasians 3.3%, p = 0.02; LOTESS data Indo-Asians 5.5% vs. Caucasians 1.6%, p < 0.0001). Subsequent management of this group should pursue immunosuppressive regimens less likely to impair post-transplant glucose tolerance.

With the advent of more potent immunosuppressive regimens, the incidence of acute rejection following renal transplantation has declined sharply in recent years. In spite of this, long-term graft outcomes remain suboptimal because of relentless attrition by cumulated insults to the allograft. As acute rejection rates have declined, other causes of graft injury and loss have recently emerged. Among these, infectious diseases remain a persistent threat and can be associated with allograft dysfunction. This group includes nephropathy due to polyoma (BK) virus infection, cytomegalovirus disease, and bacterial infection (the latter most commonly arising from the urinary tract). Rarer infectious causes of chronic allograft dysfunction include cryoglobulinemia associated with hepatitis C, Epstein-Barr virus-associated posttransplant lymphoproliferative disease, and direct cytotoxicity from adenoviral infection or parvovirus B19.

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