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The transforming growth factor (TGF)-beta-inducible integrin alpha v beta6 is preferentially expressed at sites of epithelial remodeling and has been shown to bind and activate latent precursor TGF-beta. Herein, we show that alpha v beta6 is overexpressed in human kidney epithelium in membranous glomerulonephritis, diabetes mellitus, IgA nephropathy, Goodpasture's syndrome, and Alport syndrome renal epithelium. To assess the potential regulatory role of alpha v beta6 in renal disease, we studied the effects of function-blocking alpha v beta6 monoclonal antibodies (mAbs) and genetic ablation of the beta6 subunit on kidney fibrosis in Col4A3-/- mice, a mouse model of Alport syndrome. Expression of alpha v beta6 in Alport mouse kidneys was observed primarily in cortical tubular epithelial cells and in correlation with the progression of fibrosis. Treatment with alpha v beta6-blocking mAbs inhibited accumulation of activated fibroblasts and deposition of interstitial collagen matrix. Similar inhibition of renal fibrosis was observed in beta6-deficient Alport mice. Transcript profiling of kidney tissues showed that alpha v beta6-blocking mAbs significantly inhibited disease-associated changes in expression of fibrotic and inflammatory mediators. Similar patterns of transcript modulation were produced with recombinant soluble TGF-beta RII treatment, suggesting shared regulatory functions of alpha v beta6 and TGF-beta. These findings demonstrate that alpha v beta6 can contribute to the regulation of renal fibrosis and suggest this integrin as a potential therapeutic target.

Background. The transplantation of blood group A 2 /A 2 B deceased donor kidneys into B recipients could improve access to transplantation for blood group B recipients. However, this practice is controversial, and long-term data are lacking. This study analyzed the long-term outcomes of A 2 /A 2 B deceased donor kidneys transplanted into selected B recipients. Methods. We retrospectively assessed the outcomes (graft survival, transplant rates, and acute rejection) of deceased-donor kidneys using an allocation system that transplanted A 2 /A 2 B donors into B recipients with low anti-A blood group antibody titers between 1994 and 2003. Patients received conventional immunosuppression without any specific antibody reduction procedures. We further assessed the impact this system had on access to transplantation by blood group. Results. Of 1,400 kidney transplants, 56 (4.0%) were A 2 /A 2 B to B recipients. The system reduced waiting time for all B recipients, even shorter than for blood group A recipients (median waiting times of A 2 /A 2 B to B transplants=182 days vs. B to B transplants=297 days; and A to A=307 days). Although there was a trend toward increased acute rejection in A 2 /A 2 B to B transplants, the actuarial 7-year death censored graft survival was 72% for B recipients regardless of donor type. Conclusions. Transplanting A 2 /A 2 B deceased donor kidneys into B recipients leads to an equalization of waiting time between blood groups with similar patient and graft survival using conventional immunosuppression. This protocol could lead to more equal access to kidney transplantation in blood group B recipients.

Purpose: Several recent publications have increased awareness that transplanted organs can transmit infectious diseases. In light of the recent report describing the transmission of Trypanosoma cruzi infection by an organdonor in the United States (MMWR 2002: 51: 210), we have tested archived serum samples from our Organ Procurement Organization's (OPO's) deceased organ donors and live donors from 23 October 1995 through 1 March 2002. Methods: A total of 1117 serum samples from 558 locally recovered deceased donors, 178 imported deceased donors, and 212 live donors were tested (several duplicates were included). Samples were screened for antibodies to T. cruzi, the protozoan parasite that causes Chagas' disease, with a passive particle agglutination assay (Fujirebio, Inc., Tokyo, Japan). Indeterminate samples (those agglutinating both sensitized and control particles) were absorbed with control antigen and re-tested. Inconclusive samples (those not yielding clearly negative or positive results) were re-tested using the original test format, and if persistently inconclusive, were assayed by radio-immune precipitation (RIPA). Results: Of the 770 local OPO donors (deceased and live donor) and the 178 imported donors tested, 52 (5.5%) were indeterminate, but following absorption, all were negative. Forty-four samples (4.6%) were inconclusive and after re-testing 34 were negative while 10 remained inconclusive. Those 10 samples were found to be negative by RIPA. Conclusions: The risk of transmission of Chagas' disease by organ transplantation in the Midwestern United States is low because during a 6.5 year period, none of our deceased or live donors tested positive for antibodies to T. cruzi. Although the passive particle agglutination test is simple to perform, easy to interpret and rapid enough to be used in screening organ donors, because of the rate of false positive results, it should only be utilized when the donor population is at high risk for previous exposure to T. cruzi.

National sharing of HLA zero-mismatched kidneys has improved long-term graft survival. The distribution of those HLA-matched kidneys by ABO blood group, however, has not been examined. Utilizing the UNOS/OPTN (United Network for Organ Sharing/Organ Procurement Transplantation Network) database, we analysed 112 971 kidney waiting list registrations added during 6/3/95-31/12/00, and 8162 HLA zero-mismatched (0 mm) primary kidney transplants in the USA during 1/1/88-31/3/02. We also analyzed A isoagglutinin titer histories for 87 blood group B end stage renal disease (ESRD) patients for whom at least 1 yr of testing was done. Blood group A patients received 40.1% of the HLA-0 mm kidneys while having a 26.5% representation on the national waiting list. Blood group B patients comprised 17.4% of the waiting list, but received only 10.4% of the HLA-0 mm kidneys. Most (89.6%) blood group B patients awaiting kidney transplantation have low levels of A isoagglutinins, making them eligible to receive a blood group A(2) kidney transplant. The national HLA-0 mm kidney allocation sharing system's imbalance by ABO blood group could be partially resolved in the future by allocating HLA-0 mm blood group A(2) kidneys to B patients.

Purpose: Our organ procurement organization (OPO) evaluated the clinical and financial efficacy of point-of-care testing (POCT) in management of our deceased organ donors. Methods: Before we implemented point-of care testing with the i-STAT into routine clinical donor management. we compared the i-STAT result with the result from the respective donor hospital lab (DHL) for certain analytes on 15 consecutive donors in our OPO from 26 March to 14 May 2001 The financial impact was studied by reviewing 77 donors from. July 2001 to March 2002. Results: There was a strong correlation for each analyte between the POC and DHL test results with r-values as follows pH 0.86; PCO 2 = 0.96; PO 2 = 0.98; sodium = 0.98: potassium = 0.95; chloride = 0.94; BUN = 0.98; glucose = 0.92; haematocrit = 0.87 and creatinine = 0.95. Since our OPO coordinators began using i-STAT in their routine clinical management of organ donors, they can now more quickly maximize oxygenation and fluid management of the donor and make extra-renal placement calls sooner. Finally, since we are no longer being billed for the testing performed on the i-STAT, average financial savings to our OPO are S733 per case. Conclusions: Point-of-care testing in management of our OPO donors provides a result that is equivalent to that of the donor hospital lab, has quicker turn-around time than the donor hospital laboratory. allowing more immediate clinical management decisions to be made so that extra-renal offers may begin sooner.

Since blood group B end-stage renal disease (ESRD) patients have less access to donor kidneys and a higher minority composition than any other blood group, the United Network for Organ Sharing (UNOS) approved a voluntary national kidney allocation variance to allow organ procurement organizations (OPOs) to preferentially allocate A2 and A2B kidneys to B candidates. The Midwest Transplant Network OPO has preferentially allocated and transplanted kidneys from blood group A2 and A2B donors to our blood group B waiting list candidates for more than 7 years to increase access to kidneys for the B candidates on our OPO-wide waiting list. Between 1994 and 2000, a total of 121 blood group B ESRD patients from our OPO-wide cadaveric kidney waiting list were transplanted. Thirty-four per cent (41/121) of those B candidates received either an A2 or an A2B kidney. One- and 5-year graft survival rates for the group of B recipients of A2 or A2B kidneys were 91 and 85% (died with functioning graft [DWFG] censored), respectively, which were not significantly different from those of 91 and 80% for the 80 B recipients of B or O kidneys (Wilcoxon = 0.48; log-rank = 0.55). These data support the national trial for additional OPOs to voluntarily allocate A2 and A2B kidneys preferentially to B waiting list candidates, thus increasing access of blood group B patients to renal transplantation.

A positive crossmatch that is rendered negative by treating the serum with the IgM-reducing agent dithiothreitol (DTT) is generally reported not to influence short-term renal graft outcome. Its effect on long-term (> or = 3 years) cadaveric and live-donor transplant function, however, is less clear. We evaluated the effect of IgM antibodies in a DTT-ameliorated positive crossmatch (DTT-APXM) on long-term renal graft outcome in 1,290 consecutive cadaveric renal transplants (8-year survival) and 384 live-donor renal transplants (7-year survival) from patients transplanted between 1990 and 1999. The data show that 1- and 8-year graft survival for cadaveric renal transplants in patients with IgM antibodies (n=72) (DWFG censored = 91% and 65%; DWFG not censored = 90% and 60%) was not significantly different from the group without IgM antibodies (n = 1,218) (DWFG censored = 92% and 71%; DWFG not censored = 87% and 55%) (log-rank = 0.25 for DWFG censored, log-rank = 0.92 for DWFG not censored). The one- and seven-year graft survival for live-donor renal transplants in patients with IgM antibodies seen in a DTT-APXM (n = 22) (DWFG censored = 95% and 83%; DWFG not censored = 95% and 66%) was not significantly different from the group without IgM antibodies (n = 362) (DWFG censored = 94% and 81%; DWFG not censored = 92% and 73%) (log-rank = 0.61 for DWFG censored, log-rank = 0.89 for DWFG not censored). DR phenotype was found to be associated with the strong (>40% cell death) IgM reactivity in both black and white patients. In white patients, DR2 was more frequently seen with a strong IgM crossmatch (48.2%) than in molecularly typed controls (28.5%) (P < 0.03) and concomitant with that DR increase, DR4 was decreased in white patients (6.8%) compared with controls (25.5%) (P < 0.02). In black patients with strong IgM reactivity, DR6 was increased in patients (46.1%) compared with controls (20.5%) (P = 0.07) and concomitant with that DR6 increase, DR5 was decreased in frequency in black patients (7.6%) compared with controls (41%) (P < 0.03). These data show that long-term graft survival in renal transplantation is not negatively influenced by the presence of donor-reactive lymphocytotoxic antibodies in the crossmatch ameliorated by serum DTT treatment. They also suggest that the strength of the IgM antibody response is regulated in part by certain gene (s) of the DR region.

In view of the influence of donor factors such as age on graft outcome and the performance standards that measure OPO productivity by the number of organs recovered and transplanted, it is important to understand the relationship of certain donor factors on organ recovery for transplantation from cadaveric donors. We examined the influence of donor age, gender and ethnicity on the number and type of transplanted organs recovered from 598 consecutive cadaveric donors in our OPO between 1994 and July 1999. The highest number of organs/donor ocurs in the 11-20 donor age range and declines significantly with each age range. The type of organ recovered is also influenced by age, but the least effect is on liver recovery. No difference was seen in the number of organs recovered/donor by race. When the data were re-analyzed with regard to renal and extra-renal organs transplanted/million donor population, 78% of the kidneys (n=781/1006) were from the 11-50 age range and 81% of the extra-renal organs (n=822/1,192) were from that age range. Stepwise regression yielded a model where donor age significantly influenced (P=0.001) the number of organs recovered. Finally, the incidence of recovered and transplanted organs was significantly higher in males compared with females for hearts [51% (187/360) vs. 40% (86/214); P

Background. A previous report described the 1-year results of a prospective, randomized trial designed to investigate the optimal combination of immunosuppressants in kidney transplantation. Recipients of first cadaveric kidney allografts were treated with tacrolimus+mycophenolate mofetil (MMF), cyclosporine oral solution (modified) (CsA)+MMF, or tacrolimus+azathioprine (AZA). Results at 1 year revealed that optimal efficacy and safety were achieved with a regimen containing tacrolimus+MMF. The present report describes results at 2 years. Methods. Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus+MMF, CsA+MMF, or tacrolimus+AZA. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function. Patients were followed up for 2 years. Results. The results at 2 years corroborate and extend the findings of the previous report. Patients randomized to either treatment arm containing tacrolimus experienced improved kidney function. New-onset insulin dependence remained in four, three, and four patients in the tacrolimus+MMF, CsA+MMF, and tacrolimus+AZA treatment arms, respectively. Furthermore, patients with delayed graft function/acute tubular necrosis who were treated with tacrolimus+MMF experienced a 23% increase in allograft survival compared with patients receiving CsA+MMF (P =0.06). Patients randomized to tacrolimus+MMF received significantly lower doses of MMF compared with those administered CsA+MMF. Conclusions. All three immunosuppressive regi-mens provided excellent safety and efficacy. How-ever, the best results overall were achieved with tacrolimus+MMF. The combination may provide particular benefit to kidney allograft recipients who develop delayed graft function/acute tubular necrosis. Renal function at 2 years was better in the tacrolimus treatment groups compared with the CsA group.

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.

Background Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation. Methods A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year. Results There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups. Conclusions All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy.

The purpose of our investigation was to evaluate long-term graft survival and the role of histocompatibility in patients who were highly sensitized to human leukocyte antigen (HLA) Class I antigens and received a cadaveric renal transplant. Our multi-institutional study evaluated 7-yr graft outcomes and the histocompatibility requirements of 61 (6.1%) highly sensitized (anti-human globulin panel reactive antibody [AHG PRA], > or = 80%) cadaveric renal transplantation patients, transplanted between 1988 and 1997, among 999 consecutive cadaveric renal transplants. One- and 7-yr graft survival in the high PRA group (n = 61) was 76 and 59%, and was not significantly different from that in the low PRA group (n = 938), 86 and 59% (Wilcoxon = 0.11; log-rank = 0.45) (died with a functioning graft [DWFG] not censored). When those data were divided into primary and regrafts, 1- and 7-yr graft outcomes for high and low PRA groups were not significantly different [(primary, 1- and 7-yr survival: high PRA = 83 and 74%, n = 30, and low PRA = 87 and 61%, n = 825; log-rank = 0.37 for DWFG not censored) (regrafts, 1- and 7-yr survival: high PRA = 70 and 42%, n = 31, and low PRA = 80 and 43%, n = 113; log-rank = 0.36 for DWFG not censored)]. We did observe a subgroup of the high PRA patient group that had inferior graft outcomes. Graft outcome at 1 and 6 yr in the high PRA group for patients who had one to two DR mismatches (65 and 50%, n = 41) was significantly worse than for high PRA patients who had zero DR mismatches with their donors (100 and 78%, n = 20) (log-rank = 0.01 for DWFG not censored). Furthermore, the mean number of HLA-A and -B mismatches was significantly greater in the high PRA/DR-mismatched group (1.7 +/- 1.2, n = 41) compared with the high PRA/zero DR-mismatched group (0.5 +/- 1.1, n = 19) (p < 0.001). Overall, these data suggest that the patient who is highly sensitized to HLA Class I antigens has a long-term graft outcome that is equivalent to less sensitized patients, but that HLA-DR mismatching and a higher degree of Class I mismatching may be poor prognostic indicators in such patients.

Role for transforming growth factor-β1 in Alport renal disease progression. Background Alport syndrome results from mutations in either the α3(IV), α4(IV), or α5(IV) collagen genes. The disease is characterized by a progressive glomerulonephritis usually associated with a high-frequency sensorineural hearing loss. A mouse model for an autosomal form of Alport syndrome [collagen α3(IV) knockout] was produced and characterized. In this study, the model was exploited to demonstrate a potential role for transforming growth factor-β1 (TGF-β1) in Alport renal disease pathogenesis. Methods Kidneys from normal and Alport mice, taken at different stages during the course of renal disease progression, were analyzed by Northern blot, in situ hybridization, and immunohistology for expression of TGF-β1 and components of the extracellular matrix. Normal and Alport human kidney was examined for TGF-β1 expression using RNase protection. Results The mRNAs encoding TGF-β1 (in both mouse and human), entactin, fibronectin, and the collagen α1(IV) and α2(IV) chains were significantly induced in total kidney as a function of Alport renal disease progression. The induction of these specific mRNAs was observed in the glomerular podocytes of animals with advanced disease. Type IV collagen, laminin-1, and fibronectin were markedly elevated in the tubulointerstitium at 10 weeks, but not at 6 weeks, suggesting that elevated expression of specific mRNAs on Northern blots reflects events associated with tubulointerstitial fibrosis. Conclusions The concomitant accumulation of mRNAs encoding TGF-β1 and extracellular matrix components in the podocytes of diseased kidneys may reflect key events in Alport renal disease progression. These data suggest a role for TGF-β1 in both glomerular and tubulointerstitial damage associated with Alport syndrome.

Background. We have increased the transplantation rate for blood group B cadaveric waiting list candidates by transplanting them with A 2 and A 2 B kidneys. Methods. Since 1991, five of the seven renal transplant programs in our organ procurement organization service area have preferentially transplanted blood group A 2 and A 2 B 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 A 2 (n=18) or A 2 B (n=3) cadaveric kidneys. In 1997 alone, 48% (11 of 23) of the B patient transplant recipients received A 2 or A 2 B kidneys. Conclusions. Transplantation of A 2 and A 2 B 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.

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.

Background This article summarizes our 10-year multicenter experience with transplantation of 50 blood group A 2 and A 2 B 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 A 2 (47 donors) or A 2 B (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 (

Background We evaluated health-related quality of life (HQL) in kidney transplant patients participating in a multicenter, prospective, randomized, phase III trial comparing tacrolimus to cyclosporine. HQL data were available for 303 of 412 patients and assessed with the SF-36 Health Survey and six multi-item scales: Current Health, Health Outlook, Health Distress, Fleming Self-Esteem, Bergner Physical Appearance, and Sexual Functioning. Methods. Patients completed surveys at baseline, week 6, and months 3, 6, and 12. The mean change in HQL was evaluated by rejection occurrence and number of hospitalizations. Analysis of covariance was used to model endpoint HQL scores as a function of treatment group and baseline HQL. Results. All scales but two met psychometric standards for group-level comparisons. Baseline demographics and HQL scores were not different by treatment. The mean HQL change was lower for patients with rejection compared with no rejection in seven of eight SF-36 scales and three of four remaining supplemental scales. One year after transplantation, study patients were functioning at least as well as half of the general population in Vitality and Role-Emotional Functioning, moving from the 18th percentile of the U.S. population scores to the 50th percentile for Vitality and 54th percentile for Role-Emotional Functioning. Patients improved their percentile ranking by at least 20 points in five of eight SF-36 scales. Conclusions. Patients with kidney disease demonstrate substantial HQL burden before transplantation, and transplantation is associated with substantial HQL improvements. Rejection is associated with less HQL improvement. Endpoint HQL values were significantly different (P

Nonenzymatic glycation of type IV collagen and matrix metalloproteinase susceptibility. The glomerular basement membrane (GBM) is damaged in diabetes through complex mechanisms that are not fully understood. Prominent among them is nonenzymatic protein glycation leading to the formation of so-called advanced glycation end products (AGEs). We examined the effects of in vitro glycation of intact collagen type IV in bovine lens capsule (LBM) and kidney glomerular (GBM) basement membranes on their susceptibility to matrix metalloproteinases, using stromelysin 1 (MMP-3) and gelatinase B (MMP-9). Sites of cleavage of unmodified LBM collagen were located in the triple helical region. In vitro glycation by glucose severely inhibited the release of soluble collagen cleavage peptides by MMP-3 and MMP-9. The distribution of AGEs within the three domains of collagen IV (7S, triple helical, and non-collagenous NC1) were compared for LBM glycation using AGE fluorescence, pentosidine quantitation, and immunoreactivity towards anti-AGE antibodies that recognize the AGE carboxymethyllysine (CML). Marked asymmetry was observed, with the flexible triple helical domain having the most pentosidine and fluorescent AGEs but the least CML. The in vivo relevance of these findings is supported by preliminary studies of AGE distribution in renal basement membrane (RBM) collagen IV domains from human kidneys of two insulin-dependent diabetics and one normal subject. Pentosidine and fluorescent AGE distributions of diabetic RBM were similar to LBM, but the CML AGE in diabetic kidney was less in the triple helical domain than in NCI. Our results support the hypothesis that nonenzymatic glycation of collagen IV contributes to the thickening of basement membranes, a hallmark of diabetic nephropathy.

E vety year, thousands of end-stage renal disease patients join waiting lists to receive a cadaver kidney transplant. According to the United Network for Organ Sharing (UNOS) Scientific Registry, there were 7,682 cadaveric kidney transplants performed in the United States in 1995, yet 3 1,045 patients were waiting for such transplants at the end of that year. As these ligures suggest, the major obstacle to transplantation is, and will continue to be, the shortage of cadaveric donor organs. Because of this shortage, waiting lists for kidney transplants can be quite long. For patients who received a transplant in 1994, UNOS Scientific Registry data showed that the median waiting time for a cadaver kidney transplant was 838 days. (Median waiting time data for 1995 are not yet available.) Because kidneys are allocated first to suitable candidates on local transplant waiting lists, many people believe that the odds of getting a transplant can be increased by acceptance onto waiting lists in more than one area (ie, by being multiply-listed). Sanlilippo et al’ found that patients who were multiply-listed waited significantly less time to receive their first kidney transplant, but they did not address the characteristics of multiple listers vis a vis patients on only one list. In other work we showed that multiple listing had a strong impact on access to a kidney transplant. Those who multiply-listed within 6 months of their initial listing were about 3.4 timzs as likely to obtain a transplant as others, and those who multiply-listed from 7 to 12 months of their first listing were about 2.6 times as likely to obtain a

We evaluated the cost-effectiveness of a standard immunosuppressive regimen versus an OKT3 induction regimen in cadaveric kidney transplant recipients. Cost estimates were based on results from a five-center randomized trial comparing the safety and efficacy of OKT3 induction with a conventional triple-drug regimen and financial data from the National Cooperative Transplantation Study, the Medicare Provider and Analysis Review database, and other sources. Patients received OKT3 (5 mg/day) by intravenous (IV) bolus injection for 10 to 14 consecutive days in conjunction with azathioprine, prednisone, and the delayed addition of cyclosporine (CsA) on day 11 (n = 105) or a conventional immunosuppressive regimen consisting of CsA, azathioprine, and prednisone (n = 102). The following measures were used to evaluate the two regimens: costs incurred between transplantation and graft failure; the effectiveness of the two regimens as defined by length of graft survival; and cost-effectiveness ratios through 5 years of observed follow-up and modeled through the expected duration of graft survival. Results showed that OKT3 induction uniformly adds $8,219 to the cost of the transplant hospitalization. However, most of this cost is offset by a reduction in the cost of treating rejection episodes in the OKT3 group (P = 0.002). A trend toward improved graft survival was detected in the OKT3 group (P = 0.158). Through 5 years of observed follow-up, costs per year of graft survival are $30,474 with OKT3 versus $32,687 with the conventional regimen. Modeled through the expected duration of graft survival, OKT3 induction costs $8,335 for each additional year of graft survival. Results are fairly insensitive to wide variations in baseline assumptions. We conclude that OKT3 induction improves the cost-effectiveness of kidney transplantation.

The use of the monoclonal antibody OKT3 for induction immunosuppression in renal transplantation is increasing--however, the safety of intraoperative administration continues to be questioned because of first-dose effects. The current study was designed to examine the effects of intraoperative administration of OKT3 on the cardiovascular and pulmonary systems in 161 consecutive renal transplant recipients. Patients receiving OKT3 intraoperatively during renal transplant (99 cadaver recipients) were compared with 62 patients not administered the drug (31 cadaver, 25 living-related-donor, 6 living-nonrelated donor). Intraoperative airway pressure (highest, average), O2 saturation (SaO2), temperature, blood pressure changes, cardiac rhythm, and bronchospasm were compared in these two groups. Significant physiologic changes noted in the group receiving OKT3 included increased temperature (both intraoperative and postoperative), decreased SaO2 (postoperative), and increased FiO2 (postoperative). Despite these differences, no clinically significant changes were noted in the group receiving OKT3. OKT3 induction given at the time of surgery was associated with a significantly increased one- and three-year graft function. This study demonstrates that first-dose administration of OKT3 intraoperatively during renal transplantation is safe and effective.

A randomized, prospective multicenter trial was conducted to compare the safety and efficacy of OKT3 as an induction therapy with that of conventional immunosuppressive therapy administered to cadaveric renal allograft recipients. Two hundred fifteen patients were treated either with OKT3 plus azathioprine and steroids for 14 days with the delayed addition of cyclosporine on day 11, or with conventional immunosuppression (steroids, azathioprine, and cyclosporine). OKT3 patients had significantly fewer rejection episodes (51% vs. 66%, P = 0.032), a longer time to initial rejection (46 days vs. 8 days, P = 0.001), and fewer rejection episodes per patient (0.82 vs. 1.14, P = 0.014) than conventionally treated patients. Kaplan-Meier estimates of two-year graft and patient survival rates were 84% and 95%, respectively, for the OKT3-treated group, and 75% and 94%, respectively, for the conventionally treated group. Following a subsequent first rejection episode, OKT3 reversed 93% of the rejections in patients receiving OKT3 induction therapy and 94% in patients receiving conventional therapy. Adverse experiences reported during OKT3 induction therapy were similar to those seen when the drug was used for rejection. Following initial exposure, 40.3% of the patients tested were positive for anti-OKT3 antibody, only 6.7% of which were of high titer (1:1000). In the presence of low titer (1:100 or less) antibody, OKT3 was successful in reversing rejection in five of six retreated patients tested. In conclusion, treatment with OKT3 (in combination with azathioprine, steroids, and the delayed addition of cyclosporine) is an effective approach for renal allograft maintenance.

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. Utilizing donors with the A2 subgroup for transplantation in O or B recipients has several potential advantages, including increased local organ use, increased HLA matching, and increased transplantation in black patients with endstage renal disease.

Patients with Alport syndrome progressively lose renal function as a result of defective type IV collagen in their glomerular basement membrane. In mice lacking the alpha3 chain of type IV collagen (Col4A3 knockout mice), a model for Alport syndrome, transplantation of wild-type bone marrow repairs the renal disease. It is unknown whether cell-based therapies that do not require transplantation have similar potential. Here, infusion of wild-type bone marrow-derived cells into unconditioned, nonirradiated Col4A3 knockout mice during the late stage of disease significantly improved renal histology and function. Furthermore, transfusion of unfractionated wild-type blood into unconditioned, nonirradiated Col4A3 knockout mice improved the renal phenotype and significantly improved survival. Injection of mouse and human embryonic stem cells into Col4A3 knockout mice produced similar results. Regardless of treatment modality, the improvement in the architecture of the glomerular basement membrane is associated with de novo expression of the alpha3(IV) chain. These data provide further support for testing cell-based therapies for Alport syndrome.

Introduction: The influence of a positive B-cell crossmatch on graft outcome in renal transplantation is controversial. Methods: We analyzed graft survival using Kaplan–Meier estimates for recipients of deceased donor kidneys who were either regraft transplant patients (n = 198) from 1990 to August 20, 2004, or primary transplant patients (n = 361) from December 15, 2000 to August 8, 2004, each of whom had a flow T- and B-cell IgG crossmatch performed before transplantation. The flow B-cell crossmatch (FBXM) was not used to decide whether or not to transplant. Graft survival was analyzed by whether the patient's FBXM was positive or negative. We also evaluated creatinine levels and graft survival of 131 transplant patients (June 1, 2004 to July 1, 2005) by their FBXM result and by their HLA class II flow-defined IgG PRA. Results: One- and three-yr graft survival for the primary transplant patient group with a positive FBXM (98% and 84%) was not significantly different from the group with a negative FBXM (96% and 93%) (log-rank = 0.9). Similarly, graft survival at one, five, and 10 yr for the regraft transplant group whose FBXM was positive (91%, 76%, and 61%) was not significantly different from the group whose FBXM was negative (91%, 79%, and 77%) (log-rank = 0.4). Creatinine levels in the group of patients whose FBXM was positive (1.4 ± 0.4 mg/dL; n = 76) were not significantly different from the group with a negative FBXM (1.4 ± 0.4 mg/dL; n = 42). Even in the presence of class II PRA, a positive FBXM did not impact a patient's creatinine levels or graft outcome. Conclusion: Neither short nor long-term graft survival of deceased donor kidneys is influenced by a positive flow B-cell IgG crossmatch, even when caused by HLA class II antibody.

Background Glomerular basement membrane (GBM), a key component of the blood-filtration apparatus in the in the kidney, is formed through assembly of type IV collagen with laminins, nidogen, and sulfated proteoglycans. Mutations or deletions involving α3(IV), α4(IV), or α5(IV) chains of type IV collagen in the GBM have been identified as the cause for Alport syndrome in humans, a progressive hereditary kidney disease associated with deafness. The pathological mechanisms by which such mutations lead to eventual kidney failure are not completely understood. Methods and Findings We showed that increased susceptibility of defective human Alport GBM to proteolytic degradation is mediated by three different matrix metalloproteinases (MMPs)—MMP-2, MMP-3, and MMP-9—which influence the progression of renal dysfunction in α3(IV) −/− mice, a model for human Alport syndrome. Genetic ablation of either MMP-2 or MMP-9, or both MMP-2 and MMP-9, led to compensatory up-regulation of other MMPs in the kidney glomerulus. Pharmacological ablation of enzymatic activity associated with multiple GBM-degrading MMPs, before the onset of proteinuria or GBM structural defects in the α3(IV) −/− mice, led to significant attenuation in disease progression associated with delayed proteinuria and marked extension in survival. In contrast, inhibition of MMPs after induction of proteinuria led to acceleration of disease associated with extensive interstitial fibrosis and early death of α3(IV) −/− mice. Conclusions These results suggest that preserving GBM/extracellular matrix integrity before the onset of proteinuria leads to significant disease protection, but if this window of opportunity is lost, MMP-inhibition at the later stages of Alport disease leads to accelerated glomerular and interstitial fibrosis. Our findings identify a crucial dual role for MMPs in the progression of Alport disease in α3(IV) −/− mice, with an early pathogenic function and a later protective action. Hence, we propose possible use of MMP-inhibitors as disease-preventive drugs for patients with Alport syndrome with identified genetic defects, before the onset of proteinuria., In a mouse model of Alport disease, matrix metalloproteinases appear to have a crucial dual role in disease progression, with an early pathogenic function and a later protective action.

Methods. Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus (TAC) + mycophenolate mofetil (MMF), TAC + azathioprine (AZA), or cyclosporine (Neoral; CsA) + MMF. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function (DGF). Patients were followed-up for 3 years. Results. The results at 3 years corroborate and extend the findings of the 2-year results. Patients with DGF treated with TAC+MMF experienced an increase in 3-year allograft survival compared with patients receiving CsA+MMF (84.1% vs. 49.9%, P=0.02). Patients randomized to either treatment arm containing TAC exhibited numerically superior kidney function when compared with CsA. During the 3 years, new-onset insulin dependence occurred in 6, 3, and 11 patients in the TAC+MMF, CsA+MMF, and TAC+AZA treatment arms, respectively. Furthermore, patients randomized to TAC+MMF received significantly lower doses of MMF as compared with those who received CsA+MMF. Conclusion. All three immunosuppressive regimens provided excellent safety and efficacy. However, the best results overall were achieved with TAC+MMF. The combination may provide particular benefit to kidney allograft recipients with DGF. In patients who experienced DGF, graft survival was better at 3 years in those patients receiving TAC in combination with either MMF or AZA as compared with the patients receiving CsA with MMF.

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.

Antilymphocyte induction therapy in cadaver renal transplantation is controversial. The effectiveness of antilymphocyte therapy in the current era of cyclosporine and tacrolimus use has been questioned. The United Network for Organ Sharing data set for the Center-Specific Outcomes Analysis, which has been verified by the transplant centers, was used for this study. At the time information in the database was confirmed, all transplant centers were queried on their use of an antilymphocyte preparation at the time of transplantation, and whether it was used within 24 hr of transplant surgery, the duration of the specific reagent. This allowed us to analyze 24,191 cadaver transplant procedures performed between the October 1, 1987, and the January 31, 1991. Using Cox regression analysis, as well as semiparametric logistic regression models, we demonstrated improved allograft outcomes in patients who received either Minnesota antilymphocyte globulin for 5 days or more or OKT3 for 7 days or more. The relative risk was 0.82 for Minnesota antilymphocyte globulin and 0.86 for OKT3 (for both, P

Objective: To evaluate the role of flow cytometry crossmatching 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. (Arch Surg. 1996;131:599-603)

R. Mendez, T. Gonwa, K. Rice, M. Holman, H. Yang, R. Filo, S. Steinberg, S. Weinstein, S. Jensik, B. Philosophe J. Colanna, A. Klein, J. Markowitz, M. Hardy, C. Shield, P.R. Rajagopalan, B. Ketel, G. Barone, W. Concepcion, G. Danovich, S. Tomlanovich, J. Scandling, P. Gores, G. Basadonna, M. Lorber, S. Inokuchi, D. Conti, K. Lake, A. Langnas, M. Kinkhabwala, C. Johnson, M. Johnson, M. Hart, J. Dunn, W. Fitzsimmons, D. Tolzman, G. Harrison, and P. Vanveldhuisen

Inguinal hernia repair in the patient on continuous ambulatory peritoneal dialysis (CAPD) is complicated in theory by an increased potential for recurrence. In addition to the constant increased intraabdominal pressure, chronic renal failure has been shown to impair tissue healing. Controversy exists regarding the waiting period before resuming CAPD postoperatively. A retrospective review of all CAPD patients undergoing inguinal herniorrhaphy was performed. The patient's age, type of repair, duration of renal failure preoperatively, length of time on CAPD postoperatively, and date of resumption of CAPD were recorded. An inpatient and outpatient chart review was performed on all patients. Telephone follow-up was performed on surviving patients. From April 1981 to June 1989, 30 patients underwent 36 inguinal herniorrhaphies while on CAPD. One immediate postoperative death occurred due to underlying cardiac disease. The mean follow-up for surviving patients was 34 months (range, 16 to 91) and for those deceased was 25 months (range, 1 to 60). No recurrent hernias were identified either by extensive inpatient and outpatient chart review, or by direct patient telephone contact in all surviving patients. We conclude that inguinal herniorrhaphy can be safely performed in CAPD patients. Peritoneal dialysis can be initiated immediately after repair in this high-risk group of patients. There is a low risk of recurrence; however, long-term patient survival is not expected due to concurrent underlying medical problems.

Objective. —To evaluate the relative impact of various factors that could account for differences in waiting time of cadaveric kidney transplant candidates (eg, black and sensitized patients). Design. —A cohort study using multivariate analyses to identify associations between 36 patient, donor, and center factors with waiting time for all US cadaveric kidney transplant candidates listed between October 1, 1987, and June 30, 1990. Setting. —All US kidney transplant centers. Patients. —The study included 23468 cadaveric renal transplant candidates on active waiting status. Results. —The patient characteristics most significantly associated with increased waiting time (adjusted for all other variables) were immunologic and included presensitization to HLA antigens, O or B blood type, candidacy for a repeat transplantation, and expression of rare HLA-A or HLA-B antigen phenotypes. Nonimmunologic factors also affected waiting times, which were significantly shorter for patients younger than 15 years vs those aged 15 through 44 years (8.4 vs 12.9 months, respectively; P P P 35 per million population) local kidney organ recovery rate, and an approved variance from the Organ Procurement and Transplantation Network allocation algorithm. Conclusions. —The time renal transplant candidates must wait for kidney transplantation is influenced by several factors in addition to those expected due to immunologic reasons of donor incompatibility, the algorithms used for organ distribution, or the effectiveness of local kidney recovery. The impact of these factors should be considered as the current US system for allocating scarce donor organs for kidney transplantation is modified. ( JAMA . 1992;267:247-252)

During the last fifteen years at the Wilford Hall USAF Medical Center, ten patients with islet cell tumors of the pancreas underwent surgery. The age of these patients was much lower than that previously reported, with 50 per cent of the patients between 15 and 25 years of age. These tumors have been studied extensively with endocrinologic methods, and the following types of tumors were identified: Zollinger-Ellison syndrome in four cases, two of which were associated with multiple endocrine adenomatosis (MEA), type I; insulinoma in three cases; WDHA syndrome in one case; and nonfunctioning tumors in two cases. Two of the patients have died of progressive disease, one with the Zollinger-Ellison syndrome ten years after the original operative procedure. Three of the patients had immediate cessation of the endocrine symptoms after subtotal pancreatic resection. Six patients have been followed up more than five years, with only one death, that occurring in the previously mentioned patient with a Zollinger-Ellison syndrome. The good long-term results after surgical procedures make aggressive surgery in patients with these tumors mandatory.

The clinical course and required treatment of diverticulitis were reviewed in 76 nonimmunocompromised patients and 10 immunocompromised patients. The immunocompromised patients presented with either minimal or no symptoms and findings. Therefore, to make the diagnosis of acute diverticulitis in this group, a high index of suspicion must be maintained. The required treatment varied considerably between the two groups. In 45 nonimmunocompromised patients (76 percent), medical therapy was successful. Medical treatment failed in the other 14 patients (24 percent). However, the compromised group had no patients in whom medical therapy was successful (100 percent failure rate). Thirty-one of the nonimmunocompromised patients (41 percent) required an operation, whereas 100 percent of the immunocompromised patients with acute diverticulitis required an operation. By relating postoperative complications, we were unable to determine the initial operative procedure of choice in the nonimmunocompromised group; however, in the immunocompromised group, colostomy and resection had fewer surgical complications than colostomy and drainage. The immunocompromised patient with acute diverticulitis requires operation. We believe the operation of choice is colostomy and resection of the involved segment.

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.

Aortic surgery in recipients of renal transplants requires a method of maintaining intraoperative graft perfusion. A case is presented in which a temporary shunt from the suprarenal aorta to the ipsilateral common femoral artery was used to perfuse a renal transplant during aortoiliac aneurysmectomy. Other methods of renal graft perfusion are discussed. (J VASC SURG 1985;2:600-2.)