Effect of Treatment With Tabalumab, a B Cell-Activating Factor Inhibitor, on Highly Sensitized Patients With End-Stage Renal Disease Awaiting Transplantation.

B cell-activation factor (BAFF) is critical for B cell maturation. Inhibition of BAFF represents an appealing target for desensitization of sensitized end-stage renal disease (ESRD) patients. We conducted a Phase 2a, single-arm, open-label exploratory study investigating the effect of tabalumab (BAFF inhibitor) in patients with ESRD and calculated panel reactive antibodies (cPRAs) >50%. The treatment period duration was 24 weeks. Eighteen patients received tabalumab, at doses of 240-mg subcutaneous (SC) at Week 0 followed by 120-mg SC monthly for 5 additional months. Patients were followed for an additional 52 weeks. Immunopharmacologic effects were characterized through analysis of blood for HLA antibodies, BAFF concentrations, immunoglobulins, T and B cell subsets, as well as pre- and posttreatment tonsil and bone marrow biopsies. Significant reductions in cPRAs were observed at Weeks 16 (p = 0.043) and 36 (p = 0.004); however, absolute reductions were small (<5%). Expected pharmacologic changes in B cell subsets and immunoglobulin reductions were observed. Two tabalumab-related serious adverse events occurred (pneumonia, worsening of peripheral neuropathy), while the most common other adverse events were injection-site pain and hypotension. Three patients received matched deceased donor transplants during follow-up. Treatment with a BAFF inhibitor resulted in statistically significant, but not clinically meaningful reduction in the cPRA from baseline (NCT01200290, Clinicaltrials.gov).

Allograft Pancreatectomy: Indications and Outcomes.

This study evaluated the indications, surgical techniques, and outcomes of allograft pancreatectomy based on a single center experience. Between 2003 and 2013, 47 patients developed pancreas allograft failure, excluding mortality with a functioning pancreas allograft. Early graft loss (within 14 days) occurred in 16, and late graft loss in 31. All patients with early graft loss eventually required allograft pancreatectomy. Nineteen of 31 patients (61%) with late graft loss underwent allograft pancreatectomy. The main indication for early allograft pancreatectomy included vascular thrombosis with or without severe pancreatitis, whereas one recipient required urgent allograft pancreatectomy for gastrointestinal hemorrhage secondary to an arterioenteric fistula. In cases of late allograft pancreatectomy, graft failure with clinical symptoms such as abdominal discomfort, pain, and nausea were the main indications (13/19 [68%]), simultaneous retransplantation without clinical symptoms in 3 (16%), and vascular catastrophes including pseudoaneurysm and enteric arterial fistula in 3 (16%). Postoperative morbidity included one case each of pulmonary embolism leading to mortality, formation of pseudoaneurysm requiring placement of covered stent, and postoperative bleeding requiring relaparotomy eventually leading to femoro-femoral bypass surgery 2 years after allograftectomy. Allograft pancreatectomy can be performed safely, does not preclude subsequent retransplantation, and may be lifesaving in certain instances.

Risk factors for native kidney dysfunction in patients with abdominal multivisceral/small bowel transplantation.

Kidney dysfunction is a recognized complication after non-renal solid organ transplantation, particularly after intestinal transplant. In our study, we reviewed data on 33 multivisceral transplant (MVT)- and 15 isolated small bowel (ISB)-transplant patients to determine risk factors for kidney dysfunction. Kidney function was estimated by modified diet in renal disease (MDRD) and Schwartz formula for adults and children, respectively. Acute kidney injury (AKI) was defined as an increase in the serum Cr (sCr) greater than twofold. Kidney function declined significantly at one yr after transplantation with 46% of subjects showing an estimated GFR (eGFR) <60 mL/min. Patients with an episode of AKI were more likely to have reduced eGFR than those without AKI (p < 0.025). In linear regression analyses, age, pre-transplant sCr, eGFR at postoperative day (POD) 30, 90, 180, 270, and tacrolimus level at POD 7 showed significant correlation with one yr post-transplant eGFR (p < 0.05). Pediatric patients and patients with MVT had lesser decline in kidney function compared with adults or patients with ISB. In conclusion, risk factors for post-transplant kidney dysfunction in intestinal transplantation included age, pre-transplant sCr, AKI episode, eGFR at POD 30, 90, 180, 270, and tacrolimus level at POD 7.

Simultaneous pancreas and kidney transplantation with concurrent allograft nephrectomy for recipients with prior renal transplants lost to BK virus nephropathy: two case reports.

Candidacy for retransplantation after allograft loss due to BK virus-associated nephropathy (BKVN) with or without allograft nephrectomy is controversial. This report describes 2 renal transplant recipients who lost their grafts to BKVN and subsequently underwent simultaneous kidney and pancreas transplantation with allograft nephrectomy.

Effect of desensitization in solid organ transplant recipients depends on some cytokines genes polymorphism.

Desensitization (DS) is widely used to decrease PRA in solid organs transplant candidates (TC). Various numbers of cycles of DS are required to reduce or eliminate donor specific antibodies (DSA). The goal of this study was to investigate if there was a correlation between polymorphism (PM) of some cytokine genes and intensity of DS required to make the recipient/donor cross match compatible. Thirty-one TCs were included in the study. Antibody specificity, percent of reactive antibodies (PRA) and serum concentration of cytokines were analyzed using the LUMINEX platform. PCR-SSP method was used for IL-1alpha, IL-1beta, IL-1R, IL-1Ralpha, IL-4Ralpha, IL-12, IFNgamma, TGFbeta1, TNFalpha, IL-2, IL-4, IL-6 and IL-10 gene PM analysis. Significant relationship between PM of genes encoding IL-4Ralpha, IFNgamma and IL-12 (p70) and susceptibility to DS was demonstrated (p=0.04, p=0.01 and p=0.05 respectively). Correlation between elevated serum level of IL-12 (p70) and A/A or C/A genotype at -1188 position was found in resistant to DS TCs (p=0.015). These results indicate that analysis PM of genes encoding IL-4R, IFNgamma and IL-12 enables to define the DS strategy in TCs more accurately regarding the number of plasmapheresis (PP) cycles and dose of intravenous immunoglobulin (IVIG).

Immediate retransplantation for pancreas allograft thrombosis.

Early pancreas allograft failure most commonly results from thrombosis and requires immediate allograft pancreatectomy. Optimal timing for retransplantation remains undefined. Immediate retransplantation facilitates reuse of the same anatomic site before extensive adhesions have formed. Some studies suggest that early retransplantation is associated with a higher incidence of graft loss. This study is a retrospective review of immediate pancreas retransplants performed at a single center. All cases of pancreas allograft loss within 2 weeks were examined. Of 228 pancreas transplants, 12 grafts were lost within 2 weeks of surgery. Eleven of these underwent allograft pancreatectomy for thrombosis. One suffered anoxic brain injury and was not a retransplantation candidate, one was retransplanted at 3.5 months and nine patients underwent retransplantation 1-16 days following the original transplant. Of the nine early retransplants, one pancreas was lost to heparin-induced thrombocytopenia, one recipient died with function at 2.9 years and the other grafts continue to function at 76-1137 days (mean 572 days). One-year graft survival for early retransplantation was 89% compared to 91% for all pancreas transplants at our center. Immediate retransplantation following pancreatic graft thrombosis restores durable allograft function with outcomes comparable to first-time pancreas transplantation.

Maintenance of adequate hemodialysis access. Prevention of neointimal hyperplasia.

The maintenance of adequate hemodialysis vascular access is frequently complicated in the patient with polytetrafluoroethylene (PTFE) A-V hemodialysis grafts by venous anastomotic stenosis. This stenosis is caused by neointimal hyperplasia (NIH), a response to vascular injury. In this study, the authors prospectively analyzed the effect of a short-term regimen consisting of administration of two medications, heparin and low molecular weight dextran, on the development of NIH at the venous anastomosis in 79 patients with PTFE A-V hemodialysis grafts. In addition, they evaluated other parameters' effects on the development of NIH. In comparison with control subjects, heparin had some effect in minimizing the development of NIH in the PTFE grafts when evaluated radiologically at 3 months, although this effect was not statistically significant. Low molecular weight dextran, however, had no trend or statistically significant effect on this venous anastomotic narrowing. Interestingly, patient age, use of calcium channel blockers, and presence of diabetes mellitus (DM) all appeared to affect the development of NIH. Increasing age and use of calcium channel blockers was associated with decreased development of NIH; conversely, DM was associated with worsened NIH. In evaluation of access survival (time to first access failure), degree of venous anastomosis stenosis at 3 months was not predictive. Patient time on dialysis pre graft placement was the only measured parameter related to access failure. The method of dialysis pre graft placement (hemodialysis versus peritoneal dialysis) was not a significant factor in early access failure. Pharmacologic treatment of venous anastomotic narrowing in PTFE hemodialysis grafts due to NIH continues to be difficult. Short-term treatment with the tested medication failed to statistically affect NIH. Patient age, use of calcium channel blockers, and presence of DM were all factors in the development of NIH. Of measured parameters, time on dialysis pre graft placement was the only factor correlated with early access failure. In future treatment regimens, one should consider more prolonged treatment. In addition, noted risk factors should be considered when determining type of renal replacement therapy.

A prescription model for peritoneal dialysis.

The authors have developed a mathematical model for peritoneal dialysis, based on the Popovich-Pyle-Moncrief approach, that is capable of predicting urea Kt/V and total weekly creatinine clearance for a variety of peritoneal dialysis therapies. This prescription model incorporates both diffusive and convective solute removal as well as ultrafiltration and lymphatic absorption. The primary input to the model is a single peritoneal equilibration test. Twenty-four hour dialysate collection is not required. Results from an extensive prospective clinical study performed with 100 patients at five dialysis centers indicate that the model is valid for predicting urea Kt/V and creatinine clearance for continuous ambulatory peritoneal dialysis and continuous cycling peritoneal dialysis. Predicted clearances agree with the clinical data from these patients to within an average difference of approximately 10%. This model promises to be a powerful tool to assist nephrologists in quantifying the amount of peritoneal dialysis delivered by a given prescription, tailoring it to individual patient needs, and investigating the potential efficacy of a variety of alternative therapies.

Comparison of diagnostic accuracy with carbon dioxide versus iodinated contrast material in the imaging of hemodialysis access fistulas.

PURPOSE: Imaging of dialysis fistulas was performed with use of carbon dioxide and iodinated contrast material. Images were then compared to assess the quality and accuracy of CO2 as a contrast agent. PATIENTS AND METHODS: Thirty-two patients underwent digital subtraction imaging of the fistulas performed with both iodinated contrast material and CO2 to evaluate the venous anastomosis. The images were blinded and the degree of stenosis was graded in 10% increments by two physicians. Statistical analysis including sensitivity, specificity, and accuracy of CO2 images was performed. RESULTS: There was no significant difference in physician ratings of the degree of venous stenosis (P > .30). Estimation of the degree of stenosis was significantly higher with CO2 than with ionic contrast material (P = .0001). When iodinated contrast material is used as the gold standard, the sensitivity, specificity, and accuracy of CO2 were 94%, 58%, and 75%, respectively. CONCLUSIONS: CO2 has a role as a contrast agent in the imaging of dialysis access grafts when the use of iodinated contrast material is of concern. CO2 is safe for venous injections; however, it should not be used to evaluate the arterial anastomosis with the "reflux technique."

Initial clinical experience with a new model of mass transfer for peritoneal dialysis.

A clinical pilot study compared predictions of a new model of peritoneal dialysis mass transfer to measured weekly KT/V urea (KTu/V) and weekly creatinine clearance (Ccr) in liters per 1.73 m2 in 50 patients from five centers (40 CAPD, 10 CCPD). The Robertson et al. model is unique in that it does not require a 24-hour collection of dialysate. Instead, model predictions are based on the results of a standard 4-hour peritoneal equilibration test (PET) and appropriate demographic data. Analysis revealed 12 collection errors, 8 affecting the PET and 4 affecting 24-hour dialysate volume. PET drainage volume was low in six cases, excessive in two; 24-hour volume was incomplete in three, excessive in one. Similar errors were not found in the remaining 38 patients. In the 38 patients with correctly performed PET and dialysate collections, agreement between predicted and measured values was excellent.

Self-administration of epoetin beta by peritoneal dialysis patients.

Recombinant human erythropoietin (epoetin) reverses the anemia of end stage renal disease. Benefits have been evaluated primarily in hemodialysis patients because of the ease of administration via existing intravenous access. Studies are under way to evaluate the feasibility of subcutaneous self-administration of epoetin in continuous ambulatory peritoneal dialysis (CAPD) patients. Preliminary study results, using the maintenance of target hemoglobin levels to measure success and a case study demonstrate the practicality of subcutaneous self-administration of epoetin in CAPD patients.

Treatment of Pseudomonas infections in peritoneal dialysis patients.

Pseudomonas species infections in the peritoneal dialysis population consist primarily of peritonitis or exit site infections. These organisms have traditionally proven difficult to eradicate, and the standard antibiotic regimen has carried the potential for nephrotoxicity. At our institution, all peritoneal dialysis patients with Pseudomonas exit site infections or peritonitis were treated with an antibiotic combination of intraperitoneal ceftazidime and oral ciprofloxacin. Treatment duration was dependent upon the site of infection. Recurrent exit site infections were treated with a repeated course of the antibiotics, and with surgical debridement and subsequent shaving of the external cuff of double-cuffed catheters. We saw a total of 11 Pseudomonas aeruginosa exit site infections in 7 patients (4 recurrent). Patients with recurrent infections were subsequently cured with the regimen as outlined above. Of 7 patients with Pseudomonas species peritonitis (aeruginosa, fluorescens, stutszeri, and maltophilia), 5 were cured with the initial antibiotic regimen. The 2 failures were both infected with Pseudomonas maltophilia, which is consistent with observed organism sensitivity data. The combination of ceftazidime and ciprofloxacin with the option for surgical debridement of the external cuff (in exit site infections) appears effective in the treatment of Pseudomonas species infections in the peritoneal dialysis population. Sensitivity data should be used to adjust the antibiotic regimen when appropriate.

Calcium carbonate powder as a phosphate binder.

With increasing recognition of problems regarding the use of aluminum hydroxide as a phosphate binder, calcium carbonate has become the medication of choice. Use of calcium has, however, frequently been associated with development of hypercalcemia. At this institution, calcium carbonate powder as a phosphate binder, examination of its efficacy, and the frequency of hypercalcemia with its use were of great interest. Calcium carbonate powder (CalCarb-HD, 2.4 gms elemental calcium/packet) (CalCarb-HD, Lafayette Pharmacal Inc., Fort Worth, TX) was used in the study. Twenty-one end-stage renal disease (ESRD) patients (17 hemodialysis and 4 chronic ambulatory peritoneal dialysis) were chosen and converted from their previous binder (primarily, calcium carbonate tablets) to calcium powder. The dosage was adjusted to keep phosphorus levels at 3.5 to 5.5 mg/dl and calcium less than 11.5 mg/dl. At 2 months, the average calcium level in the 16 patients remaining in the study was 9.2 mg/dl, and the average phosphorus level was 5.2 mg/dl with an average calcium dose of 1.4 packets/day. By 7 months, the 8 patients remaining in the study had an average calcium level of 9.9 mg/dl with an average phosphorus level of 5.5 mg/dl; average calcium dose was 1.8 packets/day. Total episodes of hypercalcemia (calcium greater than 11.5 mg/dl) were two. Calcium carbonate powder appears to be an effective phosphate binder in the ESRD population. The relatively few episodes of hypercalcemia may be related to possible enhanced bioavailability of the compound secondary to its powdered form.

Comparison of two non-disconnect CAPD delivery systems.

Intraluminal transmission of bacteria remains a significant factor in the morbidity and procedural success of CAPD. A worsening rate of peritonitis in a longstanding CAPD program (first patients 1978) led to a search for a system which might allow a lesser rate of peritonitis. Simplicity in the procedure was a requirement. For this reason disconnect systems were not considered. The Travenol spike system was prospectively compared with Delmed leur lock in terms of rate of peritonitis and difficulty in training. The former had been used by the center since inception of the CAPD program. 28 patients new to CAPD were alternately assigned to each system without other bias, including diagnosis, age, sex, or race. The study, while ongoing, was analyzed at 12 months. 66 patient months were involved with each system. The peritonitis rates were: 2.2 episodes: patient year with the Travenol; 0.9 episode:patient year for the Delmed systems. The Delmed system appears to provide a lower rate of peritonitis. In addition, less manual dexterity, steadiness, and hand eye coordination are necessary.

Calcium carbonate as a phosphate binder in hemodialysis patients.

Calcium carbonate appears to be as effective as aluminum hydroxide in binding dietary phosphorus in hemodialysis patients. The long-term safety of this medication appears acceptable in view of today's therapeutic options.