Antibody-incompatible kidney transplantation in 2015 and beyond.

Rejection caused by donor-specific antibodies (principally ABO and HLA antibodies) has become one of the major barriers to successful long-term transplantation. This review focuses on clinical outcomes in antibody-incompatible transplantation, the current state of the science underpinning clinical observations, and how these may be translated into further novel therapies. The clinical outcomes for allografts facing donor-specific antibodies are at present determined largely by the use of agents developed in the 20th century for the treatment of T-lymphocyte-mediated cellular rejection, such as interleukin-2 agents and anti-thymocyte globulin. These treatments are partially effective, because acute antibody-mediated rejection is mediated to a considerable extent by T lymphocytes. However these treatments are essentially ineffective in chronic antibody-mediated rejection. Future therapies for the prevention and treatment of antibody-mediated rejection are likely to fall into the categories of those that reduce antibody production, extracorporeal antibody removal and disruption of the effector arms of antibody-mediated tissue damage.

Cryofiltration in the treatment of cryoglobulinemia and HLA antibody-incompatible transplantation.

Cryofiltration is a technique in which plasma is separated from blood and chilled, leading to the formation of "cryogel", a composite of heparin, fibronectin, fibrinogen, immunoglobulins, and other proteins. This is retained by further filtration and plasma is returned to the patient. There may be a role for cryofiltration in the treatment of cryoglobulinemia or where the application of other forms of plasmapheresis or immunoadsorption is limited. Five patients received six courses of cryofiltration. Two patients had cryoglobulinemia and three were treated before HLA antibody-incompatible renal transplantation. The treatment was associated with few adverse effects, and it was possible to treat up to 120 mL/kg plasma per session. There was a good clinical response in four patients. One patient was switched back to double filtration plasmapheresis (DFPP) because cryofiltration seemed to remove HLA antibodies less effectively, but the other two transplants have excellent function. In the cryoglobulinemia patients there was excellent clearance of cryoglobulins during each treatment (mean decrease of 78.2 (SD 14.1)% per treatment). Compared with DFPP, fewer immunoglobulins were removed and the mean percentage reductions in immunoglobulin G per treatment were 36.0 (4.0)% for cryoglobulinemia and 59.2 (2.5)% for DFPP (P < 0.01), with respective mean plasma volumes of 64.2 (10.3) and 71.1 (6.8) mL/kg treated. Cryofiltration offers a treatment choice in patients with cryoglobulinemia and in those who may not be able to tolerate high-volume DFPP. The technique used in the patients described here was less effective than DFPP; however, use of an alternative fractionator and treatment of higher plasma volumes may enhance the efficiency of cryofiltration.

Cyclosporine dose reduction in stable renal transplant patients with high C2 level: simplified method of single C2 measurement and individualization of C0 target.

It is recommended that cyclosporine dosing should be based on the whole blood level 2 h after a dose (C2), not the trough level (C0). Initial studies did not however establish the outcome of dosing according to C2 levels in long-term patients previously managed by C0 levels. C0 and C2 were measured in 152 stable patients receiving Neoral therapy, mean 86.9 months after transplantation. This showed that 38 (25%) had C2 levels above a target range of 700-900 microg/l. Higher C2 levels were associated with higher cholesterol levels (P = 0.0058) and higher diastolic blood pressure (P = 0.0163). Cyclosporine dose reduction was undertaken in 32 patients with high C2 levels. For logistical reasons, C2 was not performed regularly, but an individualized C0 level was set for each patient. A 16% reduction in mean cyclosporine dose was achieved, associated with a 28% fall in mean C0, from 212 to 153 microg/l, and a 25% fall in mean C2, from 1075 to 820 microg/l. There was no excess in adverse events in the dose reduction cohort, compared with patients with initial C2 levels <900 microg/l. Over a mean 15 month follow-up period in the dose reduction cohort, there was a 4.4% reduction in mean diastolic blood pressure, from 84.9 (SEM 2.1) to 80.2 (1.9) mmHg, P = 0.023; and a 10.4% reduction in mean cholesterol, from 5.71 (0.27) to 5.11 (0.25), P = 0.005 (patients starting on statin during follow-up excluded). In patients with initial C2 <900 microg/l, blood pressure did not fall and the cholesterol fell by 3.9%, from 5.27 (0.14) to 5.07 (0.15) mmol/l (P = 0.0405). In conclusion, cyclosporine dose reduction was safe in stable long-term renal allograft recipients with high C2 levels. There was an improvement cholesterol levels and a small improvement in blood pressure after cyclosporine dose reduction.

Quality of life in peritoneal dialysis patients: decline over time and association with clinical outcomes.

BACKGROUND: Quality of life (QoL) is increasingly well recognized as an important measure of treatment outcome. The aim of this study was to determine which key factors affect QoL, which aspects of QoL change over time, and if measurements of QoL were associated with clinical outcome in our peritoneal dialysis (PD) population. METHODS: The results of 88 patients (70% of our PD population) enrolled in longitudinal studies of dialysis adequacy, nutrition, and quality of life were reviewed. The sample comprised Indo-Asian [N=35 (diabetic N=18)], and white Europeans [N=53 (diabetic N=18)] heritage. At enrollment (>3 months on PD) demographic data was recorded. At enrollment, and six-month intervals, the dialysis adequacy, nutritional status, QoL (using the KDQOL-SF instrument), hospital admissions, PD infections, and changes in treatment modality were recorded. RESULTS: Male gender, Asian ethnicity, and poor nutritional status as measured by Subjective Global Assessment were the most significant characteristics independently associated with worse overall QoL dimension scores (physical health, mental health, kidney disease issues, patient satisfaction). Comorbidity, months of renal replacement, social deprivation and serum albumin were related to some of the 19 health domains measured. QoL declined steadily during the two-year study period. The most significant changes were for the items general health symptoms/problems, burden of kidney disease, emotional well-being, and patient satisfaction. Increased hospital admissions were associated with a worse QoL. CONCLUSIONS: Quality of life declines in patients on PD over time. Certain aspects of QoL are especially poor in Asian and male patients. This study suggests that further research is necessary to determine the effects of interventions directed at enhancing emotional and social support.