The impact of direct-acting antiviral agents on liver and kidney transplant costs and outcomes.

Direct-acting antiviral medications (DAAs) have revolutionized care for hepatitis C positive (HCV+) liver (LT) and kidney (KT) transplant recipients. Scientific Registry of Transplant Recipients registry data were integrated with national pharmaceutical claims (2007-2016) to identify HCV treatments before January 2014 (pre-DAA) and after (post-DAA), stratified by donor (D) and recipient (R) serostatus and payer. Pre-DAA, 18% of HCV+ LT recipients were treated within 3 years and without differences by donor serostatus or payer. Post-DAA, only 6% of D-/R+ recipients, 19.8% of D+/R+ recipients with public insurance, and 11.3% with private insurance were treated within 3 years (P < .0001). LT recipients treated for HCV pre-DAA experienced higher rates of graft loss (adjusted hazard ratio [aHR] 1.34 1.852.10 , P < .0001) and death (aHR 1.47 1.681.91 , P < .0001). Post-DAA, HCV treatment was not associated with death (aHR 0.34 0.671.32 , P = .25) or graft failure (aHR 0.32 0.641.26 , P = .20) in D+R+ LT recipients. Treatment increased in D+R+ KT recipients (5.5% pre-DAA vs 12.9% post-DAA), but did not differ by payer status. DAAs reduced the risk of death after D+/R+ KT by 57% (0.19 0.430.95 , P = .04) and graft loss by 46% (0.27 0.541.07 , P = .08). HCV treatment with DAAs appears to improve HCV+ LT and KT outcomes; however, access to these medications appears limited in both LT and KT recipients.

Prescription opioid use before and after kidney transplant: Implications for posttransplant outcomes.

Evolving literature suggests that the epidemic of prescription opioid use affects the transplant population. We examined a novel database wherein national U.S. transplant registry records were linked to a large pharmaceutical claims warehouse (2007-2015) to characterize prescription opioid use before and after kidney transplant, and associations (adjusted hazard ratio, 95%LCL aHR95%UCL ) with death and graft loss. Among 75 430 eligible patients, 43.1% filled opioids in the year before transplant. Use was more common among recipients who were women, white, unemployed, publicly insured, and with longer pretransplant dialysis. Of those with the highest level of pretransplant opioid use, 60% continued high-level use posttransplant. Pretransplant opioid use had graded associations with one-year posttransplant outcomes; the highest-level use predicted 46% increased risk of death (aHR 1.28 1.461.66 ) and 28% increased risk of all-cause graft failure (aHR 1.17 1.281.41 ). Effects of high-level opioid use in the first year after transplant were stronger, predicting twice the risk of death (aHR 1.93 2.242.60 ) and 68% higher all-cause graft failure risk (aHR 1.50 1.681.89 ) over the subsequent year; increased risk persisted over five years. While associations may, in part, reflect underlying conditions or behaviors, opioid use history is relevant in assessing and providing care to transplant candidates and recipients.

Graft vasculopathy in clinical hand transplantation.

Allogeneic hand transplantation is now a clinical reality. While results have been encouraging, acute rejection rates are higher than in their solid-organ counterparts. In contrast, chronic rejections, as defined by vasculopathy and/or fibrosis and atrophy of skin and other tissues, as well as antibody mediated rejection, have not been reported in a compliant hand transplant recipient. Monitoring vascularized composite allograft (VCA) hand recipients for rejection has routinely involved punch skin biopsies, vascular imaging and graft appearance. Our program, which has transplanted a total of 6 hand recipients, has experience which challenges these precepts. We present evidence that the vessels, both arteries and veins may also be a primary target of rejection in the hand. Two of our recipients developed severe intimal hyperplasia and vasculopathy early post-transplant. An analysis of events and our four other patients has shown that the standard techniques used for surveillance of rejection (i.e. punch skin biopsies, DSA and conventional vascular imaging studies) are inadequate for detecting the early stages of vasculopathy. In response, we have initiated studies using ultrasound biomicroscopy (UBM) to evaluate the vessel wall thickness. These findings suggest that vasculopathy should be a focus of frequent monitoring in VCA of the hand.

Under-recognition of chronic kidney disease in elderly outpatients.

The elderly are the fastest growing segment of the United States population. Age is a key predictor of chronic kidney disease (CKD). A major obstacle in the recognition of CKD in the elderly is the reliance on serum creatinine measurements as an estimation of glomerular filtration rate (GFR). We hypothesized that early stages of CKD would not be recognized by primary care clinicians providing care to elderly men in a highly structured setting. This study was a retrospective study of outpatients 70 years and older seen in VISN 9 at Veterans Administration Medical Centers from 1/1/2001 thru 12/31/2003. GFR was estimated using the MDRD formula. We abstracted demographic and medical data from the electronic medical record. The population consisted primarily of elderly white male (7,289 men; 91% Caucasian). In CKD Stage 2, 3, and 4, men had a diagnosis code reflecting kidney disease in 1.2%, 20%, and 74.6% of the charts. Despite declining kidney function, nephrology consults were requested in fewer than 5%. In summary, we have shown in a large outpatient population of elderly men that CKD is frequently under-recognized, but most pronounced in CKD Stages 2 and 3. Stages 2 and 3 may be the stages in which the most beneficial effects of interventions can be obtained.

Recurrent and de novo glomerular disease after renal transplantation: a report from Renal Allograft Disease Registry (RADR).

INTRODUCTION: Short-term and long-term results of renal transplantation have improved over the past 15 years. However, there has been no change in the prevalence of recurrent and de novo diseases. A retrospective study was initiated through the Renal Allograft Disease Registry, to evaluate the prevalence and impact of recurrent and de novo diseases after transplantation. MATERIALS AND METHODS: From October 1987 to December 1996, a total of 4913 renal transplants were performed on adults at the Medical College of Wisconsin, University of Cincinnati, University of California at San Francisco, University of Louisville, University of Washington, Seattle, and Washington University School of Medicine. The patients were followed for a minimum of 1 year. A total of 167 (3.4%) cases of recurrent and de novo disease were diagnosed by renal biopsy. These patients were compared with other patients who did not have recurrent and de novo disease (n=4746). There were more men (67.7% vs. 59.8%, P<0.035) and a higher number of re-transplants (17% vs. 11.5%, P<0.005) in the recurrent and de novo disease group. There was no difference in the rate of recurrent and de novo disease according to the transplant type (living related donor vs. cadaver, P=NS). Other demographic findings were not significantly different. Common forms of glomerulonephritis seen were focal segmental glomerulosclerosis (FSGS), 57; immunoglobulin A nephritis, 22; membranoproliferative glomerulonephritis (GN), 18; and membranous nephropathy, 16. Other diagnoses include: diabetic nephropathy, 19; immune complex GN, 12; crescentic GN (vasculitis), 6; hemolytic uremic syndrome-thrombotic thrombocytopenic purpura (HUS/TTP), 8; systemic lupus erythematosus, 3; Anti-glomerular basement membrane disease, 2; oxalosis, 2; and miscellaneous, 2. The diagnosis of recurrent and de novo disease was made after a mean period of 678 days after the transplant. During the follow-up period, there were significantly more graft failures in the recurrent disease group, 55% vs. 25%, P<0.001. The actuarial 1-, 2-, 3-, 4, and 5-year kidney survival rates for patients with recurrent and de novo disease was 86.5%, 78.5%, 65%, 47.7%, and 39.8%. The corresponding survival rates for patients without recurrent and de novo disease were 85.2%, 81.2%, 76.5%, 72%, and 67.6%, respectively (Log-rank test, P<0.0001). The median kidney survival rate for patients with and without recurrent and de novo disease was 1360 vs. 3382 days (P<0.0001). Multivariate analysis using the Cox proportional hazard model for graft failure was performed to identify various risk factors. Cadaveric transplants, prolonged cold ischemia time, elevated panel reactive antibody, and recurrent disease were identified as risk factors for allograft failure. The relative risk (95% confidence interval) for graft failure because of recurrent and de novo disease was 1.9 (1.57-2.40), P<0.0001. The relative risk for graft failure because of posttransplant FSGS was 2.25 (1.6-3.1), P<0.0001, for membranoprolifera. tive glomerulonephritis was 2.37 (1.3-4.2), P<0.003, and for HUS/TTP was 5.36 (2.2-12.9), P<0.0002. There was higher graft failure (64.9%) and shorter half-life (1244 days) in patients with recurrent FSGS. CONCLUSION: In conclusion, recurrent and de novo disease are associated with poorer long-term survival, and the relative risk of allograft loss is double. Significant impact on graft survival was seen with recurrent and de novo FSGS, membranoproliferative glomerulonephritis, and HUS/TTP.

Increasing dialysate flow rate increases dialyzer urea mass transfer-area coefficients during clinical use.

Dialyzer clearance depends on blood and dialysate flow rates and the product of the membrane surface area and mass transfer coefficient for the solute of interest, K(o)A. K(o)A is usually assumed to be constant for a given dialyzer and solute. Results of two recent studies challenge this assumption. Therefore, we examined the hypothesis that K(o)A depends on blood and dialysate flow rates during clinical dialysis. Urea clearances were measured for two different dialyzers at all four combinations of two blood flow rates (300 and 400 mL/min) and two dialysate flow rates (500 and 800 mL/min). Urea K(o)A was calculated by using standard equations for mass transfer in dialyzers operated with countercurrent flows. The impact of blood and dialysate flow rates on K(o)A was assessed by analysis of variance. Increasing dialysate flow rate from 500 to 800 mL/min significantly increased K(o)A (P = 0.018). Increasing blood flow rate from 300 to 400 mL/min did not significantly increase K(o)A (P = 0.083). Also, K(o)A decreased significantly with increasing hematocrit (P = 0.022). The results of this study extend previous in vitro findings by showing that increasing the dialysate flow rate increases urea K(o)A during clinical dialysis. However, the increase in K(o)A observed during clinical dialysis (5.7%) is less than that previously reported in vitro (14.7%), possibly because of the impact of blood cells and proteins on blood-side mass transfer resistance.

Improved dialyzer reuse after use of a population pharmacodynamic model to determine heparin doses.

Anticoagulation with heparin is performed to prevent clotting during dialysis. However, heparin doses are usually determined empirically, and dialyzer clotting is a common reason for discarding reused dialyzers. We hypothesized that using a population pharmacodynamic model to determine individual heparin doses would improve dialyzer reuse rates. A previously published model was used to determine the loading dose and infusion rate of heparin needed to increase the intradialytic whole-blood clotting time to 150% of the predialysis value. The effectiveness of the model was assessed by comparing dialyzer reuse rates and delivered Kt/V(urea) before and after implementation of the model in 22 chronic hemodialysis patients. As an additional control, a similar group of 22 patients were followed up during the same period without adjustment of their heparin doses. Implementation of the model resulted in no change in the average loading dose (2,382 +/- 628 versus 2,425 +/- 908 IU; P = not significant) or average infusion rate (1,398 +/- 367 versus 1,393 +/- 532 IU/h; P = not significant) of heparin. However, individual patients required changes in loading dose or infusion rate. Dialyzer reuse rates increased significantly over time in the treatment group but remained unchanged in the control group (P < 0.003). Kt/V(urea) remained unchanged throughout the study period in both patient groups. From these data, we conclude that the use of a heparin model can improve dialyzer reuse rates without compromising the delivered dose of dialysis.

Hyperkalemia associated with cyclosporine (CsA) use in bone marrow transplantation.

Two adult leukemia patients underwent allogeneic bone marrow transplantation and received cyclosporine (CsA) as part of their immunosuppressive therapy. Despite adequate kidney function, both patients developed hyperkalemia. Cyclosporine was the only pharmaceutical agent to which this electrolyte abnormality could be attributed. Although the mechanism of the hyperkalemia is unclear, it seems to be related to an aldosterone-resistant state. Cyclosporine-induced hyperkalemia is a relatively common occurrence; however, there is only a single 'case report' addressing this phenomenon in bone marrow transplantation patients. We propose both mechanisms and methods of managing CsA-associated hyperkalemia in allogeneic transplantation patients.

Patent foramen ovale presenting as refractory hypoxemia after heart transplantation.

Hypoxemia can be an early life-threatening complication of orthotopic heart transplantation. Commonly, hypoxemia after orthotopic heart transplantation is due to pulmonary hypertension or pulmonary complications. Rarely, structural defects either in the donor or recipient heart can lead to life-threatening hypoxemia. This case illustrates hypoxemia after orthotopic heart transplantation caused by the development of a right-to-left shunt through a patent foramen ovale in the recipient which had preoperatively been hemodynamically insignificant. The refractory hypoxemia required emergency surgical correction of the patent foramen ovale within the first postoperative week. In addition, this case illustrates the unique application of different methods of echocardiograms providing noninvasive diagnosis of structural defects in orthotopic heart transplantation.

Lymphoproliferative disease seen as a cardiac mass after orthotopic heart transplantation.

Posttransplantation lymphoproliferative disorder (PTLD) occurs in approximately 5% of patients after orthotopic heart transplantation. PTLD is frequently fatal. PTLD rarely involves the cardiac allograft. We report the first case of PTLD seen as a mass in the cardiac allograft.

Calcitriol and the parathyroid hormone-ionized calcium curve: a comparison of methodologic approaches.

Investigations of the effects of calcitriol on the inverse sigmoidal relationship between parathyroid hormone (PTH) and ionized calcium (iCa) have yielded contradictory conclusions, possibly because of variations in experimental and analytical approaches. To clarify the existing literature, PTH-iCa curves were constructed by inducing hypo- and hypercalcemia through alterations in dialysate calcium concentration in eight hemodialysis patients with mild to moderate secondary hyperparathyroidism. The effects of low (metabolic acidosis) versus normal bicarbonate dialysis were compared before and after 4 wk of intravenous calcitriol, in a cross-over design. The PTH-iCa curves were primarily evaluated by using a four-parameter model. In addition, a variety of alternative published analytic approaches were examined and PTH-iCa curve slopes were further evaluated after normalization by (maximum - minimum PTH). The latter partially corrects for gland mass and cell-secretory capacity, and therefore yields a purer measure of the sensitivity of secretory activity to changes in iCa. The results of the study indicate that calcitriol decreased basal, maximal, and minimal PTH and non-normalized slope (all P < 0.05), but did not affect set point or normalized slope, independent of the specific analytic approach. Acute metabolic acidosis did not affect the PTH-iCa curve. Thus, intravenous calcitriol appears to decrease parathyroid gland functional mass, as reflected by decreases in maximal and minimal PTH levels, but does not affect the sensitivity of the parathyroid gland to changes in iCa, as set point and normalized slope were unaffected.

Maintaining blood compartment volume in dialyzers reprocessed with peracetic acid maintains Kt/V but not beta2-microglobulin removal.

A dialyzer is reused if its blood compartment volume is 80% of its initial value, a condition believed to ensure that the urea clearance remains at 90% of its initial value. This criterion was developed for dialyzers containing low permeability cellulose membranes reprocessed with formaldehyde. We tested the hypothesis that the criterion is also valid for more permeable membranes when dialyzers are reprocessed with peracetic acid/hydrogen peroxide. Kt/V for urea and reduction in beta2-microglobulin concentration were measured for up to 15 uses in dialyzers containing polysulfone or cellulose membranes. Kt/V for urea did not change for either dialyzer provided blood compartment volumes remained 80% of their initial value. The reduction in plasma beta2-microglobulin concentration from predialysis to postdialysis was 30% for the first use of the dialyzer containing polysulfone membranes, but decreased significantly (P = 0.042) following reuse to 12% for the tenth use. For the dialyzers containing cellulose membranes, the reduction in plasma beta2-microglobulin concentration was 18% for the first use and decreased to 12% by the twelfth use; however, this change was not significant. We conclude that removal of urea is maintained during reuse with peracetic acid/hydrogen peroxide provided the blood compartment volume remains 80% of its initial value. However, removal of beta2-microglobulin may not be maintained, even though blood compartment volumes remain at 80% of their initial value.

Continuous venovenous hemofiltration and hemodialysis after orthotopic heart transplantation.

Orthotopic heart transplantation (OHT) is an accepted treatment for heart failure refractory to medical management. International registry data reported a 1-year survival after OHT of 79%. The risk factors associated with requiring continuous venovenous hemofiltration or hemodialysis and mortality in patients requiring continuous venovenous hemofiltration (CVVH)/hemodialysis (HD) have not been studied, since improvements have been made in OHT. We tested the hypothesis that requiring CVVH/HD in the immediate posttransplantation period increases mortality after OHT. We studied pretransplantation factors to predict those patients who would need CVVH/HD. Patients undergoing OHT from 1995 to 1996 were studied. Fifty-two patients underwent OHT. Eight patients (15%) needed CVVH/HD. Initial immunosuppression included cyclosporine, azathioprine, and solumedrol. Patients were changed to antilymphocyte therapy if they had oliguric acute renal failure, T or B cell incompatibility, or biopsy-proven rejection. Overall, survival at 1 year was 84.6%. Survival in patients not needing CVVH/HD was 91%, and survival in patients needing CVVH/HD was 36.5%. For each year of age over 55 years, patients had a relative risk of requiring CVVH/HD of 7.