The Incremental Cost of Incompatible Living Donor Kidney Transplantation: A National Cohort Analysis.

Incompatible living donor kidney transplantation (ILDKT) has been established as an effective option for end-stage renal disease patients with willing but HLA-incompatible living donors, reducing mortality and improving quality of life. Depending on antibody titer, ILDKT can require highly resource-intensive procedures, including intravenous immunoglobulin, plasma exchange, and/or cell-depleting antibody treatment, as well as protocol biopsies and donor-specific antibody testing. This study sought to compare the cost and Medicare reimbursement, exclusive of organ acquisition payment, for ILDKT (n = 926) with varying antibody titers to matched compatible transplants (n = 2762) performed between 2002 and 2011. Data were assembled from a national cohort study of ILDKT and a unique data set linking hospital cost accounting data and Medicare claims. ILDKT was more expensive than matched compatible transplantation, ranging from 20% higher adjusted costs for positive on Luminex assay but negative flow cytometric crossmatch, 26% higher for positive flow cytometric crossmatch but negative cytotoxic crossmatch, and 39% higher for positive cytotoxic crossmatch (p < 0.0001 for all). ILDKT was associated with longer median length of stay (12.9 vs. 7.8 days), higher Medicare payments ($91 330 vs. $63 782 p < 0.0001), and greater outlier payments. In conclusion, ILDKT increases the cost of and payments for kidney transplantation.

Quantifying the risk of incompatible kidney transplantation: a multicenter study.

Incompatible live donor kidney transplantation (ILDKT) offers a survival advantage over dialysis to patients with anti-HLA donor-specific antibody (DSA). Program-specific reports (PSRs) fail to account for ILDKT, placing this practice at regulatory risk. We collected DSA data, categorized as positive Luminex, negative flow crossmatch (PLNF) (n = 185), positive flow, negative cytotoxic crossmatch (PFNC) (n = 536) or positive cytotoxic crossmatch (PCC) (n = 304), from 22 centers. We tested associations between DSA, graft loss and mortality after adjusting for PSR model factors, using 9669 compatible patients as a comparison. PLNF patients had similar graft loss; however, PFNC (adjusted hazard ratio [aHR] = 1.64, 95% confidence interval [CI]: 1.15-2.23, p = 0.007) and PCC (aHR = 5.01, 95% CI: 3.71-6.77, p < 0.001) were associated with increased graft loss in the first year. PLNF patients had similar mortality; however, PFNC (aHR = 2.04; 95% CI: 1.28-3.26; p = 0.003) and PCC (aHR = 4.59; 95% CI: 2.98-7.07; p < 0.001) were associated with increased mortality. We simulated Centers for Medicare & Medicaid Services flagging to examine ILDKT's effect on the risk of being flagged. Compared to equal-quality centers performing no ILDKT, centers performing 5%, 10% or 20% PFNC had a 1.19-, 1.33- and 1.73-fold higher odds of being flagged. Centers performing 5%, 10% or 20% PCC had a 2.22-, 4.09- and 10.72-fold higher odds. Failure to account for ILDKT's increased risk places centers providing this life-saving treatment in jeopardy of regulatory intervention.

Estimating kinetic parameters from HIV primary infection data through the eyes of three different mathematical models.

The dynamics of HIV-1 infection consist of three distinct phases starting with primary infection, then latency and finally AIDS or drug therapy. In this paper we model the dynamics of primary infection and the beginning of latency. We show that allowing for time delays in the model better predicts viral load data when compared to models with no time delays. We also find that our model of primary infection predicts the turnover rates for productively infected T cells and viral totals to be much longer than compared to data from patients receiving anti-viral drug therapy. Hence the dynamics of the infection can change dramatically from one stage to the next. However, we also show that with the data available the results are highly sensitive to the chosen model. We compare the results using analysis and Monte Carlo techniques for three different models and show how each predicts rather dramatic differences between the fitted parameters. We show, using a chi(2) test, that these differences between models are statistically significant and using a jackknifing method, we find the confidence intervals for the parameters. These differences in parameter estimations lead to widely varying conclusions about HIV pathogenesis. For instance, we find in our model with time delays the existence of a Hopf bifurcation that leads to sustained oscillations and that these oscillations could simulate the rapid turnover between viral strains and the appropriate CTL response necessary to control the virus, similar to that of a predator-prey type system.

Anaphylactic reaction and cardiopulmonary arrest following intravenous cyclosporine.

Cyclosporine, a new immunosuppressive agent useful in recipients of a variety of organ transplants, has been associated with a number of adverse effects, most notably nephrotoxicity. This report describes a woman about to undergo liver transplantation in whom intravenous administration of cyclosporine was associated with an apparent anaphylactic reaction resulting in cardiopulmonary arrest. Similar reactions have thus far not been reported after oral administration of cyclosporine. Intravenous cyclosporine must be administered under close supervision and should be avoided in any patients with a history of prior allergic reactions to the drug or to a component of its intravenous formulation.

The use of local allograft irradiation following renal transplantation.

Over a 10 year period, 67 recipients of 71 renal allografts received graft irradiation following the diagnosis of rejection. The majority of kidneys were treated with a total dose of 600 rad, 150 rad per fraction, in 4 daily fractions. Fifty-three kidneys were irradiated following the failure of standard systemic immunosuppression and maximally tolerated antirejection measures (pulse high dose steroids, Actinomycin, ATG) to reverse an episode of acute rejection. Seven of these patients (13%) had greater than a 50% improvement in serum creatinine (Cr) 1 week following completion of the irradiation. Twenty-two (42%) of these allografts were noted to have stable (i.e. no deterioration) or improved function 1 month following the treatment with irradiation. Eleven (21%) of these allografts maintained function 1 year following transplantation. There were 10 patients whose allografts were irradiated because of renal dysfunction in a clinical setting which did not permit the administration of further immunosuppression, i.e., infection or hematologic dyscrasias. Three of these patients (30%) had greater than a 50% improvement in serum Cr 1 week following completion of the irradiation. Nine (90%) of these allografts had stable or improved function 1 month following the treatment with irradiation. Biopsies were obtained of 41 allografts. Of the 24 renal allografts with predominantly cellular rejection, 10 (42%) had the process reversed or stabilized at 1 month following irradiation. Five (21%) of these allografts were functioning at 1 year following irradiation. Rejection was reversed or stabilized in 6 of 17 (35%) allografts at 1 month when the histologic features of renal biopsy suggested predominantly vascular rejection. One (6%) of these allografts was functioning at 1 year following transplantation. Local graft irradiation has helped maintain a limited number of allografts in patients whose rejection has failed to respond to systemic immunosuppression. Irradiation may also benefit patients with ongoing rejection in whom further systemic immunosuppression is contra-indicated.

Successful transplantation of blood group A2 kidneys into non-A recipients.

The ABO subgroup A2 has been reported to be less reactive with the anti-A1 antibody naturally occurring in the serum of group O and B recipients and to occur in approximately 20% of group A individuals. Between March 1986 and February 1987, the Midwest Organ Bank (MOB) in Kansas City, screened all group A renal donors for the A2 subgroup. A total of 190 cadaverdonor kidneys were retrieved during this time, of which 68 were subgroup A1 and 16 were subgroup A2 (incidence of A2 = 19% of As and 8.5% of all donors). Of the subgroup A2 kidneys, 13 were transplanted into 9 group O and 4 group B recipients. One group O recipient received an HLA-identical A2 living-related graft. Recipients were not preselected or modified by splenectomy, plasmapheresis, or other means, and were treated with cyclosporine, steroids--and, in most cases, azathioprine, after transplantation. There was one hyperacute rejection and there were 5 acute cellular rejection episodes, 3 of which were reversed. One additional patient died at 2.5 months with a functioning graft. Including the successful living-related graft, 10 of 14 patients (71%) have functioning grafts, with a follow-up of 5 to 14 months, and a mean creatinine of 1.7 mg/dl. We find that the A2 subgroup represents a small but important minority of A donors, and that transplantation into non-A recipients can generally, but not universally, be safely accomplished. We recommend the screening of A donors for the A2 subgroup in both the cadaver-donor and living-related groups, and suggest that the utilization of A2 donors in non-A patients may contribute to the transplantation of group O and highly sensitized patients--and, in some cases, improve the degree of HLA matching.

Evolving use of OKT3 monoclonal antibody for treatment of renal allograft rejection.

OKT3, a monoclonal antibody reactive with a surface glycoprotein present on all postthymic T cells, was used to treat the initial acute episode of rejection in 30 recipients of cadaveric donor renal allografts. The first 16 patients received 1-5 mg daily for a period of 10-21 days during which the azathioprine and prednisone dosages were sharply reduced. Circulating T cells were eliminated within minutes after the first OKT3 infusion. T cells reactive with OKT3 remained depressed throughout the period of treatment, although a significant number of cells reactive with other T cells subset reagents became detectable after several days of OKT3 treatment. In all instances, the established rejection episode was reversed in 2-8 days without the addition of other immunosuppressive measures. Recurrent rejection occurred in 12 of 16 patients, but with further conventional immunosuppression, 50% of the renal allografts remain functional 20-44 months after transplantation. Fever, chills, and, in some instances, dyspnea following the first dose of OKT3 were the only side-effects observed. Most patients developed antiidiotypic or antimouse immunoglobulin antibodies without apparent clinical sequelae. In the subsequent 14 patients, modifications in the protocol included a steroid bolus prior to the first OKT3 infusion, limitation of therapy to 10 days, resumption of maintenance levels of azathioprine and prednisone prior to discontinuing OKT3, and addition of 3 i.v. doses of cyclophosphamide at the termination of treatment. Respiratory symptoms after the first infusion of the reagent have been eliminated. Antibody responses to OKT3 have been reduced, occurring in 38% as compared with 73% of patients treated previously. Recurrent rejection episodes observed in 8 of 14 patients have been reversible in all but one case. Allograft survival is 86% at 6-17 months posttransplantation. In the entire series of 30 OKT3-treated patients, only 4 grafts (13%) have been lost because of recurrent episodes of rejection.

Cold ischemia time: an independent predictor of increased HLA class I antibody production after rejection of a primary cadaveric renal allograft.

BACKGROUND: Cadaveric kidneys experiencing longer cold ischemia time (CIT) are associated with higher levels of delayed graft function, acute rejection, and early graft loss. One mechanism to explain these results is that ischemia/reperfusion (I/R) injury makes the allograft more immunogenic by upregulating molecules involved in the immune response (e.g., HLA Class I/II). METHODS: We evaluated the influence of CIT on the production of HLA Class I antibody level, measured by an antihuman globulin panel reactive antibody (AHG PRA) level, in 90 unsensitized recipients of primary cadaveric renal transplants (from a total of 1442 between 1985 and 1997) who rejected their kidneys. RESULTS: By multivariate analysis, a CIT of 15 hr or more (vs. < 15 hr) independently increased the risk of the AHG Class I PRA level being > or = 20% after unsensitized patients rejected their first kidneys (relative risk=3.57; 95% confidence interval=1.26 to 10.14; P=0.01), despite the same degree of Class I/II mismatch between the two CIT groups. The overall mean peak PRA level after primary kidney rejection was significantly lower for the CIT < 15 hr group (25.9%+/-33.9; n=24) compared with the CIT > or = 15 hr group (46.3%+/-36.5; n=66) (P<0.001). CONCLUSION: Longer CIT induces a humorally more immunogenic kidney.

HLA-DR and DQ typing by polymerase chain reaction using sequence-specific primer mixes reduces the incidence of phenotypic homozygosity (blanks) over serology.

Because of the inherent difficulties in allele assignment with HLA-DR serological typing, in 1993 our organ procurement organization-based HLA laboratory replaced serology with the molecular method of polymerase chain reaction using sequence-specific primer mixes (PCR-SSP) to type for DR and DQ at a resolution level equivalent to that of serologically defined antigens. In this study, we compared the incidence of DR blanks, where allocative homozygosity occurred, and graft outcome during our serology epoch (1987-1993) with that of our molecular epoch (1993-1996). The incidence of DR blanks by PCR-SSP (17.0%; 138/1101) was significantly lower (P<0.005) than in the serology epoch (21.5%; 569/2647). Although DQ is not a component of the allocation algorithm, the incidence of blanks in the molecular era (21.9%; 196/895) was 46% lower (P<0.001) than in the serology epoch (40.8%; 931/2277). Graft survival in 163 cadaveric renal transplant recipients for whom molecular DR allocation occurred (patient and donor were molecularly typed) showed that PCR-SSP typing had no significant effect on 2.5-year graft survival for patients mismatched for 0 (97%), 1 (90%), or 2 (94%) HLA-DR antigens (P=0.4; log-rank). In conclusion, molecular typing lowered the rate of DR and DQ blanks, but molecular matching for HLA DR and DQ did not influence graft outcome at 2.5 years.

Long-term graft survival is improved in cadaveric renal retransplantation by flow cytometric crossmatching.

BACKGROUND: Cadaveric renal retransplantation is associated with a higher risk of early graft failure than primary grafts. A large proportion of those graft losses is likely attributable to donor-directed HLA class I antibodies, detectable by flow cytometry cross-matching but not by conventional crossmatching techniques. METHODS: Long-term graft survival in a group of 106 recipients of consecutive cadaveric renal regrafts between 1990 and 1997, in whom a negative flow T-cell IgG crossmatch was required for transplantation, was compared with two other groups of cadaveric transplant recipients. The first group consisted of 174 cadaveric regrafts transplanted between 1985 and 1995 using only a negative anti-human globulin (AHG) T-cell IgG crossmatch. The second group was primary cadaveric transplants done concurrently with the flow group (1990 to 1997) using only the AHG T-cell IgG crossmatch. RESULTS: The long-term (7 year) graft survival rate of flow crossmatch-selected regraft recipients (68%; n= 106) was significantly improved over that of regraft recipients who were selected for transplantation by only the AHG crossmatch technique (45%; n=174; log-rank=0.001; censored for patients dying with a functioning graft). Graft outcome for the flow cross-matched regraft recipients was not significantly different from that of primary cadaveric patients (72%; n=889; log-rank=0.2; censored for patients dying with a functioning graft). Finally, a positive B-cell IgG flow cytometric crossmatch had no influence on long-term regraft outcome. CONCLUSIONS: The use of the flow T-cell IgG cross-match as the exclusion criterion for cadaveric renal retransplantation yields an improved long-term graft outcome over that obtained when only the AHG cross-match is used and has improved survival of regraft recipients to the level of our primary cadaveric renal transplant population.

Ten-year experience in transplantation of A2 kidneys into B and O recipients.

BACKGROUND: This article summarizes our 10-year multicenter experience with transplantation of 50 blood group A2 and A2B kidneys into B and O patients. METHODS: Since 1986, we have transplanted kidneys from 46 cadaver donors and 4 living donors who were blood group A2 (47 donors) or A2B (3 donors) into 19 B and 31 O patients. In 1991, we began allocating these kidneys preferentially to B and O recipients who were selected based on a history of low (< or =4) anti-A IgG isoagglutinin titers. Immunosuppression was no different from that used in ABO-compatible grafts. RESULTS: The 1-month function rate before thus selecting the patients was 68% (19/28), but is now 94% (17/18). Two-year cadaver-donor graft survival with this selection method is 94%, compared with 88% for 640 concurrent and consecutive ABO-compatible transplants (log-rank, 0.15). All four living-related transplants are still functioning, with a mean follow-up of 71 months. Since we began allocating A2 kidneys preferentially to B and O recipients, the percentage of the B patients who received A2 or A2B kidneys has increased from 29% (8/28) to 55% (10/18). CONCLUSIONS: Transplantation of A2 or A2B kidneys into B and O patients is clinically equivalent to that of ABO-compatible transplantation when recipients are selected by low pretransplant anti-A titer histories. This approach increases access of blood group B recipients to kidneys.

Influence of the Rh (D) blood group system on graft survival in renal transplantation.

BACKGROUND: The Rh (D) blood group system has not traditionally been considered to be a clinically relevant histocompatibility barrier in transplantation since conflicting results of its clinical importance have been reported. METHODS: We analyzed 786 consecutive primary cadaveric renal transplants performed by transplant centers in our Organ Procurement Organization (OPO) between 1990 and 1997. We also analyzed United Network for Organ Sharing (UNOS) data on 26,469 kidney transplants done from April 1994 to June 1996. RESULTS: Multivariate analysis revealed that Rh identity between the recipient and donor was significantly related to better graft outcome (risk ratio, 0.43; 95% confidence interval, 0.30 to 0.61; P=0.0001). Multivariate analysis of the UNOS data revealed that the Rh -/- group may have a positive influence on graft survival with a risk ratio of 0.43 (P=0.14). CONCLUSION: Multivariate analysis of primary cadaveric renal allografts performed within the Midwest Organ Bank OPO indicates that Rh (D) is a clinically relevant histocompatibility barrier that influences 7-year graft survival.

Transplantation rate of the blood group B waiting list is increased by using A2 and A2B kidneys.

BACKGROUND: We have increased the transplantation rate for blood group B cadaveric waiting list candidates by transplanting them with A2 and A2B kidneys. METHODS: Since 1991, five of the seven renal transplant programs in our organ procurement organization service area have preferentially transplanted blood group A2 and A2B cadaveric kidneys to B blood group waiting list candidates with histories of low anti-A isoagglutinin titers. RESULTS: Between 1991 and 1997, these five centers performed transplantations on 71 patients from the B cadaveric waiting list. Of those 71 patients, 29% (21 of 71) underwent transplantation with either A2 (n=18) or A2B (n=3) cadaveric kidneys. In 1997 alone, 48% (11 of 23) of the B patient transplant recipients received A2 or A2B kidneys. CONCLUSIONS: Transplantation of A2 and A2B kidneys into B waiting list patients has successfully increased access of B patients to kidneys. Such an allocation algorithm implemented nationally may similarly increase the transplantation rate of B waiting list candidates.

Improved graft survival in cadaveric renal retransplantation by flow crossmatching.

OBJECTIVE: To evaluate the role of flow cytometry cross-matching on graft survival in patients undergoing cadaveric renal retransplantation compared with our conventional antihuman globulin cytotoxic crossmatch. DESIGN: In 1990, 6 of 7 transplantation centers in 1 organ procurement organization service area began performing cadaveric renal retransplantation only if the flow T-cell IgG crossmatch was negative. During that period, 1 center continued to use only the antihuman globulin T-cell IgG crossmatch. Prior to 1990, all centers used only the antihuman globulin T-cell IgG crossmatch as their crossmatch selection criterion for retransplantation. Regraft survival was compared between those centers by crossmatch selection criteria. PATIENTS: Patient selection and immunosuppression decisions were made at the transplantation center. SETTING: All flow cytometry crossmatches for all 7 centers participating in the evaluation were performed at the Histocompatibility Laboratory of the Midwest Organ Bank Inc, Westwood, Kan. RESULTS: Graft survival is significantly better (P = .03 [logrank test]) in regrafts when the flow crossmatch is used to select patients for transplantation. CONCLUSION: Flow crossmatching improves graft survival in cadaveric renal retransplantation by identifying a subset of patients with donor-directed HLA class I antibodies that are not detectable by our conventional antihuman globulin crossmatch.

Current experience with renal transplantation across the ABO barrier.

Solid organ transplantation has traditionally been governed by the rules of blood group compatibility. Thus, it has been demonstrated that crossing the ABO blood group barrier generally results in hyperacute rejection. However, the A2 subtype of the blood group A is a weaker antigen. Under certain circumstances, organs from donors with blood group A2 can be transplanted across the ABO blood group barrier into recipients of O or B blood type. Since 1986, 33 patients including 24 blood group O and 9 blood group B patients received A2 (30) or A2B (3) donor kidneys. Both cadaver donor (31) and living-related grafts (2) have been undertaken. The mean follow-up since transplantation for the 21 patients with functioning grafts is 36 months, with a 67.2% current graft survival. Immunosuppression for these transplants consisted of azathioprine, prednisone, and cyclosporine, often in combination with prophylactic OKT3 or antilymphocyte globulin as protocol dictated. Special immunosuppressive protocols such as splenectomy or plasmapheresis were not used. The serum of the potential recipient was analyzed for immunoglobulin G (IgG) and immunoglobulin M (IgM) forms of antibody against A1 and A2 red blood cells. There is a strong correlation between a low (less than or equal to 1:8) anti-A1 IgG titer and both early and long-term graft function. Recipients with an IgG titer greater than 1:8 in the pretransplant serum had a much higher incidence of early graft failure. We no longer recommend transplantation of A2 kidneys into O or B recipients with a pretransplant titer of greater than 1:8 but found that recipients with low titers have graft function rates essentially equal to those of ABO-compatible patients. Patients with blood group B have, over time, lower anti-A IgG titers than do blood group O patients. In addition, the graft survival among blood group B patients is 89% compared with 58% among group O recipients. This may be due to the generally low titers found in blood group B recipients. Since instituting a policy in 1988 of not transplanting the kidney when the anti-A IgG titer is greater than 1:8, the survival in O patients is 88%. We recommend the screening of all organ donors with blood group A for the A2 subgroup and believe that transplantation can be safely and successfully performed in certain patients with blood group O or B.(ABSTRACT TRUNCATED AT 400 WORDS)

Is staging laparotomy for Hodgkin's disease still justified?

The records of 50 consecutive patients who underwent staging laparotomy for Hodgkin's disease were reviewed. Preoperative clinical stages were as follows: stage I, 12 patients; stage II, 20 patients; and stage III, 18 patients. The accuracy of preoperative lymphangiography, confirmed pathologically, was 80 percent. Early experience with computed axial tomographic scanning is promising. The stages of 20 patients (40 percent) were changed by laparotomy, and their treatment was altered as a result. Fourteen patients were upstaged and 6 downstaged. Patient who were upstaged to stage IIIB and IV received chemotherapy; those downstaged to stage I and II received radiotherapy only. Sixty-seven percent of patients with preoperative constitutional symptoms (class B) had positive findings at laparotomy, compared with only 28 percent of patients without such symptoms (class A). Patients with mixed cellularity or lymphocyte-depleted histology were more likely to have positive findings at laparotomy. There were four complications and operative deaths. We conclude that staging laparotomy retains a useful role in the diagnosis and management of Hodgkin's lymphoma.

A model of HIV-1 pathogenesis that includes an intracellular delay.

Mathematical modeling combined with experimental measurements have yielded important insights into HIV-1 pathogenesis. For example, data from experiments in which HIV-infected patients are given potent antiretroviral drugs that perturb the infection process have been used to estimate kinetic parameters underlying HIV infection. Many of the models used to analyze data have assumed drug treatments to be completely efficacious and that upon infection a cell instantly begins producing virus. We consider a model that allows for less then perfect drug effects and which includes a delay in the initiation of virus production. We present detailed analysis of this delay differential equation model and compare the results to a model without delay. Our analysis shows that when drug efficacy is less than 100%, as may be the case in vivo, the predicted rate of decline in plasma virus concentration depends on three factors: the death rate of virus producing cells, the efficacy of therapy, and the length of the delay. Thus, previous estimates of infected cell loss rates can be improved upon by considering more realistic models of viral infection.

A seven year experience with kidney transplantation for pediatric end stage renal disease.

Renal transplantation for pediatric end stage renal disease (ESRD) is a preferred option in dealing with these chronically ill patients. The pediatric renal transplant program at University of Missouri-Kansas City School of Medicine was begun in 1986 at St. Luke's Hospital and subsequently shifted to the Children's Mercy Hospital as experience was accumulated. To date 35 transplants have been performed in 31 recipients. Fifty-one per cent of the patients transplanted were adolescents (older than 13 years) and 91% of the patients were older than 4 years. Sixteen of the 35 transplants were from living related donors and 19 patients received their kidneys from cadaveric donors. Immunosuppression consisted of corticosteroids, azathioprine, cyclosporine and antilymphoblast globulin. No patients died following transplantation with a functioning kidney. Allograft survival with living related transplants at one year and three years was 91% and 86% respectively. Cadaveric allograft survival at one year and three years was 78% and 46% respectively. Most kidneys were lost due to either acute or chronic rejection although there were three patients who lost their kidney due to primary nonfunction, including one child age 23 months. The growth pattern of all but the youngest children (< or = 2 years) following transplantation showed no evidence of accelerated growth. Results in this early series of pediatric renal transplant patients is encouraging from the standpoint of patient and allograft survival and even though accelerated growth is not seen in the older children, it seems to offer a better quality of life for children with end stage renal disease.