Mycophenolate mofetil and tacrolimus versus tacrolimus alone for the treatment of idiopathic membranous glomerulonephritis: a randomised controlled trial.

BACKGROUND: Tacrolimus (TAC) is effective in treating membranous nephropathy (MN); however relapses are frequent after treatment cessation. We conducted a randomised controlled trial to examine whether the addition of mycophenolate mofetil (MMF) to TAC would reduce relapse rate. METHODS: Forty patients with biopsy proven idiopathic MN and nephrotic syndrome were randomly assigned to receive either TAC monotherapy (n = 20) or TAC combined with MMF (n = 20) for 12 months. When patients had been in remission for 1 year on treatment the MMF was stopped and the TAC gradually withdrawn in both groups over 6 months. Patients also received supportive treatment with angiotensin blockade, statins, diuretics and anticoagulation as needed. Primary endpoint was relapse rate following treatment withdrawal. Secondary outcomes were remission rate, time to remission and change in renal function. RESULTS: 16/20 (80%) of patients in the TAC group achieved remission compared to 19/20 (95%) in the TAC/MMF group (p = 0.34). The median time to remission in the TAC group was 54 weeks compared to 40 weeks in the TAC/MMF group (p = 0.46). There was no difference in the relapse rate between the groups: 8/16 (50%) patients in the TAC group relapsed compared to 8/19 (42%) in the TAC/MMF group (p = 0.7). The addition of MMF to TAC did not adversely affect the safety of the treatment. CONCLUSIONS: Addition of MMF to TAC does not alter the relapse rate of nephrotic syndrome in patients with MN. TRIAL REGISTRATION: This trial is registered with EudraCTN2008-001009-41 . Trial registration date 2008-10-08.

Peritubular Capillary Basement Membrane Multilayering in Renal Allograft Biopsies of Patients With De Novo Donor-Specific Antibodies.

BACKGROUND: Severe peritubular capillary basement membrane multilayering (PTCBML) is part of the Banff definition of chronic antibody-mediated rejection. We retrospectively investigated whether assessment of the mean number of layers of basement membrane (BM) around peritubular capillaries (PTC) can be used in a cohort of patients with de novo donor-specific antibodies (dnDSA) as an early marker to predict long-term antibody-mediated injury. METHODS: This is a retrospective cohort study with 151 electron microscopy samples from 54 patients with dnDSA, assessed at around 1 year after transplantation, for a mean number of BM layers around PTC and in serial biopsies. Graft survival and time to transplant glomerulopathy (TG) development were estimated in survival analyses. RESULTS: We found that a mean PTCBML count greater than 2.5 layers assessed in a sample of 25 PTCs around 1 year after transplantation is indicative of the development of TG in patients with dnDSA (P = 0.001). In addition, in patients with serial biopsies available for electron microscopy analysis, we could distinguish 2 groups: patients with a mean PTCBML count of 2.5 or less on all biopsies, and patients who developed greater than 2.5 layers at any time after transplantation. The latter group reflected dnDSA patients at risk for TG development (P < 0.001). In patients with dnDSA, PTCBML score added significantly to the sensitivity and specificity of prediction of TG compared with microcirculation injury score alone. CONCLUSIONS: Our results highlight the potential value of assessing the mean number of BM in PTC for early prediction of progression to chronic antibody-mediated injury.

Antibody removal before ABO-incompatible renal transplantation: how much plasma exchange is therapeutic?

BACKGROUND: ABOi transplantation is an accepted method of expanding the kidney donor pool but there is little analysis of the protocols used. We established an ABOi programme utilising leukocyte depletion, tacrolimus, TPE and IvIg. There are few reports in the literature on the success rates of antibody removal protocols or relating to patients in whom antibody removal fails. The purpose of this study was to define the likelihood of achieving transplantation depending on ABO antibody titers. METHODS: 56 patients entered our ABOi program. Data were analysed to determine the likelihood of achieving transplantation, ABO antibody titre prior to antibody removal and amount of TPE required to achieve transplantation. The median antibody titer was 1:64 (Range 0-1:1024). Transplantation proceeded when the ABO titer reached ≤1:4. RESULTS: 51/56 (91%) patients achieved transplantation after 8.3±5 TPE. Five patients with high ABO titers were not transplanted despite extensive TPE. The number of TPE required to reach an ABO titer of ≤1:4 correlates best with pre-treatment IgG titers. CONCLUSIONS: This is the first study to demonstrate a cut off titer for entry in to the ABO incompatible program using the relationship between ABO titer and amount of TPE required to reach transplantation. We now tailor the antibody removal protocol prior to transplantation and have introduced a cut-off entry titer to the program (≤1:256), because of the unacceptable risk of exposing patients with higher titers to long-lasting immunosuppression and costly, prolonged, courses of TPE without the guarantee of successful transplantation. Patients whose ABO titer exceeds the cut-off are counselled and offered alternative routes to transplantation.

Antibody-mediated rejection after alemtuzumab induction: incidence, risk factors, and predictors of poor outcome.

BACKGROUND: Antibody-mediated rejection (AMR) is associated with allograft loss. Identification of factors associated with poor outcome has not been extensively studied. METHODS: We retrospectively studied 469 patients who received a negative crossmatch renal transplant with alemtuzumab induction. Forty-eight of 469 (10.2%) patients were treated for AMR. Thirty of 48 (62.5%) of the cases fulfilled the Banff criteria for definite AMR, whereas 18 of 48 (37.5%) were categorized as suspicious for AMR (tissue injury with C4d staining or donor-specific antibodies [DSAbs]). Sensitization, high human leukocyte antigen, and -DR mismatch were risk factors for the development of AMR (P = 0.0016, 0.001, and 0.012, respectively). RESULTS: Allograft survival was inferior in the AMR group (70.2%) compared with the nonrejector group (97.0%) (P<0.001). Forty-two of 48 (87.5%) of patients with acute AMR had DSAbs. Patients with CII DSAbs at the time of AMR, whether alone or in combination with CI DSAbs had the worst allograft survival (P = 0.014). Both the mean cumulative and immunodominant mean fluorescence index were higher in those patients who subsequently lost their grafts (P<0.001). Patients with diffuse C4d staining had inferior allograft survival than those with focal C4d or no staining (P = 0.02). There was no significant difference in survival by histological grade but a trend to inferior outcomes in those with vascular involvement (P = 0.06). Those patients who met the full Banff criteria had worse survival than those with suspicion for AMR only (P = 0.04). CONCLUSION: This study identifies patients at risk of graft failure from AMR. These patients may benefit from newer therapeutic strategies including the use of eculizumab or bortezomib.

Switching from subcutaneous to intravenous erythropoietin alpha in haemodialysis patients requires a major dose increase.

BACKGROUND: A change in the licensing arrangements for the use of erythropoietin alpha in haemodialysis patients has required a switch in the route of administration from subcutaneous (SC) to intravenous (IV). Previous work suggested that the IV route was less efficacious but studies since the enforced switch have not confirmed this. METHODS: We studied haemoglobin levels and the mean weekly dose of erythropoietin alpha in 86 haemodialysis patients at monthly intervals over the 6 month period before and after a change in the route of administration of erythropoietin alpha from SC to IV. Changes in other parameters known to be associated with erythropoietin response were also monitored. RESULTS: Mean haemoglobin level fell following the switch from 11.9 g/dl+/-1.4 at baseline to 11.3 g/dl+/-1.4 at 1 month (P = 0.001) and to a trough of 11.0 g/dl+/-1.3 at 2 months (P<0.001) before partial recovery to 11.4 g/dl+/-1.2 (P = 0.007) at 6 months. Mean weekly dose of erythropoietin after 2 months was significantly higher than baseline (8791 IU+/-5314 vs 8035 IU+/-4893). The dose continued to increase and by 6 months was 10605 IU (P<0.001), 32% higher than baseline. There was a small reduction in residual renal function, which was an independent predictor of change in dose requirement. There was a small increase in parathyroid hormone levels, but no change in serum ferritin, dosing frequency, total Kt/V, serum albumin, normalised protein catabolic rate, C-reactive protein, hospitalization rate and dialyser reuse rate. CONCLUSIONS: Switching from SC to IV erythropoietin alpha caused a significant fall in haemoglobin levels in the first 2 months. This was partially reversed by 6 months at the expense of a 32% dose increase in the dose of erythropoietin alpha by 6 months. The economic impact may be considerable.