Successful treatment of severe ABO antibody-mediated rejection using bortezomib: a case report.

BACKGROUND: Our program for ABO-incompatible renal transplantation includes antigen-specific immunoadsorption (extracorporeal columns with the A or B trisaccharides), rituximab, and standard maintenance immunosuppression. Anti-A or -B titers ≤ 8 in the indirect antiglobulin test (IAT) against panel A1 or B RBC are acceptable for transplantation. CASE REPORT: A previously healthy, 15-month-old girl was diagnosed with Wilms' tumor and proteinuria. Denys-Drash syndrome was confirmed. Bilateral nephrectomy was performed. At 3.5 years of age she received an ABO-incompatible renal transplant from her father (A1 to O). The anti-A titers before transplantation were low. She was treated preoperatively with rituximab, immunoadsorption, immunoglobulin and mycophenolate mofetil (MMF). The maintenance immunosuppression protocol included basiliximab, tacrolimus, MMF, and prednisolone. The initial postoperative course was uncomplicated with rapid normalization of serum creatinine. The anti-A titers started to increase on postoperative day 5 (8 NaCl/16 IAT). Despite daily immunoadsorptions the titers rose to 1024 NaCl/1024 IAT on day 9. Renal function deteriorated and hemodialysis was started. A renal biopsy on day 9 showed acute severe antibody-mediated rejection. Additional treatment with bortezomib was given and after 2 doses the titers started to decline, renal allograft function improved and hemodialysis was stopped. On day 21 posttransplant the titers went down, creatinine was 28 µmol/L, and no more immunoadsorptions were performed. CONCLUSION: By using bortezomib, we were able to successfully reverse a severe ABO antibody-mediated rejection.

Long-term clinical effects of a peritoneal dialysis fluid with less glucose degradation products.

BACKGROUND: Glucose degradation products (GDPs) are cytotoxic in vitro and potentially toxic in vivo during peritoneal dialysis (PD). We are presenting the results of a two-year randomized clinical trial of a new PD fluid, produced in a two-compartment bag and designed to minimize heat-induced glucose degradation while producing a near neutral pH. The effects of the new fluid over two years of treatment on membrane transport characteristics, ultrafiltration (UF) capacity, and effluent markers of peritoneal membrane integrity were investigated and compared with those obtained during treatment with a standard solution. DESIGN: A two-group parallel design with 80 continuous ambulatory peritoneal dialysis patients was used. The patients were randomly assigned to either the new fluid (N = 40) or to a conventional one (N = 40), and were stratified with respect to age, diabetes, and time on PD. Peritoneal transport characteristics were assessed by the Personal Dialysis Capacity (PDCtrade mark) test at 1, 6, 12, 18, and 24 months after inclusion and by weighing the overnight bag daily. Infusion pain and handling were evaluated using a questionnaire. Peritoneal mesothelial and interstitial integrity were evaluated by analyzing overnight effluent dialysate concentrations of CA 125, hyaluronan (HA), procollagen-1-C-terminal peptide (PICP), and procollagen-3-N-terminal peptide (PIIINP) at 1, 6, 12, 18, and 24 months. RESULTS: The handling of the new two-compartment bag was considered easy, and there were no indications of increased discomfort with the new system. Furthermore, no changes in peritoneal fluid or solute transport characteristics were observed during the study period for either fluid, and neither were there any differences with regard to peritonitis incidence. However, significantly higher dialysate CA 125 (73 +/- 41 vs. 25 +/- 18 U/mL), PICP (387 +/- 163 vs. 244 +/- 81 ng/mL), and PIIINP (50 +/- 24 vs. 29 +/- 13 ng/mL) and significantly lower concentrations of HA (395 +/- 185 vs. 530 +/- 298 ng/mL) were observed in the overnight effluent during treatment with the new fluid. CONCLUSIONS: We conclude that the new fluid with a higher pH and less GDPs is safe and easy to use and has no negative effects on either the frequency of peritonitis or peritoneal transport characteristics as compared with conventional ones. Our results indicate that the new solution causes less mesothelial and interstitial damage than conventional ones; that is, it may be considered more biocompatible than a number of conventional PD solutions currently in use.

Plasmapheresis as a rescue therapy to resolve cardiac rejection with vasculitis and severe heart failure. A report of five cases.

The predominant causes of late graft loss and death after cardiac transplantation are graft rejection and infection. The histopathological classification of acute rejection is based on cellular phenomena such as lymphocytic infiltration and myocyte damage. The adverse prognostic importance of vascular or humoral rejection has been reported, but there is no well-documented treatment available. In our experience, comprising 151 orthotopic transplants, five patients presented with graft rejection characterized by a lymphocytic vasculitis that did not respond to conventional therapy. Because of a deteriorating condition, in spite of vigorous antirejection treatment that included inotropic drugs and circulatory support. plasmapheresis was tried as a last, desperate means to stop the process from developing further. The clinical symptoms rapidly subsided in all five patients after the first couple of plasma exchanges. All of the patients are alive and well after 2-3.5 years of follow-up. Although the mechanism of action is unclear, plasmapheresis was beneficial in these critically ill patients.

Computer simulations of peritoneal fluid transport in CAPD.

To model the changes in intraperitoneal dialysate volume (IPV) occurring over dwell time under various conditions in continuous ambulatory peritoneal dialysis (CAPD), we have, using a personal computer (PC), numerically integrated the phenomenological equations that describe the net ultrafiltration (UF) flow existing across the peritoneal membrane in every moment of a dwell. Computer modelling was performed according to a three-pore model of membrane selectivity as based on current concepts in capillary physiology. This model comprises small "paracellular" pores (radius approximately 47 A) and "large" pores (radius approximately 250 A), together accounting for approximately 98% of the total UF-coefficient (LpS), and also "transcellular" pores (pore radius approximately 4 to 5 A) accounting for 1.5% of LpS. Simulated curves made a good fit to IPV versus time data obtained experimentally in adult patients, using either 1.36 or 3.86% glucose dialysis solutions, under control conditions; when the peritoneal UF-coefficient was set to 0.082 ml/min/mm Hg, the glucose reflection coefficient was 0.043 and the peritoneal lymph flow was set to 0.3 ml/min. Also, theoretical predictions regarding the IPV versus time curves agreed well with the computer simulated results for perturbed values of effective peritoneal surface area, LpS, glucose permeability-surface area product (PS or "MTAC"), intraperitoneal dialysate volume and dialysate glucose concentration. Thus, increasing the peritoneal surface area caused the IPV versus time curves to peak earlier than during control, while the maximal volume ultrafiltered was not markedly affected. However, increasing the glucose PS caused both a reduction in the IPV versus time curve "peak time" and in the "peak height" of the curves. The latter pattern was also seen when the dialysate volume was reduced. It is suggested that computer modelling based on a three-pore model of membrane selectivity may be a useful tool for describing the IPV versus time relationships under various conditions in CAPD.

Clinical implications of a three-pore model of peritoneal transport.

The peritoneal barrier exchange characteristics are in this article described in terms of a three-pore model of membrane permselectivity. The peritoneal membrane during continuous ambulatory peritoneal dialysis (CAPD) is thus simulated to have a large number of small pores of radius 40-55 A, a small number of large pores of radius 200-300 A, and an abundance of transcellular pores of radius 4-5 A. Due to the heteroporous nature of the peritoneal membrane, peritoneal small solute sieving coefficients are of the order of 0.5-0.6, and not near unity, as predicted for a homoporous membrane having 50 A (radius) equivalent pores, but lacking transcellular pores. As a consequence, the dialysate during CAPD is diluted during the first 50-100 minutes of the dwell. Furthermore, there is a marked coupling between the increased net transperitoneal volume flow, occurring early in the cycle, and the transfer of "small" macromolecules, such as beta 2-microglobulin and albumin, across the peritoneal membrane. This coupling is, however, small for "large" macromolecules, such as IgG and IgM, or for small solutes. Increasing the peritoneal surface area, in computer simulations of peritoneal transport according to the three-pore model, causes the simulated intraperitoneal (i.p.) volume vs. time (V(t)) curves to peak earlier than during control, while the maximum volume ultrafiltered is not markedly affected. However, selectively increasing the glucose PS (mass transfer area coefficient) causes a reduction both in the peak time and the peak "height" of the V(t) curves. The latter pattern is also seen when the dialysate volume is reduced. It is concluded that a three-pore model of membrane permselectivity selectivity can adequately describe the kinetics of peritoneal transport of small and large solutes and of fluid.

A phenomenological interpretation of the variation in dialysate volume with dwell time in CAPD.

Intraperitoneal fluid volume (IPV) changes versus time were followed in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) using a simple volume recovery method. In each patient dialysates containing 1.36 and 3.86 percent glucose as an osmotic agent were investigated. The patients' IPV versus time data were fitted to a function determined by four "arbitrary" coefficients, from which both the initial ultrafiltration (UF) rate immediately following intraperitoneal (i.p.) fluid instillation and the "final" peritoneal-to-blood fluid absorption rate could be assessed. The peritoneal osmotic conductance to glucose, that is, the peritoneal ultrafiltration coefficient (Kf), times the peritoneal osmotic reflection coefficient to glucose (sigma g), Kf sigma g, was determined using two related approaches. Kf sigma g is a major determinant of the transperitoneal volume exchange, and it was calculated to be 3.54 +/- 0.85 (+/- SE) and 3.81 +/- 0.52 microliters/min/mm Hg, respectively, depending on the assumption employed. Kf sigma g was further analysed according to a three-pore model of membrane permeability to determine the possible range of Kf and sigma g compatible with a peritoneal small solute sieving coefficient (phi) ranging from 0.3 to 0.61. According to these calculations both Kf and sigma g ranged from 0.043 to 0.081 (ml/min/mm Hg and dimensionless, respectively). The maximal peritoneal lymph flow (L) realistic according to this analysis, and compatible with a measured total peritoneal-to-blood fluid absorption rate of 1.25 +/- 0.14 ml/min, was 0.75 ml/min, the most plausible values, however, falling between 0.3 to 0.5 ml/min.

How does peritoneal dialysis remove small and large molecular weight solutes? Transport pathways: fact and myth.

The overall exchange characteristics of the peritoneal 'membrane' are similar to those of continuous microvascular walls in general. The capillary walls in the peritoneum appear to be the principal structures determining the blood-peritoneal exchange.

Simulations of peritoneal solute transport during CAPD. Application of two-pore formalism.

Blood peritoneal clearances of various endogenous solutes in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) were evaluated according to recent developments of the two-pore theory of membrane permeability, using a non-linear transport formalism for the analysis. Based on results obtained from these calculations and taking lymphatic drainage into account, transport from peritoneal cavity to the blood was also simulated. With respect to solute transport the data were compatible with a functional blood-peritoneal barrier consisting of a two-pore membrane containing a large number of paracellular "small pores" of radius 40 to 55 A and a small number of "large pores" of radius 200 to 300 A. Solutes smaller than 25 A in radius were found to be permeating across the peritoneal membrane mainly by means of diffusion across the small pores, whereas solutes larger than 40 A were calculated to reach the peritoneal cavity exclusively by unidirectional convection across the large pores. In addition, water was simulated to be transported through transcellular "ultrapores" (radius less than 8 A) not accessible to hydrophilic solute permeation. Small solute absorption from the peritoneal cavity was found to occur by diffusion across small pores. Molecules larger than 25 to 30 A in radius (molecular weight above 25,000) were simulated to be absorbed from the peritoneal cavity exclusively via non-size-selective lymphatic drainage.

Influence of dialysis on prednisolone kinetics.

Six patients with end-stage renal disease were given prednisolone, 0.7-1.0 mg/kg/b.wt. parenterally. Prednisolone kinetics were investigated during dialysis, in 3 patients on hemodialysis and in 3 on continuous peritoneal dialysis, and also on days without dialysis. Mean plasma half-life was 250 min in five patients and 690 min in one patient who also suffered from intermittent porphyria. No change was found in prednisolone kinetics when the dialysis-free period was compared to the dialysis periods.