Variability of cyclosporine exposure and its relevance to chronic allograft nephropathy: a case-control study.

BACKGROUND: Population data indicate that cyclosporine (CsA)-based immunosuppression has had relatively little effect on late renal allograft loss. For individual patients, however, the degree and variability of CsA exposure may be of prognostic importance. This case-control study has examined the contribution of these and other factors to the development of chronic allograft nephropathy (CAN) in patients receiving follow-up care in our unit. METHODS: The electronic record was interrogated to identify adult, CsA-treated renal transplant recipients with CAN (group A) and CsA-treated controls with stable graft function for a minimum of 4 years posttransplantation and serum creatinine less than 200 micromol/L (group B). Age at transplantation, gender, years posttransplantation, donor source and age, kidney preservation time, human leukocyte antigen match, occurrence of delayed graft function, immunosuppressive regimen, weight-adjusted maintenance CsA dose, and coefficient of variation (CvarC0 ) of dose-adjusted CsA trough blood levels (C0/dose) were recorded (CvarC0 =[SD (C0/dose)/mean (C0/dose)]x100). Statistical analysis included binary logistic regression analysis. RESULTS: Three transplant recipients were excluded because of known noncompliance with immunosuppressive medication, leaving a study population of 102 patients. Recipient age (AB, <0.01) and CsA dose (A>B, <0.02) were significantly different by univariate analysis. Only low recipient age ( P<0.001) and high CvarC0 ( P<0.02) were independent predictors of CAN in the regression model. CONCLUSION: Younger renal transplant recipients and those with highly variable CsA exposure are predisposed to developing CAN. Investigation of such patients may reveal correctable factors such as poor treatment compliance and lead to appropriate interventions.

Indo-Asian experience of renal transplantation in Yorkshire: results of a 10-year survey.

BACKGROUND: There is a significant Indo-Asian community in Yorkshire. The rate of end-stage renal failure is disproportionately high in this ethnic group. There have not been any large studies of this ethnic minority's access to and outcome after cadaveric renal transplantation. METHODS: Three local cohorts were studied: 846 adult patients (9.1% Asian) who started renal replacement therapy 1990-1994, 822 adult patients (11.4% Asian) registered on the transplant waiting list 1985-1994; and 608 adult patients (8.6% Asian) transplanted 1985-1994. RESULTS: At 1 year from the start of dialysis, 34% of Asian and 31% of non-Asian patients were registered onto the waiting list. After adjustment for age in a multifactorial model, Asian patients were less likely to be listed (relative risk, 0.68), although this did not reach statistical significance (P=0.06). There was a significant difference in graft rate between the groups: at 3 years 72% of non-Asians versus 55% of Asians had been transplanted from the waiting list (P<0.001). For those transplanted, HLA matching was superior for white patients: 34% versus 20% of pairings achieved a 000 mismatched or favorably matched graft (P<0.05). Transplant survival at 5 years was 71% in the non-Asian and 58% in the Asian patients (P=0.07). Asian cadaveric donation was identified in 2 of 608 transplants during a 10-year period. CONCLUSION: Asian patients gained access to the transplant waiting list at a similar rate to the non-Asian white majority. Because of difficulties with HLA matching, Asian patients were significantly disadvantaged in receiving a transplant once listed, and there was a trend towards reduced posttransplant survival. Cadaveric donation was uncommon from within the Asian community; the reasons for which are likely to be complex.

Patient-specific prompts in the cholesterol management of renal transplant outpatients: results and analysis of underperformance.

BACKGROUND: Renal transplant recipients have an increased risk of cardiovascular disease compared with age- and gender-matched controls. It is recommended that "high-risk" patients are treated with hydroxymethylglutaryl CoA reductase inhibitors to reduce cholesterol levels. METHOD: We evaluated the effect of a computer-based decision support algorithm in delivering patient-specific prompts to manage cholesterol in renal transplant outpatients. Data were analyzed retrospectively for a 2-year period with attention to changes in cholesterol levels, prescribing patterns of statins, and causes of underperformance. RESULTS: At baseline, 36.7% of patients achieved a total serum cholesterol level less than 5.0 mmol/L, compared with 67.2% at 2 years, with mean values of 5.6+/-0.1 mmol/L and 4.8+/-0.1 mmol/L (P<0.0001). At baseline, 24% of the patients were receiving statin therapy, increasing to 61% at 2 years. There were no significant changes in creatinine phosphokinase, trough cyclosporine levels, or total cyclosporine dose. Alkaline phosphatase levels increased (166.1+/-3.6-184.6+/-6.1 mmol/L, P=0.009), but remained within the normal clinical range; creatinine clearance increased (58.6+/-1.0-61.0+/-1.2 mL/min, P=0.05). For patients followed concurrently in two units without the algorithm, serum cholesterol measurements decreased from 5.57 mmol/L and 5.34 mmol/L to 5.31 mmol/L and 5.27 mmol/L, respectively (P=0.05), both higher than that achieved contemporaneously at St. James's. Underperformance depended less on medical noncompliance than with systematic features of the methodology and patient preference/collaboration with treatment. CONCLUSIONS: The introduction of the algorithm coincided with a significant reduction in cholesterol levels, an increase in the number of patients receiving appropriate therapy, and no serious adverse effects. Our results illustrate the positive effect of computer-generated prompts and decision support software.

Intravenous immunoglobulin-induced panel reactive antibody A reduction: not all preparations are created equal.

BACKGROUND: Use of intravenous (IV) immunoglobulin (Ig) to obtain panel reactive antibody (PRA) A reduction in sensitized patients has been widely reported. Because no IVIg preparation is formulated specifically for this purpose, the authors have sought to determine whether, through laboratory testing, they could guide the rational choice of product for clinical use. METHODS: Using a flow cytometric approach, the authors have quantitatively determined the capacity of 22 different IVIg preparations to cause PRA reduction. RESULTS: IVIg preparations showed considerable variability in their individual capacity to reduce serum PRA. Protein-A pretreatment of IVIg preparations was found to reduce their capacity to cause PRA reduction. CONCLUSION: Laboratory screening of IVIg preparations provides a rational basis for the selection of product for administration to patients in whom the aim is to produce a PRA reduction. Experiments involving protein-A treatment of IVIg preparations indicate that immunoglobulin G is the principal factor involved in the abrogation of serum reactivity.

The ratio of extracellular fluid to total body water and technique survival in peritoneal dialysis patients.

BACKGROUND: Patients receiving peritoneal dialysis experience a high technique failure rate and are often overhydrated. We examined whether an increased extracellular fluid volume (VECF) as a proportion of the total body water (VTBW) predicted technique survival (TS) in a prevalent patient cohort. METHODS: The VECF and VTBW were estimated by multiple-frequency bioelectric impedance in 59 prevalent peritoneal dialysis patients (median time on dialysis 14 months). Demographic, biochemical (albumin, C-reactive protein, and ferritin), and anthropometric data, forearm muscle strength, nutritional score by three-point Subjective Global Assessment, residual renal function, dialysate-to-plasma (D/P) creatinine ratio, total weekly Kt/V urea, total creatinine clearance, normalized protein equivalent of nitrogen appearance, and midarm muscle circumference were also assessed. Technique survival was determined at 3 years, and significant predictors of TS were sought. RESULTS: In patient groups defined by falling above or below the median value for each parameter, only residual renal function (p = 0.002), 24-hour ultrafiltrate volume (p = 0.02), and VECF/VTBW ratio (p = 0.05) were significant predictors of TS. Subjects with a higher than median VECF/VTBW ratio had a 3-year TS of 46%, compared to 78% in subjects with a lower than median value. In multivariate analysis, systolic blood pressure and VECF/VTBW ratio (both p < 0.05) were significant predictors of TS. C-reactive protein approached significance. CONCLUSION: Increased ratio of extracellular fluid volume to total body water is associated with decreased TS in peritoneal dialysis.

Acceptable outcome after kidney transplantation using "expanded criteria donor" grafts.

INTRODUCTION: With the worldwide shortage of donors, extra lengths are ongoing to enlarge the donor pool. One means has been a greater use of "expanded criteria donor" (ECD) grafts. A major concern regarding ECD kidneys is poor long-term graft survival. The aims of this study were to determine whether ECD grafts, as defined by the United Network for Organ Sharing, had a negative impact on graft survival and to identify the principle donor and recipient factors that influenced graft survival in our patient cohort. METHODS: We analyzed all deceased donor renal transplants in our unit from January 1995 to October 2005, in total 1,053 transplants. RESULTS: ECD grafts (United Network for Organ Sharing criteria) demonstrated higher rates of delayed graft function and higher early mean creatinine levels. However, there was no significant difference in 5-year graft survival. Multivariate analysis of our patient group identified donor hypertension and ischemic heart disease (IHD) as independent predictors of poor graft survival. Recipient age was significant on univariate but not on multivariate analysis. However, although younger recipients maintained acceptable 5-year graft survival despite donor hypertension, IHD, or a combination of both, these factors significantly reduced graft survival in older recipients. CONCLUSION: Although ECD grafts had slightly worse function, 5-year survival was comparable with standard grafts in all recipients. Donor hypertension, IHD, or a combination of both significantly reduced graft survival in older recipients, not evident in younger patients. We discuss the possible factors for improved outcome with ECD grafts in our patients and the implications of our patient analysis.

A randomized controlled trial of immunosuppression conversion for the treatment of chronic allograft nephropathy.

BACKGROUND: This study was conducted to assess the effect of immunosuppression conversion on progression of chronic allograft nephropathy (CAN). METHODS: Forty-two cyclosporin-treated renal transplant recipients were studied. Patients were included if they had a negatively sloping reciprocal of creatinine vs time (ROCT) plot for >6 months and biopsy-proven CAN. Patients were excluded if they had previously been treated with tacrolimus/mycophenolate mofetil (MMF) or their serum creatinine was >400 micromol/l. Subjects were randomly treated with either: (A) MMF/reduced dose cyclosporin [MMF for azathioprine 0.5-1.0 g bd; cyclosporin trough level (C(0)): 75-100 ng/ml]; (B) tacrolimus for cyclosporin (C(0): 5-10 ng/ml); or (C) continuation of standard therapy. Glomerular filtration rate (GFR) was measured at baseline and after 6 months. RESULTS: Two patients started dialysis within 6 months (one each from groups A and B). One patient in group A was intolerant of MMF, six others reported gastrointestinal symptoms and three developed anaemia. Cyclosporin dose was reduced by 24% [interquartile range (IQR): 14-27%] in group A [end-of-study C(0): 99 ng/ml (IQR: 90-113 ng/ml)]. In group B, the end-of-study tacrolimus C(0) was 7 ng/ml (5-9 ng/ml). The end-of-study cyclosporin C(0) in group C was 163 ng/ml (145-215 ng/ml). Comparison of ROCT slopes before and after intervention revealed a treatment advantage for group A (P<0.05). The GFR analysis was supportive (P = 0.05). When patients with GFR <20 ml/min/1.73 m(2) at enrollment were excluded from the analysis, the treatment advantage for group A reached statistical significance (n = 27, P<0.05). CONCLUSIONS: MMF/reduced dose cyclosporin is superior to tacrolimus-for-cyclosporin and standard dose cyclosporin in patients with CAN, at least in the short term. The cyclosporin dose reduction component is likely to be of particular importance. Other findings suggest that early intervention is beneficial.