The functional and structural changes of the glomerulus throughout the course of murine lupus nephritis.

The glomerular functional and structural changes in a murine model (MRL-lpr/lpr) of progressive lupus nephritis were studied. Animals were grouped into three age categories. (I, 14 wk; II, 20 wk; and III, 26 wk). GFR fell with age (257 +/- 43, 178 +/- 50, and 150 +/- 40 microL/min for Groups I through III, respectively). Similarly, the ultrafiltration coefficient (Kf) measured on isolated glomeruli fell with time (0.030 +/- 0.006, 0.023 +/- 0.006, and 0.013 +/- 0.002 nL/s/mm Hg, respectively). Both indomethacin and a selective thromboxane receptor antagonist L-670,596 significantly improved GFR in Group II animals to values seen in Group I animals. Neither agent had any effect to increase GFR in older group III animals. L-670,596 had no effect on Kf in Group II or III animals. Glomerular morphometric evaluation demonstrated a progressive rise in glomerular tuft volume, mesangial matrix expansion, proliferation in cells, and a reduction in open capillary loops and epithelial filtration slits with age. However, because of the increase in glomerular volume, calculated surface area remained well preserved over the three respective groups (61 +/- 18, 76 +/- 15, and 71 +/- 13 microns2 x 10(3)). Therefore, the fall in Kf is likely due to a fall in hydraulic permeability (Lp). The ultrastructural component of the glomerular capillary wall that correlated best with Lp was the epithelial filtration slit number per micrometer of glomerular basement length (r = 0.73; P < 0.0001), which suggests that the structural correlate Kf is in the filtration slit length (FSL). Despite the cell proliferation and mesangial matrix expansion in early disease (Group II), the overall FSL remains stable because of a slight increase in filtration surface area and a slight reduction in epithelial slits per micrometer of glomerular basement membrane. The fall in GFR appears to be hemodynamically mediated by thromboxane A2. In older Group III animals, the fall in GFR appears to be due to a 40% reduction in FSL rather than being hemodynamically based. Thus, the early improvement in function with pharmacological agents is deceptive because considerable disease may be present because of adaptive structural changes. Eventually, with disease progression, compensating hemodynamic and structural factors fail to maintain GFR within normal limits.     

Population pharmacokinetics of mycophenolic acid during the first week after renal transplantation

Objective To investigate the population pharmacokinetics of mycophenolic acid (MPA) in adult kidney transplant recipients during the crucial first week after transplantation.Methods Data were collected from 117 patients. MPA plasma concentrations were determined at t=0, 1, 2, 3 and 4 h after mycophenolate mofetil dosing on days 3, 5 and 7. Population analysis was performed using NONMEM. Covariates screened were sex, age, body weight, serum creatinine, creatinine clearance, serum albumin, days of therapy, diabetes mellitus, organ source (live or cadaveric) and co-therapy (tacrolimus or cyclosporine). Final model validity was evaluated using 200 bootstrapped samples from the original data. Bias and precision were determined through comparison of observed and predicted concentrations.Results Individual concentration–time profiles showed evidence of an absorption lag time and enterohepatic recirculation of MPA in some patients on some occasions. The best base model had bi-exponential elimination with a typical population (SE%) apparent clearance (CL/F) of 29 l/h (5%) and apparent volume of the central compartment of 65 l (7%). CL/F decreased significantly with increasing serum albumin (1.42 l/h reduction in total plasma CL/F with each 1 g/l increase in albumin) and was 27% greater in patients receiving cyclosporine than in those receiving tacrolimus. Evaluation of the final model showed close agreement between pairs of bootstrapped and final model parameter estimates (all differences <7%). Predictions were non-biased (0.11 mg/l) but imprecise (2.8 mg/l).Conclusion Population pharmacokinetic parameters for MPA were determined. These can be used to achieve specific target MPA concentrations or areas under the concentration–time curve.     

Item response theory and its applications to patient-reported outcomes measurement

This article provides an overview of item response theory (IRT) models and how they can be appropriately applied to patient-reported outcomes (PROs) measurement. Specifically, the following topics are discussed: (a) basics of IRT, (b) types of IRT models, (c) how IRT models have been applied to date, and (d) new directions in applying IRT to PRO measurements.     

The impact of waiting time and comorbid conditions on the survival benefit of kidney transplantation

BACKGROUND: Longer waiting times may limit the survival benefit of kidney transplantation in older patients or those with a high burden of comorbid disease. METHODS: We performed a longitudinal study of mortality among 63,783 transplant candidates who started dialysis between April 1995 and December 2000. We determined the relative risk (RR) of death and increase in life expectancy among subjects who received a first deceased donor transplant after different waiting times compared to subjects who had equivalent waiting times but remained on dialysis. RESULTS: Transplant recipients had a lower long-term RR of death and the risk reduction was greatest in recipients with longer waiting times (RR of death 12 months after transplantation for recipients with waiting times of 0, 1, 2, 3 years was 0.49, 0.43, 0.38, 0.34, P = 0.0006).The average increase in life expectancy in transplant recipients was 9.8 years and was lower in older recipients and recipients with comorbid conditions. Increased waiting times from 1 to 3 years only moderately decreased the overall survival benefit of transplantation from 7.1 to 5.6 years, and all subjects derived a survival benefit from transplantation with waiting times up to 3 years. CONCLUSION: These findings do not support limiting access to transplantation for otherwise suitable candidates on the basis of longer anticipated waiting times.     

Impact of mycophenolate mofetil loading on drug exposure in the early posttransplant period

Achieving adequate therapeutic levels of immunosuppressive medications is important in rejection prevention. This study examined exposure to mycophenolic acid (MPA) in kidney transplant patients within the first 5 days posttransplantation. METHODS: This single-center, nonrandomized study of first solitary kidney allograft recipients receiving cyclosporine (n = 116) or tacrolimus (n = 50) included patients who received either 1 g or 1.5 g of mycophenolate mofetil twice daily starting postoperatively. Exposure to MPA was measured at days 3 and 5 posttransplant using published limited sampling time equations. RESULTS: There were no significant differences in exposure in the cyclosporine-treated patients receiving 3-g (n = 22) compared to 2-g (n = 94) daily doses (AUC([0-12]) 33.8 +/- 10.0 mg*h/L versus 30.1 +/- 9.7 mg*h/L, P = .20, respectively). About half the patients in both groups had AUC([0-12]) <30 mg*h/L on days 3 and 5 posttransplant. On the other hand, there was significantly greater exposure on day 3 in the tacrolimus-treated patients receiving 3 g (n = 21) compared to 2 g (n = 29) daily (AUC([0-12]) 43.1 +/- 9.0 mg*h/L versus 36.8 +/- 11.1 mg*h/L, P = .016, respectively). On day 3 one (4.8%) patient receiving 3 g had an AUC([0-12]) of <30 mg*h/L; whereas, eight (27.5%) receiving 2 g were below this level (P = .068). The AUC([0-12]) levels were not different on day 5. CONCLUSIONS: Loading with higher doses of mycophenolate mofetil results in greater exposure and a trend toward more patients in the therapeutic window within the first week for tacrolimus- but not for cyclosporine-treated patients.     

Scaling up integrated management of childhood illness to the national level: achievements and challenges in Peru

This paper presents the first published report of a national-level effort to implement the Integrated Management of Childhood Illness (IMCI) strategy at scale. IMCI was introduced in Peru in late 1996, the early implementation phase started in 1997, with the expansion phase starting in 1998. Here we report on a retrospective evaluation designed to describe and analyze the process of taking IMCI to scale in Peru, conducted as one of five studies within the Multi-Country Evaluation of IMCI Effectiveness, Cost and Impact (MCE) coordinated by the World Health Organization. Trained surveyors visited each of Peru's 34 districts, interviewed district health staff and reviewed district records. Findings show that IMCI was not institutionalized in Peru: it was implemented parallel to existing programmes to address acute respiratory infections and diarrhoea, sharing budget lines and management staff. The number of health workers trained in IMCI case management increased until 1999 and then decreased in 2000 and 2001, with overall coverage levels among doctors and nurses calculated to be 10.3%. Efforts to implement the community component of IMCI began with the training of community health workers in 2000, but expected synergies between health facility and community interventions were not realized because districts where clinical training was most intense were not those where community IMCI training was strongest. We summarize the constraints to scaling up IMCI, and examine both the methodological and policy implications of the findings. Few monitoring data were available to document IMCI implementation in Peru, limiting the potential of retrospective evaluations to contribute to programme improvement. Even basic indicators recommended for national monitoring could not be calculated at either district or national levels. The findings document weaknesses in the policy and programme supports for IMCI that would cripple any intervention delivered through the health service delivery system. The Ministry of Health in Peru is now working to address these weaknesses; other countries working to achieve high and equitable coverage with essential child survival interventions can learn from their experience.     

Improving facility-based care for sick children in Uganda: training is not enough

This study assessed the effects of scaling-up Integrated Management of Childhood Illness (IMCI) on the quality of care received by sick children in 10 districts in Uganda. Health workers trained in IMCI were found to deliver significantly better care than health workers who had not yet been trained, but absolute levels of service quality remained low. Achieving training coverage alone is not sufficient as a strategy to improve and sustain care quality. Other factors including training quality, effective supervision, availability of essential drugs, vaccines and equipment, and the policy context are also important and must be included in child survival policies and plans.     

Circumferential negative-pressure dressing (VAC) to bolster skin grafts in the reconstruction of the penile shaft and scrotum

This paper presents 4 consecutive cases using negative-pressure dressings (VAC) to bolster skin grafts in male genital reconstruction. In this series reconstruction followed 1 case of tumor ablation and 3 cases of debridement of abscesses or Fornier's gangrene. The VAC was applied circumferentially to the penis to secure skin grafts either directly to the penile shaft or to facilitate skin grafting to the scrotum. Graft areas ranged from 75 to 250 cm. All cases resulted in successful genital wound coverage; minor complications are described. Three practical points are brought forth. First, the VAC facilitates skin grafting to the complex contour of male genitalia. Second, the VAC can be applied circumferentially to the penis without the need for perfusion monitoring or fears of avascular necrosis. Third, with the use of the VAC, bolster use can likely be discontinued as early as 72 hours with good graft adherence and survival.